Methods of treating cancer and / or chemotherapy related conditions using non-naturally occurring melanocortin analogs

Abstract

Provided herein are methods of treating, preventing, or reducing conditions and / or side effects associated with anti-cancer agents (e.g., chemotherapeutic agents) via administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of the anti-cancer agents. The methods reduce adverse effects associated with the anti-cancer agent, such as anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, thereby enhancing tolerance of the anti-cancer agents and survival of the subject having cancer or having a disease or condition that is not cancer but is treated, reduced, or prevented by administration of an anti-cancer agent.

Description

Attorney Docket No.146316.8005.WO00 METHODS OF TREATING CANCER AND / OR CHEMOTHERAPY RELATED CONDITIONS USING NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application 63 / 514212 filed July 18, 2023, U.S. Provisional Patent Application 63 / 497580 filed April 21, 2023, and U.S. Provisional Patent Application 63 / 486160 filed February 21, 2023, each of which are incorporated herein by reference in their entireties. SEQUENCE LISTING INCORPORATED BY REFERENCE

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format via Patent Center and is hereby incorporated by reference in its entirety. The .xml copy, created on February 16, 2024, is named 146316_8005_WO00_SL.xml and is 1,080,166 bytes in size. TECHNICAL FIELD

[0003] The present technology comprises methods of using non-naturally occurring melanocortin analogs, which may prevent or reduce side effects induced by anti-cancer agents and / or symptoms or conditions associated with cancer in a subject. BACKGROUND

[0004] The use of anti-cancer agents, including chemotherapeutic agents, to treat patients is often restricted because the patient suffers from certain conditions such as anorexia, emesis, weight loss, fat and muscle wasting, and fatigue. These conditions may be caused by the subject’s cancer or may be side effects of the anti-cancer agents. Restrictions on anti-cancer agent use may include limited duration and dose of cancer treatment due to subject’s suffering from one or more of these conditions. Accordingly, these conditions limit treatment tolerance of a subject to an anti-cancer agent thereby reducing the -1- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 overall treatment efficacy, reducing quality of life in cancer patients, and increasing risk that treatments are not as effective as they otherwise could be.

[0005] Despite recent advances in cancer treatment, there is a demand for novel approaches to make anti-cancer agents and associated cancer therapeutic methods more tolerable for patients, including reduced adverse side effects compared to conventional methods, yet retaining or increasing robust therapeutic activity. SUMMARY

[0006] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0007] In some embodiments, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0008] In some embodiments, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0009] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to treat, prevent, or reduce one or more side effects associated with an anti-cancer agent in a subject, the one or more side effects are selected -2- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0010] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, wherein, the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0011] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non- naturally occurring melanocortin analog to the subject, wherein, the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0012] In some embodiments, the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

[0013] In some embodiments, the present technology comprises a method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0014] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to maintain or increase muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent. -3- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0015] In some embodiments, the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

[0016] In some embodiments, the present technology comprises a method of preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0017] In some embodiments, the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

[0018] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non- naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0019] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non- naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0020] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to maintain or increase bone density in a subject prior to, during, and / or after administration of an anti-cancer agent. -4- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0021] In some embodiments, the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

[0022] In some embodiments, the present technology comprises a method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0023] In some embodiments, the present technology comprises a method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0024] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog to stimulate appetite or reduce loss of appetite induced by an anti-cancer agent in a subject.

[0025] In some embodiments, the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

[0026] In some embodiments, the present technology comprises a method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and / or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0027] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. -5- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0028] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0029] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog for preventing or reducing an anti-cancer agent induced side effect in a subject having cancer.

[0030] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog for treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer.

[0031] In some embodiments, the present technology comprises a use of a non- naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving ECOG score and / or KPS score of a subject having cancer relative to a baseline or a control.

[0032] In some embodiments, the subject experiences a reduction in ECOG performance score by about 1, 2, or 3 compared to baseline or control.

[0033] In some embodiments, the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

[0034] In some embodiments, the method or use maintains or increases lean body mass, fat body mass, and / or weight of the subject.

[0035] In some embodiments, the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

[0036] In some embodiments, the nutritional intervention further comprises nutritional supplementation. -6- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0037] In some embodiments, the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0038] In some embodiments, the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0039] In some embodiments, the ECOG score and / or KPS score is improved, maintained, and / or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0040] In some embodiments, the subject has a cancer.

[0041] In some embodiments, the anti-cancer agent comprises a chemotherapy.

[0042] In some embodiments, the method or use reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject.

[0043] In some embodiments, the method or use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and the method or use reduces mass loss and / or wasting in the subject.

[0044] In some embodiments, the anorexia is associated with weight loss.

[0045] In some embodiments, the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

[0046] In some embodiments, the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non- naturally occurring melanocortin analog. -7- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0047] In some embodiments, the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein, the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

[0048] In some embodiments, the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti- cancer agent.

[0049] In some embodiments, the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0050] In some embodiments, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

[0051] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by a cancer.

[0052] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

[0053] In some embodiments, the subject is receiving an antiemetic.

[0054] In some embodiments, the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

[0055] In some embodiments, the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

[0056] In some embodiments, the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent. -8- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0057] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

[0058] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0059] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0060] In some embodiments, administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anti- cancer agent in the subject.

[0061] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.

[0062] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment.

[0063] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention.

[0064] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject. -9- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0065] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anti- cancer agent in the subject.

[0066] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and / or Karnofsky performance status score of the subject.

[0067] In some embodiments, the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0068] In some embodiments, the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0069] In some embodiments, the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0070] In some embodiments, the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0071] In some embodiments, the method or use lowers the ECOG scale of the subject.

[0072] In some embodiments, the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0073] In some embodiments, the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0074] In some embodiments, the method or use increases the subject’s KPS score.

[0075] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), -10- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein, R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta- alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; -11- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; R10is absent or is lysine; R11-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; -12- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y4is absent or is D-proline or D-valine; Y5is absent or is D-proline or D-valine; Y6is absent or is D-proline or D-valine; Y7is absent or is D-proline or D-valine; Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; provided that: when R2is dAsp, then R7is not dLys; -13- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.

[0076] In some embodiments, the chemotherapy comprises at least one chemotherapeutic agent.

[0077] In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum- coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.

[0078] In some embodiments, the at least one chemotherapeutic agent comprises a platinum-coordination complex.

[0079] In some embodiments, the at least one chemotherapeutic agent comprises an antimetabolite.

[0080] In some embodiments, the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

[0081] In some embodiments, the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.

[0082] In some embodiments, the at least one chemotherapeutic agent comprises a cytotoxic antibiotic. -14- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0083] In some embodiments, the platinum-coordination complex is carboplatin and / or cisplatin.

[0084] In some embodiments, the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

[0085] In some embodiments, the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

[0086] In some embodiments, the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0087] In some embodiments, the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

[0088] In some embodiments, the platinum-coordination complex is cisplatin.

[0089] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU).

[0090] In some embodiments, the tubulin binding agent or the plant alkaloid is vincristine.

[0091] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide.

[0092] In some embodiments, the cytotoxic antibiotic is doxorubicin.

[0093] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell -15- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.

[0094] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

[0095] In some embodiments, the cancer is breast cancer, and wherein, the anti- cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.

[0096] In some embodiments, the anthracycline is doxorubicin.

[0097] In some embodiments, the taxane is paclitaxel.

[0098] In some embodiments, the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0099] In some embodiments, the subject is receiving radiation therapy, and wherein, the anti-cancer agent is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

[0100] In some embodiments, subject is not receiving radiation therapy, and wherein, the anti-cancer agent is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.

[0101] In some embodiments, the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and / or temozolomide.

[0102] In some embodiments, the cancer is non-Hodgkin's lymphoma, and wherein, the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin. -16- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0103] In some embodiments, the method or use does not reduce efficacy of the anti- cancer agent.

[0104] In some embodiments, the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

[0105] In some embodiments, the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein, the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

[0106] In some embodiments, the subject is a human.

[0107] In some embodiments, the subject is an animal.

[0108] In some embodiments, the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.

[0109] In some embodiments, the cardiac muscle mass loss is determined by measuring change in heart weight.

[0110] In some embodiments, the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

[0111] In some embodiments, anorexia is determined by daily food intake, daily food consumption, and / or weekly food intake.

[0112] In some embodiments, the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

[0113] In some embodiments, the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.

[0114] In some embodiments, the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

[0115] In some embodiments, the weight loss is determined by daily body weight, and / or daily body weight gain. -17- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0116] In some embodiments, the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0117] In some embodiments, the heart weight of the subject treated with the method is at least 0.1% to 10% greater than a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0118] In some embodiments, the gastrocnemius tissue weight of the subject treated with the method is at least 0.1% to 10% greater than a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0119] In some embodiments, the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0120] In some embodiments, the daily body weight of the subject treated with the method is at least 1% to 15% greater than a baseline or control subject, wherein, the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0121] In some embodiments, appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

[0122] In some embodiments, appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog. -18- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0123] In some embodiments, appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.

[0124] In some embodiments, appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

[0125] In some embodiments, the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0126] In some embodiments, the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

[0127] In some embodiments, the appetite is assessed between meals.

[0128] In some embodiments, the subject comprises two or more subjects, and wherein, the appetite is an average appetite of the two or more subjects.

[0129] In some embodiments, anorexia is determined by food consumption.

[0130] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0131] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt.

[0132] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier.

[0133] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the pharmaceutical composition.

[0134] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the pharmaceutical composition. -19- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0135] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0136] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0137] In some embodiments, the pharmaceutical composition comprising the non- naturally occurring melanocortin analog is administered to the subject parenterally.

[0138] In some embodiments, the pharmaceutical composition comprising the non- naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0139] In some embodiments, the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0140] In some embodiments, the pharmaceutical carrier comprises water.

[0141] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.

[0142] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject with a meal.

[0143] In some embodiments, a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0144] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

[0145] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject. -20- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0146] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

[0147] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0148] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0149] In some embodiments, the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.

[0150] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the single composition.

[0151] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the single composition.

[0152] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg / mL, relative to a total volume of the single composition.

[0153] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0154] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume -21- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 of about 2 mL to 10 mL, and wherein, the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0155] n some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein, the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0156] In some embodiments, the administration is performed once per day.

[0157] In some embodiments, the anti-cancer agent is present in a first pharmaceutical composition; and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.

[0158] In some embodiments, the first and the second pharmaceutical compositions are different and are administered sequentially.

[0159] In some embodiments, the first and the second pharmaceutical compositions are different and are administered simultaneously but separately.

[0160] In some embodiments, the second pharmaceutical composition is administered subcutaneously.

[0161] In some embodiments, anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0162] In some embodiments, the chemotherapy is cisplatin, and cisplatin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0163] In some embodiments, the chemotherapy is 5-FU, and 5-FU is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0164] In some embodiments, the chemotherapy is doxorubicin, and doxorubicin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50, relative to a total volume of the first pharmaceutical composition. -22- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0165] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0166] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0167] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0168] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and In some embodiments, the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0169] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and In some embodiments, the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0170] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0171] In some embodiments, the administration is performed once per day. -23- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 BRIEF DESCRIPTION OF THE DRAWINGS

[0172] FIG. 1A is a graph depicting daily food intake of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food intakes in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0173] FIG.1B is a graph depicting daily food consumption of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0174] FIG. 1C is a graph depicting daily body weight of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weights in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0175] FIG.1D is a graph depicting daily body weight gain of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weight gains (% -24- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 initial) in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5- FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5- FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0176] FIG.2A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0177] FIG.2B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0178] FIG.2C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week -25- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0179] FIG.2D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0180] FIG.3 is a bar graph depicting fat mass, lean mass, and total water changes of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the changes in fat mass, lean mass, and total water of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.

[0181] FIG.4 is a bar graph depicting serum GDF-15 (growth differentiation factor-15) concentration of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the serum GDF-15 concentrations of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.

[0182] FIG.5 is a graph depicting the design of studies using one or more compositions of the present technology. -26- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0183] FIG. 6A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0184] FIG. 6B is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0185] FIG.6C is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0186] FIG.6D is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 70 mg / kg / week 5- FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0187] FIG.7A is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0188] FIG.7B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats -27- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0189] FIG. 7C is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0190] FIG. 7D is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0191] FIG. 8A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0192] FIG.8B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0193] FIG. 9A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline -28- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0194] FIG.9B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0195] FIG. 10A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered cisplatin, saline, and IgG (Group 1), cisplatin plus saline plus an anti-GDF-15 monoclonal antibody (mAb) comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0196] FIG.10B is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus an anti-GDF- 15 mAb comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0197] FIG.10C is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus an anti-GDF- 15 mAb comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001. -29- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0198] FIG. 10D is a graph depicting total food intake of Sprague Dawley rats in a combination therapy study over 21 days. The graph compares total food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus an anti-GDF- 15 mAb comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0199] FIG. 11A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0200] FIG. 11B is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0201] FIG.11C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0202] FIG.11D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001. -30- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0203] FIG.11E is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of day 0) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively. Daily body weight gains are shown from day -10 to day 21, where day 0 signifies initiation of cisplatin administration. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0204] FIG.12A is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0205] FIG.12B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0206] FIG.13A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0207] FIG.13B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001. -31- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0208] FIG.14A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 650.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0209] FIG.14B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 650.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0210] FIG.15A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF- 15 mAb of FIG.10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the anti-GDF-15 mAb of FIG.10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0211] FIG.15B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the body weight change (% of initial) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG.10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the anti-GDF-15 mAb of FIG.10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0212] FIG.15C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight change (% of initial) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG.10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the -32- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 anti-GDF-15 mAb of FIG.10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0213] FIG.15D is a graph depicting total body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the net body weight gain (% of baseline) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG.10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the anti-GDF-15 mAb of FIG.10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0214] FIG. 16A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0215] FIG.16B is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0216] FIG. 16C is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21, 28, and 35.

[0217] FIG.16D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week -33- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21, 28, and 35.

[0218] FIG. 17A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0219] FIG. 17B is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0220] FIG.17C is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0221] FIG.17D is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0222] FIG.17E is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0223] FIG.17F is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0224] FIG. 18A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 65 -34- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0225] FIG.18B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0226] FIG. 19A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0227] FIG.19B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0228] FIG.20A is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0229] FIG.20B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration -35- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0230] FIG.20C is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0231] FIG.20D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0232] FIG. 21A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0233] FIG.21B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0234] FIG. 21C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001. -36- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0235] FIG.21D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0236] FIG. 22A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0237] FIG.22B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0238] FIG. 22C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0239] FIG.22D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001. -37- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0240] FIG. 23A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0241] FIG. 23B is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0242] FIG.23C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0243] FIG.23D is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0244] FIG. 24A is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose. -38- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0245] FIG. 24B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0246] FIG.24C is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0247] FIG.24D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0248] FIG. 25A is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0249] FIG. 25B is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after -39- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0250] FIG.25C is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats after combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0251] FIG.25D is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats after combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0252] FIG.26A is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0253] FIG.26B is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0254] FIG. 26C is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. -40- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0255] FIG. 26D is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0256] FIG.27A is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 7 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin (DOX) plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 7 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and B07 was administered by subcutaneous injection. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0257] FIG.27B is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 14 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 14 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and B07 was administered by subcutaneous injection. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0258] FIG.27C is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 21 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 21 days. N=10, 16, and 12 rats for Group 1, Group 2, -41- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 and Group 3, respectively. DOX was administered by intraperitoneal injection and B07 was administered by subcutaneous injection.

[0259] FIG.27D is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 28 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a % of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 28 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and B07 was administered by subcutaneous injection. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0260] FIG.28A is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 17 days.

[0261] FIG.28B is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 26 days. N = 12 rats per group. B07 was administered subcutaneously. DETAILED DESCRIPTION

[0262] Described herein are methods of treating, preventing, or reducing one or more conditions, including but not limited to side effects and iatrogenic injury, associated with an anti-cancer agent (e.g., chemotherapy agent) in a subject in need thereof using non-naturally occurring melanocortin analogs, as well as methods of treating subjects with having one or more such conditions. In some embodiments, the present technology includes methods for preventing or reducing one or more of the conditions associated with an anti-cancer agent by administering a non-naturally occurring melanocortin analog to the subject in need thereof -42- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 prior to administration of the anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject after an anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject concurrently with an anti-cancer agent or during an anti-cancer agent dosing regimen. In any of the embodiments of the present technology, the subject has cancer or the subject has another condition (e.g., not cancer) which may be treated with an anti-cancer agent such as, but not limited to, a chemotherapy agent.

[0263] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology of the present technology. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0264] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in descriptions, any method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0265] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the -43- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0266] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Likewise, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment.

[0267] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. In some embodiments, such variation may be as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0268] The terms “administering” or “administer” include delivery of therapies (e.g., combination therapies, non-naturally occurring melanocortin analogs (also referred to herein as peptides), anti-cancer agents) of the present technology to a subject either by local or systemic administration. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

[0269] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss. -44- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0270] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0271] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®(ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™(BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0272] As used herein, “a side effect associated with the anti-cancer agent”, “an adverse side-effect associated with the anti-cancer agent”, or “a side effect induced by the anti-cancer agent”, refers to any unwanted, undesirable, or deleterious biological activity -45- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 occurs during or after independent use of the anti-cancer agent. Examples of such side effects include, but are not limited to, anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. Such anti-cancer agents may also be administered to subjects for therapeutic uses besides cancer, for example, to treat, reduce, or prevent a condition or disease in a subject not having cancer.

[0273] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e.g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers). The term “biomarker” refers to a biological output that is used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms. The term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health.

[0274] The terms “treat”, “treatment”, and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease (e.g., cancer), the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1) a stabilization, reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the population of cancer cells and / or tumor size before administration), or elimination of the cancer cells, (2) inhibiting cancerous cell division and / or cancerous cell proliferation, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant cellular division, (4) an increase in disease-free, relapse-free, progression-free, and / or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) eradication, removal, or control of primary, regional and / or metastatic cancer, (8) a stabilization or reduction (e.g. by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial growth rate) in the growth of a tumor -46- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 or neoplasm, (9) an impairment in the formation of a tumor, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond or are in remission, (12) the size of the tumor is maintained and does not increase or increases by less than 10%, less than 5%, less than 4%, or less than 2%, (13) a decrease in the need for surgery (e.g. colectomy, mastectomy), and (14) preventing or reducing the metastasis of cancer cells. The terms “treat”, “treatment”, and “treating” include prophylactic and / or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length or frequency of the disease.

[0275] As used herein, the terms “effective amount” or “therapeutically effective amount”, refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0276] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0277] "Appetite" in a subject and / or patient is typically assessed by their desire to eat and / or the amount of food they consume. As used herein, appetite may be assessed through -47- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and / or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).

[0278] “Cachexia” refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and / or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term “cancer cachexia” refers to cachexia induced by cancer. Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2% in patients with a body mass index (BMI) less than 20 kg / m2; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et al., Lancet Oncol.12(5):489-95 (2011). Cachexia may be used interchangeably with the term “Protein- Energy Wasting” (i.e., PEW).

[0279] “Anorexia” refers to a loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.

[0280] The term “Body Mass Index” or “BMI” refers to a value derived from an individual’s body weight and height. Specifically, BMI is determined by body weight (kilograms) divided by the square of height (m2) and is expressed in units of “kg / m2”. "Normal" BMI ranges are known to a person of ordinary skill in the art and consider factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is about 18.5 kg / m2to about 25 kg / m2.

[0281] The terms “subject” and “patient” refer to anyone being evaluated for disease or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, or cachexia. -48- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0282] The term “control subject,” as used herein, refers to any subject used as a basis for comparison to the subject (e.g., test subject). A control subject includes, but is not limited to, any subject who has not been administered the therapeutic or pharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo.

[0283] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro- opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule—i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1) or a modified version thereof, or a structural or functional peptide mimetic thereof. -49- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0284] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0285] A melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. By a melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor-associated responses normally induced by a melanocortin receptor agonist agent. A melanocortin receptor “inverse agonist” is a drug or a compound that stabilizes the inactive conformation of the melanocortin receptor and inhibits basal activity.

[0286] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and / or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological half-life.

[0287] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0288] The “peptides” described herein may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0289] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The -50- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with non- amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0290] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0291] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N—CHR— COOH, wherein R represents a side chain group. The various α-amino acids differ in the side-chain moiety that is attached to the α-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Non-naturally occurring melanocortin analogs: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are -51- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 described generally in Non-naturally occurring melanocortin analogs: A User’s Guide, supra; Hruby et al., Biochem. J.268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res.35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0292] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.

[0293] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.

[0294] In the peptides described herein, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8thEd. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Val” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” is L-phenylalanine; “D-Phe” is D-phenylalanine; “D- / L-Phe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on. Non-standard amino acids are “Nle” is -52- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 norleucine; “Nal” is naphthylalanine; “D-Nal” is D-naphthylalanine; D-Nal(2′) is D-2′- naphthylalanine; L-Nal(2') is L-2′-naphthylalanine; L-Nal(1') is L-1′-naphthylalanine; D- Nal(1') is D-1′-naphthylalanine; Tle is tert-Leucine; Nva is norvaline; Orn is ornithine; Bip is biphenylalanine; and so on.

[0295] An alpha (α)-amino acid has the generic formula H2N—CαHR—COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the α-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ. For example, α-alanine has the formula H2N—CαH(CH3)— COOH. In contrast, β-alanine has the general formula H2N—CβH2—CαH2—COOH (i.e., 3- aminopropanoic acid).

[0296] When β-amino acids are incorporated into peptides, two main types of β- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2amino acids. As a non-limiting example, “β-valine” may refer to: —NH—CβH2—CαH(CH3)2—CO—, i.e., β2-valine (R on carboxy side); —NH—CβH(CH3)2—CαH2—CO—, i.e., β3-valine (R on amino side); or —NH—CβH(CH3)2—CαH(CH3)2—CO—, i.e., β2,3-valine (R at both positions).

[0297] Gamma (γ)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms. For example, γ-amino butyric acid has the formula, H2N—CγH2—CβH2—CαH2—COOH.

[0298] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” refers to a cyclic structure, which is also shown in the literature as “c” or referred to as a “lactam.” “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an —NH2moiety on the C-terminus of a peptide indicates an amide, i.e., — CO—NH2. In addition, the following abbreviations are used herein: Harg is Homo arginine; Hlys is Homo lysine. -53- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0299] Additional abbreviations are used as follows: tBu is tert-butyl; Hyp(Bzl) is benzyl-L-hydroxy-proline; glutaric acid linker is CO—(CH2)3—CO; Pen is L-Penicillamine; Aib is 2-Aminoisobutyric acid; Aba is 4-amino-1,2,4,5-tetra-hydro-2-benzazepin-3-one; Pip is piperidine-2-carboxylic acid; Nip is piperidine-3-carboxylic acid; Tic is tetrahydroquinoline- 3-carboxylic acid; Bip is biphenylalanine; Phg is α-Phenyl-glycine; Sar is Sarcosine; Azt is 3′-azido-3′-deoxythymidine; Oic is Octohydroindole-2-carboxylic acid; Ata is 7-amino-7,8- dihydro4H-(1,2,3)triazolo(1,5-a)(1,4)diazepin-6(5H)-one; Aia is 4-amino-1,4,5,6- tetrahydroazepino(4,3-b)indol-3(2H)-one; Aba is 4-amino-1,2,4,5-tetrahydro-2-benzazepin- 3-one; Mamb is 3-aminomethylbenzoic acid; Atc is 2-Aminotetraline-2-carboxylic acid; APC is 1-Amino-4-phenylcyclohexane-carboxylic acid; APPC is 4-Aminophenylpiperidine-4- carboxylic acid; Acpc is 1-aminocyclo-propane-1-carboxylic acid; Aic is 2-aminoindone-2- carboxylic acid; p(Cl)Phe is para-chloro-phenylalanine (I – iodo, Br- bromo) and p(Cl)dPhe is para-chloro-D-phenylalanine (I – iodo, Br- bromo).

[0300] The term “alkene” includes unsaturated hydrocarbons that contain one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.

[0301] The term “alkenyl” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond; examples thereof include ethenyl, 2-propenyl, and the like.

[0302] The “alkyl” groups specified herein include those alkyl radicals of the designated length in either a straight or branched configuration. Examples of such alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

[0303] The term “alkynal” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond; examples thereof include ethynyl, propynal, butynyl, and the like. -54- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0304] The term “aryl” includes a monovalent or bicyclic aromatic hydrocarbon radical of 6-to-12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, or alkoxy-carbonyl. Examples of an aryl group include phenyl, biphenyl, naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.

[0305] The term “aliphatic” includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0306] The term “acyl” includes a group RCO—, where R is an organic group. An example is the acetyl group CH3CO—, referred to herein as “Ac.”

[0307] The term “fatty acid” describes a carboxylic acid with an aliphatic chain, which may be fully saturated or partially unsaturated, and optionally attached to a functional group such as a hydroxyl group or a carboxyl group. The aliphatic chain may contain e.g., from 6 to 26 carbon atoms and hydrogen atoms.

[0308] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl {—(C═O)—} groups. A peptide is most usually acylated at the N-terminus.

[0309] An “omega amino derivative” includes an aliphatic moiety with a terminal amino group. Examples of omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.

[0310] The term “heteroaryl” includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or six-membered heteroaryl are monocyclic heteroaromatic rings; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine, and thienopyridine.

[0311] An “amine” includes compounds that contain an amine group (—NH2). -55- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0312] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., —CO—NH2), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine (—NH2) moiety to the C-terminal carboxyl group.

[0313] An “imine” includes compounds that have a carbon-nitrogen double bond, with the nitrogen also attached to a hydrogen (NH═CH—R).

[0314] An “imide” includes compounds containing an imido group (—OC—NH—CO—).

[0315] A “nitrile” includes compounds that are carboxylic acid derivatives and contain a (—CN) group bound to an organic group.

[0316] The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine, and groups including one or more halogen atoms, such as —CF3 and the like.

[0317] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0318] A peptide or amino acid “mimetic” is a non-amino acid molecule that mimics a peptide (a chain of amino acids) or one amino acid residue.

[0319] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and / or -56- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0320] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference, including but not limited to U.S. Patent Nos.8,541,545 and 9,534,018. Non-naturally Occurring Melanocortin Analogs

[0321] The present technology comprises a non-naturally occurring melanocortin analog that may be administered to a subject in need thereof. The present technology also comprises methods of treating, preventing, or reducing unwanted side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms associated with cancer via administration of a non-naturally occurring melanocortin analog, which may be the non-naturally occurring melanocortin analog as of the present technology in any of its embodiments.

[0322] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein: R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n- pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D- arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D- glutamine, and acetylated D-asparagine; -57- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone-2- carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of D-tryptophan, L- tryptophan, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), 4-amino- 1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid, methionine, proline, tryptophan, D-Nal(2′), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; -58- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R10is absent or is lysine; R11-R20are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, prolylglycine (Pro-Gly), D-Nal(2′), L-Nal(2′), Bip, ornithine, and tryptophan; wherein if R2is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2and X3are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L- isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D- leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, D-valine, L-valine, β- valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin- 2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1is selected from the group consisting of D-alanine, L-alanine, β-alanine, D- threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D- leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, L-proline, D-proline, β-homo proline, a piperazin-2-one ring, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; -59- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Y2is absent or is selected from the group consisting of D-proline, L-proline, β-homo proline, a piperazin-2-one ring, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β- valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β- isoleucine, Hyp, dHyp, D-alanine, L-alanine, β-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3is absent or is selected from the group consisting of D-threonine, L-threonine, D- alanine, L-alanine, D-proline, L-proline, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D- leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, and a piperazin-2- one ring; Y4is absent or is D-proline or D-valine; Y5is absent or is D-proline or D-valine; Y6is absent or is D-proline or D-valine; Y7is absent or is D-proline or D-valine; Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is glycine, proline or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; -60- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; and a lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino- propionic acid; X1X2X3represents an optionally present N-terminus; and Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus.

[0323] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n- pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D- arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic -61- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone-2- carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of D-tryptophan, L- tryptophan, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diaminopropionic acid, methionine, proline, tryptophan, D-Nal(2′), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; R10is absent or is lysine; R11-R20are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, prolylglycine (Pro-Gly), D-Nal(2′), L-Nal(2′), Bip, ornithine, and tryptophan; wherein if R2is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2and X3are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L- -62- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D- leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, D-valine, L-valine, β- valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin- 2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L- valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine; Y5is absent or is D-proline or D-valine; Y6is absent or is D-proline or D-valine; Y7is absent or is D-proline or D-valine; Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: -63- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; and a lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino- propionic acid.

[0324] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, tyrosine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D- penicillamine (dPen); -64- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D- valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D- phenylalanine, leucine, isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1- aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 1- amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; R10is absent or is lysine; R11-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D- -65- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine; Y5is absent or is D-proline or D-valine; Y6is absent or is D-proline or D-valine; Y7is absent or is D-proline or D-valine; Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: -66- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; comprised that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified.

[0325] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; -67- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta- alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; R10is absent or is lysine; -68- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 R11-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y4is absent or is D-proline or D-valine; Y5is absent or is D-proline or D-valine; Y6is absent or is D-proline or D-valine; Y7is absent or is D-proline or D-valine; Y8is absent or is D-proline or D-valine; -69- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; comprised that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent. -70- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0326] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, R3of the sequence according to Formula (I), which may be hydroxyproline, hydroxy-D- proline, D-alanine, D-methionine, D-valine, prolylglycine (Pro-Gly), glycine, comprises the β- hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, comprises the β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog.

[0327] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by a functional group selected from the group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0328] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments, themelanocortin analog, if present, is modified by an imine group.

[0330] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an amide group. In some embodiments, the amide group is a pyroglutamyl (pGlu) In some-71- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 embodiments, the amide group is derived from a fatty acid (e.g., to,melanocortin analog, if present, is not modified.

[0333] As discussed above, Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus of the non- naturally occurring melanocortin analog. In some embodiments, Y1-Y8are absent. In some embodiments, Y1is present and Y2-Y8are absent.

[0334] In some embodiments, Y1and Y2are present and Y3-Y8are absent. In some embodiments, Y3-Y8are absent, and Y1is D-valine and Y2is D-proline, or Y1is D-proline and Y2is D-valine.

[0335] In some embodiments, Y3is present and Y4-Y8are absent. In some embodiments, Y3is present and Y4-Y8are absent, and (i) Y1is D-valine or D-proline, (ii) Y2is D-valine or D-proline, and / or (iii) Y3is D-valine or D-proline. In some embodiments, Y3is present and Y4-Y8are absent, and (i) Y1is D-valine, Y2is D-valine, and Y3is D-proline, (ii) Y1is D-proline, Y2is D-valine, and Y3is D-valine, or (iii) Y1is D-valine, Y2is D-proline, and Y3is D-valine. -72- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0336] In some embodiments, Y3and Y4are present, and Y5-Y8are absent. In some embodiments, Y3and Y4are present, and Y5-Y8are absent, and (i) Y1is D-valine or D- proline, (ii) Y2is D-valine or D-proline, (iii) Y3is D-valine or D-proline, and / or (iv) Y4is D- valine or D-proline. In some embodiments, Y3and Y4are present, and Y5-Y8are absent, and (i) Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline, (ii) Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine, (iii) Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine, or (iv) Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine.

[0337] In some embodiments, the C-terminus includes additional derivatives to extend the length of C-terminus of the non-naturally occurring melanocortin analog. Exemplary additional C-terminus include, but are not limited to, Y1Y2Y3Y4Y5Y6Y7Y8Y9, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23, and Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23Y24, etc., wherein Y9-Y24, if present, are each independently D-proline or D-valine.

[0338] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

[0339] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group ). In some-73- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 embodiments, the amide group is an N-alkyl amide group ,aryl amide group. In some embodiments, the N-aryl amidegroup is p-nitroanilide 4-).

[0340] In naturally occurringmelanocortin analog is modified by an ester group ,).

[0341] embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an aldehyde ).

[0342] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In some embodiments, the C-terminus of the non- naturally occurring melanocortin analog is not modified, and the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 2; B07a). -74- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0343] In some embodiments, R1is absent, and R2is D-aspartic acid.

[0344] In some embodiments, X1, X2, and X3are absent.

[0345] In some embodiments, R4is not D-phenylalanine. In some embodiments, R4is D-Nal(2′). When R4is D-Nal(2′), the non-naturally occurring melanocortin analog of the present technology may act as a melanocortin receptor antagonist. When R4is D- phenylalanine, the non-naturally occurring melanocortin analog of the present technology may act as a melanocortin receptor agonist.

[0346] In some embodiments, R1, R2, and R7are present and R8-R20are absent, and the sequence of Formula (I) is cyclized through R2and R7via a lactam bond. In some embodiments, R1is acetylated norleucine, R2is aspartic acid, R3is selected from the group consisting of proline, hydroxyproline, and hydroxy-D-proline, R4is D-Nal(2′), R5is arginine, R6is D-tryptophan or L-tryptophan, R7is lysine, Y1is D-valine, and / or Y2is D-proline.

[0347] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c(Asp-Pro- dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3; B07), or Ac-Nle-c(Asp-Hyp-dNal(2')- Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 4), wherein c represents cyclization through R2and R7via a lactam bond.

[0348] In some embodiments, R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond. In some embodiments, R1is acetylated norleucine, R2is aspartic acid, R3is selected from the group consisting of proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine, R4is histidine or D-Nal(2′), R5is D-Nal(2′) or arginine, R6is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan, R7is tryptophan or proline, R8is lysine, Y1is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y2is D- proline.

[0349] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 5); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 6); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dIle-dPro-NH2(SEQ ID NO: 7); -75- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 9), wherein c represents cyclization through R2and R8via a lactam bond.

[0350] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R2and R10via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Phe-Phe-Pro-His-dNal(2')-Arg- Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 10), wherein c represents cyclization through R2and R10via a lactam bond.

[0351] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R4and R10via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-Phe-Phe-c(Asp-Phe-His-dNal(2')-Arg- Trp-Lys)-dVal-dPro-Nh2 (SEQ ID NO: 11), wherein c represents cyclization through R4and R10via a lactam bond.

[0352] In some embodiments, the sequence of Formula (I) is linear. In some embodiments, the sequence of Formula (I) is Ac-Nle-Asp-Pro-dNal(2’)-Arg-Trp-Lys-dVal- dPro-NH2(SEQ ID NO: 12; B07L).

[0353] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-dArg-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 13); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 14); Ac-dIle-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dLeu-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dVal-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 17); Ac-dAla-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-Ala-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 19); Ac-Tle-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 20); Ac-dTle-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 21); -76- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-dNle-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-dArg-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nva-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 24); Ac-Gly-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-dPro-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dCys-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 27); Ac-dPhe-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 28); Ac-dTyr-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dGln-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 30); and Ac-dAsn-c(Asp-Pro-DNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 31), wherein c represents cyclization through R2and R7via a lactam bond.

[0354] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 34); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 35); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 37); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 38); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 41); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 42); -77- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 45); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 48); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 49); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 51); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 52); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 55); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 58); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 59); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 60); and Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 61), wherein c represents cyclization through R2and R6or R7via a lactam bond or a disulfide bond.

[0355] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 62); -78- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 65); Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 68); Ac-Nle-c(Asp-Gly-DNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 69); Ac-Nle-c(Asp-Leu-DNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Nle-c(Asp-Ile-DNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 71); and Ac-Nle-c(Asp-Val-DNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 72), wherein c represents cyclization through R2and R7via a lactam bond.

[0356] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 75); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 76); Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 78); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 79); Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 82); and Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 83), -79- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 wherein c represents cyclization through R2and R7via a lactam bond.

[0357] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Lys)-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO: 86); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2(SEQ ID NO: 87); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 88); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 89); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2(SEQ ID NO: 90), wherein c represents cyclization through R2and R7via a lactam bond.

[0358] In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-Bip- Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 91), wherein c represents cyclization through R2and R7via a lactam bond.

[0359] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2(SEQ ID NO: 92); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 93); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH2(SEQ ID NO: 94); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO: 95); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH2 (SEQ ID NO: 96); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH2 (SEQ ID NO: 97); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH2(SEQ ID NO: 98); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH2 (SEQ ID NO: 99); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH2 (SEQ ID NO: 100); -80- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2 (SEQ ID NO: 101); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO: 103); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH2 (SEQ ID NO: 105); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO: 106); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO: 107); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH2 (SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH2 (SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO: 110); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH2 (SEQ ID NO: 111); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH2 (SEQ ID NO: 112); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO: 113); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH2 (SEQ ID NO: 114); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH2 (SEQ ID NO: 115); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH2(SEQ ID NO: 116); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH2(SEQ ID NO: 117); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH2 (SEQ ID NO: 118); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO: 123); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH2 (SEQ ID NO: 124); -81- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH2 (SEQ ID NO: 126); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO: 127); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH2 (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH2 (SEQ ID NO: 129); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO: 130); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO: 131); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2 (SEQ ID NO: 132); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2 (SEQ ID NO: 133); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO: 134); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2 (SEQ ID NO: 135); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO: 137); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2(SEQ ID NO: 140); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2(SEQ ID NO: 141); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 142); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2(SEQ ID NO: 143); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2(SEQ ID NO: 144); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO: 145), wherein c represents cyclization through R2and R7via a lactam bond.

[0360] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: -82- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 148); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 149); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 150), wherein c represents cyclization through R2and R7via a lactam bond.

[0361] In some embodiments, X1is present and is acetylated norleucine, and R1is present and is norleucine. In some embodiments, X2is present and is norleucine. In some embodiments, X3is present and is norleucine. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 151); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 152); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 153), wherein c represents cyclization through R2and R7via a lactam bond.

[0362] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 155); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH2(SEQ ID NO: 156); c(CO-cis-CH = CH-CO-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Nle-c(Asp-β-Ala-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 159); Ac-Nle-c(Asp-Mamb-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Nle-c(Asp-Acpc-dNal(2′) Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 161); -83- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO: 162); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO: 163), wherein c represents cyclization through R2and R7or R8via a lactam bond or through R2and R5via a disulfide bond.

[0363] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 164); Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 165); Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 166); Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 167); Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 168); Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 170); Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 171); Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 172); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 173); and Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 174), wherein c represents cyclization through R2and R7or R8via a lactam bond.

[0364] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c(Asp-Pro-dPhe-Arg-dTrp-Lys)-dVal-dPro-NH2(SEQ ID NO: 175); or Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 176), wherein c represents cyclization through R2and R7or R8via a lactam bond.

[0365] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c(Asp-Aic-D-Nal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 177); or -84- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Cpe-D-Nal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 178), wherein c represents cyclization through R2and R7via a lactam bond.

[0366] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 179); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 180); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 181); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 184); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 185); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 186); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 187); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 188); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 189); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 190); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO: 191); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β2Val-NH2 (192); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β3Val-NH2(193); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO: 194); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2 (SEQ ID NO: 195); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2 (SEQ ID NO: 196); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO: 197); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β2Val-β3Pro-NH2 (198); -85- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Val-β3Pro-NH2 (199); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2 (SEQ ID NO: 200); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2(SEQ ID NO: 201); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2 (SEQ ID NO: 202); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 203); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β3Pro-NH2(204); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO: 205); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 206); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 207); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO: 208); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2 (SEQ ID NO: 209); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO: 210); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2(SEQ ID NO: 211); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO: 212); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO: 213); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 214); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO: 217); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO: 218); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 219); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 220); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 221); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 222); -86- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 223); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 224); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 225); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 226); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 228); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 229); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 230); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO: 232); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 233); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 234); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO: 235); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2 (SEQ ID NO: 236); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2 (SEQ ID NO: 237); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2(SEQ ID NO: 238); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2(SEQ ID NO: 239); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO: 240); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2(SEQ ID NO: 241); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2(SEQ ID NO: 242); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO: 243); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 244); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2(SEQ ID NO: 245); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 246); -87- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 247) Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 248); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 249); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 250); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 251); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 252); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 253); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 254); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 255); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 256); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 257); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 258); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 259); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 260); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 261); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO: 262); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO: 263); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 264); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO: 265); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO: 266); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 267); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 268); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 269); -88- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 270); and Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 271), wherein c represents cyclization through R1and R7via a lactam bond.

[0367] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 273); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dThr-dPro-dThr (SEQ ID NO: 274); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-Dlys)-dThr-dPro-dThr (SEQ ID NO: 275); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 276); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dVal-NH2 (SEQ ID NO: 277); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 279); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 281); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dVal-dPro-NH2(SEQ ID NO: 282); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-dVal-dPro-NH2 (SEQ ID NO: 283); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO: 284); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO: 285); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2 (SEQ ID NO: 286); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2 (SEQ ID NO: 287); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO: 288); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2 (SEQ ID NO: 289); -89- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βPro-NH2 (SEQ ID NO: 290); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-βVal-βPro-NH2 (SEQ ID NO: 291); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO: 292); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2 (SEQ ID NO: 293); Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-DLys)-βPro-βPro-NH2 (SEQ ID NO: 294); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-βPro-βPro-NH2(SEQ ID NO: 295); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO: 296); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2 (SEQ ID NO: 297); Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-DLys)-βVal-βVal-NH2 (SEQ ID NO: 298); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βVal-NH2(SEQ ID NO: 299); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 300); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 301); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2(SEQ ID NO: 302); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 303); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO: 304); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 305); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 306); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO: 307); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 308); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 309); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr (SEQ ID NO: 310); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr (SEQ ID NO: 311); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 312); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 313); -90- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2 (SEQ ID NO: 314); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2 (SEQ ID NO: 315); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 316); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 317); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2 (SEQ ID NO: 318); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2(SEQ ID NO: 319); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO: 320); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2 (SEQ ID NO: 321); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2 (SEQ ID NO: 322); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2(SEQ ID NO: 323); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2 (SEQ ID NO: 324); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2 (SEQ ID NO: 325); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2(SEQ ID NO: 326); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2 (SEQ ID NO: 327); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2 (SEQ ID NO: 328); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO: 329); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2(SEQ ID NO: 330); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2 (SEQ ID NO: 331); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 332); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 333); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO: 334); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 335); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 336); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 337); -91- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO: 338); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 339); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 340); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 341); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO: 343); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 344); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 345); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 346); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 347); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 348); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 349); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO: 350); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 351); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 352); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO: 353); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO: 354); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 355); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 356); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 357); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 358); and Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 359), wherein c represents cyclization through R1and R7via a lactam bond. -92- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0368] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172,188-190, 228- 231, 252-255, 280-283, 316-319, or 340-343. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-178. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, and 172.

[0369] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3 (TCMCB07). The structure of TCMCB07 (“B07”), which comprises Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2, is shown below:Anti-Cancer Agents

[0370] The anti-cancer agent described herein is a therapeutic agent useful for the treatment or prevention of neoplasm, of tumor or cancer cell division, growth, proliferation and / or metastasis in a subject; induction of death or apoptosis of tumor and / or cancer cells; and / or any other forms of proliferative disorder. In some embodiments, such anti-cancer agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not cancer, or besides cancer. The present technology is -93- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 expected to be useful for subjects that may receive, have received, or are receiving one or more doses of an anti-cancer agent regardless of the underlying disease or condition that the subject has or develops.

[0371] Conventional anti-cancer agents include chemotherapeutic agents such as platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents. Conventional cancer therapies may include more than one anti-cancer agent, for example, a combination of two or more chemotherapeutic agents (e.g., 5-FU plus leucovorin (FOLFOX), sunitinib plus oxaliplatin), a combination of chemotherapeutic agent and immunotherapy, as well as a combination of two or more immunotherapies. In contrast, the methods of the present technology are directed to administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent.

[0372] Exemplary chemotherapeutic agents include, but are not limited to, (i) alkylating antineoplastic agents such as cyclophosphamide (CYTOXAN), thiotepa, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, mercaptopurine, and procarbazine; (ii) anti-metabolites such as 5-fluorouracil (5-FU), cladribine, cytarabine, fludarabine, gemcitabine (GEMZAR), tegafur (UFTORAL), pentostatin, clofarabine, capecitabine (XELODA), methotrexate, pemetrexed, and thioguanine; (iii) cytotoxic antibiotics such as doxorubicin (including ADRIAMYCIN, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, a doxorubicin salt (e.g., hydrochloride salt), doxorubicin HCl liposome injection (DOXIL), and deoxydoxorubicin), daunorubicin, idarubicin, mitomycins such as mitomycin C, actinomycin, epirubicin, calicheamicin, dynemicin, including dynemicin A, aclacinomysins, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, esorubicin, idarubicin, marcellomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; (iv) tubulin binding agents such as vincristine (ONCOVIN), paclitaxel, epothilone, docetaxel, discodermolide, etoposide, vinblastine, teniposide, vinorelbine, and vindesine; and (v) platinum-coordination complexes such as cisplatin, oxaliplatin, carboplatin, and nedaplatin. -94- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0373] Additional examples of chemotherapeutic agents include, but are not limited to, tyrosine-kinase inhibitors such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and sunitinib; topoisomerase inhibitors such as CPT-11 (irinotecan, CAMPTOSAR), mitoxantrone, and topotecan (HYCAMTIN); thymidine phosphorylase (TPase) inhibitors such as tipiracil, and trifluridine; mitotic inhibitors; cell cycle inhibitors; enzymes; biological response modifiers; antiangiogenic agents such as MMP-2, MMP-9, and COX-2 inhibitor; anti-androgens such as fiutamide, nilutamide and bicalutamide; a substituted urea such as hydroxyurea; adrenocortical suppressants such as mitotane, aminoglutethimide, and trilostane; anti-hormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX tamoxifen), raloxifene (EVISTA), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (FARESTON®); hormone and / or hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate), and estrogens (e.g., diethylstilbestrol); androgens, such as testosterone propionate; and aromatase inhibitors, such as anastrozole (ARIMIDEX), exemestane (AROMASIN), 4(5)- imidazoles, aminoglutethimide, megestrol acetate (MEGASE), formestanie, fadrozole, vorozole (RJVISOR), and letrozole (FEMARA).

[0374] In some embodiments, the anti-cancer agent comprises a chemotherapy and the chemotherapy comprises at least one chemotherapeutic agent. In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic. In some embodiments, the chemotherapeutic agent is an antimetabolite, a pyrimidine antagonist, an alkylating agent, a topoisomerase inhibitor, a mitotic inhibitor, an antitumor antibiotic, a protein kinase inhibitor, a proteosome inhibitor, a poly(ADP-ribose) polymerase inhibitor, a plant alkaloid, an antimicrotubule agent, an antineoplastic agent, or an enzyme.

[0375] In some embodiments, the chemotherapeutic agent is an antimetabolite. Nonlimiting examples of antimetabolites include fluorouracil, 5-fluorouracil, 6- mercaptopurine, azacytidine, capecitabine, cladribine, clofarabine, cytarabine, floxuridine, -95- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil. In some embodiments, the chemotherapeutic agent comprises an antimetabolite selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

[0376] In some embodiments, the chemotherapeutic agent is a pyrimidine antagonist. Nonlimiting examples of pyrimidine antagonists include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0377] In some embodiments, the chemotherapeutic agent is an alkylating agent. Nonlimiting examples of alkylating agents include altretamine, bendamustine, busulfan, carboplatin, carmustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0378] In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Nonlimiting examples of topoisomerase inhibitors include irinotecan, camptothecin, etoposide, doxorubicin, topotecan, mitoxantrone, teniposide, daunorubicin, idarubicin, epirubicin, SN-38, dexrazoxane, belotecan, levofloxacin, anthracycline, rubitecan, sacituzumab govitecan, moxifloxacin, gatifloxacin, rubitecan, nalidixic acid, nalidixic acid, novobiocin, enoxacin, flumequine, clinafloxacin.

[0379] In some embodiments, the chemotherapeutic agent is a mitotic inhibitor. Nonlimiting examples of mitotic inhibitors include paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, ixabepilone, colchicine, demecolcine, etoposide, teniposide, alisertib, barasertib, volasertib, paclitaxel protein-bound particles, albumin-bound paclitaxel, ispinesib, and eribulin.

[0380] In some embodiments, the chemotherapeutic agent is an antitumor antibiotic. Nonlimiting examples of antitumor antibiotics include daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitomycin, and valrubicin.

[0381] In some embodiments, the chemotherapeutic agent is a protein kinase inhibitor. Nonlimiting examples of protein kinase inhibitors include imatinib, dasatinib, nilotinib, bosutinib, ponatinib, sorafenib, sunitinib, pazopanib, cabozantinib, vandetanib, crizotinib, -96- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 ceritinib, alectinib, brigatinib, osimertinib, larotrectinib, entrectinib, dabrafenib, trametinib, and cobimetinib.

[0382] In some embodiments, the chemotherapeutic agent is a proteosome inhibitor. Nonlimiting examples of proteosome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib, delanzomib, oprozomib, delanzomib, belinostat, panobinostat, romidepsin, vorinostat, belinostat, pracinostat, resminostat, givinostat, quisinostat, mocetinostat, chidamide, rocilinostat, and tucidinostat.

[0383] In some embodiments, the chemotherapeutic agent is a poly(ADP-ribose) polymerase inhibitor. Nonlimiting examples of poly(ADP-ribose) polymerase inhibitors include olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, ceralasertib, talazoparib, iniparib, niraparib, olaparib, rucaparib, veliparib, talazoparib, pamiparib, iniparib, veliparib, olaparib, talazoparib, and rucaparib.

[0384] In some embodiments, the chemotherapeutic agent is a plant alkaloid. Nonlimiting examples of plant alkaloids include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0385] In some embodiments, the chemotherapeutic agent is an antimicrotubule agent. Nonlimiting examples of antimicrotubule agents include docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, eribulin, ixabepilone, and cabazitaxel.

[0386] In some embodiments, the chemotherapeutic agent is an antineoplastic agent. Nonlimiting examples of antineoplastic agents include estramustine, mitomycin, hydroxydaunorubicin, chlorambucil, cisplatin, carboplatin, oxaliplatin, methotrexate, 5- fluorouracil, capecitabine, doxorubicin, epirubicin, idarubicin, daunorubicin, bleomycin, etoposide, teniposide, mitoxantrone, irinotecan, topotecan, gemcitabine, pemetrexed, paclitaxel, and docetaxel.

[0387] In some embodiments, the chemotherapeutic agent is an enzyme. Nonlimiting examples of enzymes include L-asparaginase, pegaspargase, glucarpidase, carboxypeptidase G2, methioninase, arginine deiminase, ADI-PEG 20, protease-activated receptor 1 (PAR-1) inhibitors, thymidylate synthase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, dihydrofolate reductase inhibitors, ribonucleotide reductase -97- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 inhibitors, hypoxanthine-guanine phosphoribosyltransferase inhibitors, DNA polymerase inhibitors, telomerase inhibitors, histone deacetylase inhibitors, protein kinase C inhibitors, sirtuin inhibitors, and matrix metalloproteinase inhibitors.

[0388] In some embodiments, the at least one chemotherapeutic agent comprises a platinum-coordination complex. In some embodiments, the platinum-coordination complex is carboplatin and / or cisplatin.

[0389] In some embodiments, the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid. In some embodiments, the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

[0390] In some embodiments, the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent. In some embodiments, the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0391] In some embodiments, the at least one chemotherapeutic agent comprises a cytotoxic antibiotic. In some embodiments, the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

[0392] In some embodiments, the platinum-coordination complex is cisplatin. In some embodiments, the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

[0393] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU). In some embodiments, the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

[0394] In some embodiments, the tubulin binding agent or the plant alkaloid is vincristine. In some embodiments, the chemotherapy comprises vincristine, and the non- naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3. -98- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0395] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide. In some embodiments, the chemotherapy comprises cyclophosphamide, and the non- naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

[0396] In some embodiments, the cytotoxic antibiotic is doxorubicin. In some embodiments, the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

[0397] The present technology further encompasses combinations of two or more of anti-cancer agents, including the above chemotherapeutic agents, as the anti-cancer agent of the combination therapy. Non-limiting examples include gemcitabine in combination with cisplatin; carboplatin in combination with pemetrexed; CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin combined with 5-FU and leucovovin.

[0398] In some embodiments, the method further comprises administering an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF15) such as, but not limited to, ponsegromab. See U.S. Patent No. 11,566,066 (or U.S. Patent Application No.16 / 541,817, incorporated herein by reference). In some embodiments, the non-naturally occurring melanocortin analog treats, prevents, and / or reduces one or more side effects that an antibody, or antigen binding fragment thereof, that specifically binds to GDF15 may also treat, prevent, and / or reduce. Therapeutic Methods

[0399] The present technology comprises methods of treating, preventing, or reducing one or more conditions and / or side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms or conditions associated with cancer via administration of a non-naturally occurring melanocortin analog to a subject in need thereof. The methods may promote appetite and food consumption, and increase or maintain body weight, muscle mass, and / or fat mass of the subject. The methods are also effective in treating anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, nausea, and emesis. The methods of the present technology include -99- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to onset, during, and / or after onset of such conditions and / or side effects. These methods also include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to, during, and / or after administration of an anti-cancer agent to the subject who may have cancer or may have another condition which is not cancer but administration of the anti-cancer agent comprises therapeutic benefit to the non-cancer condition.

[0400] The subject applicable to the methods of the present technology may be any subject who experiences involuntary loss of appetite, reduced appetite, decreased food consumption, and / or weight loss. For example, the subject may be a cancer patient, including those that have received, are receiving, or will receive anti-cancer treatment (e.g., chemotherapy) and a subject having another condition which is not cancer but administration of the anti-cancer agent comprises therapeutic benefit to the non-cancer condition.

[0401] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti- cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the method maintains or increases lean body mass, fat body mass, and / or weight of the subject. In some embodiments, the subject has a cancer. In some embodiments, administration of the non- naturally occurring melanocortin analog treats, prevents, reduces, or otherwise ameliorates the one or more side effects associated with an anti-cancer agent in a subject.

[0402] In some aspects, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject. In some embodiments, the subject has a cancer. In -100- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0403] In some aspects, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing, reducing, or otherwise ameliorating one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0404] In some aspects, the present technology comprises a method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent. In some embodiments, the method maintains or increases lean body mass, fat body mass, and / or body weight of the subject. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anti-cancer agent in the subject.

[0405] In some aspects, the present technology comprises a method of preventing, reducing, restoring, or otherwise ameliorating weight loss induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent. In some embodiments, the subject has a cancer. In some embodiments, administration of the non- -101- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 naturally occurring melanocortin analog prevents, reduces, restores, or otherwise ameliorates weight loss induced by an anti-cancer agent in the subject.

[0406] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, reduces, or otherwise ameliorates the one or more side effects associated with an anti-cancer agent in the subject who failed to respond to an antiemetic treatment.

[0407] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. wherein the nutritional intervention further comprises nutritional supplementation. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, reduces, or otherwise ameliorates the one or more side effects associated with an anti-cancer agent in the subject who failed to respond to nutritional intervention.

[0408] In some aspects, the present technology comprises a method of preventing, reducing, or otherwise ameliorating an anti-cancer agent induced side effect in a subject -102- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject. In some embodiments, the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, administration of the non- naturally occurring melanocortin analog prevents, reduces, or otherwise ameliorates the anti-cancer agent induced side effect in the subject having cancer.

[0409] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non- naturally occurring melanocortin analog to the subject. In some embodiments, the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, reduces, or otherwise ameliorates the iatrogenic injury caused by an anti-cancer agent in the subject having cancer.

[0410] In some aspects, the present technology provides a method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and / or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject. In some embodiments, the ECOG score and / or KPS score is improved, maintained, and / or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject. In some embodiments, administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and / or KPS score of the subject having cancer.

[0411] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such -103- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is a human. In some embodiments, the subject is an animal such as a rat or a dog.

[0412] In some embodiments, the subject has a body mass index (BMI) of about 18.5 kg / m2to about 35 kg / m2. In some embodiments, the subject has a BMI of less than about 20 kg / m2. In some embodiments, the subject has a BMI of less than about 18.5 kg / m2.

[0413] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, about 5% or less, about 10% or less, about 20% or less, or about 30% or less, than the lower end of "normal" BMI (e.g., 18.5 kg / m2).

[0414] In some embodiments, the subject is a patient who has experienced an involuntary weight loss prior to commencement of the administration. For example, the subject is a patient who has experienced a weight loss of about 1% per month, about 2% per month, about 5% per month, or about 10% per month, or more for at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months, prior to commencement of the administration.

[0415] In some embodiments, the subject has a cancer. In other embodiments, the subject has another condition which is not cancer but administration of the anti-cancer agent comprises therapeutic benefit to the non-cancer condition.

[0416] In any of the foregoing aspects, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the cancer. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cancer cachexia. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

[0417] In any of the foregoing aspects, the anti-cancer agent may comprise a chemotherapy. In some embodiments, the method reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the -104- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 subject. In some embodiments, the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject.

[0418] The methods of the present technology using anti-cancer agents (e.g., chemotherapy) may inhibit, remove, eradicate, reduce, regress, diminish, arrest or stabilize a cancerous tumor, including at least one of the tumor growth, tumor cell viability, tumor cell division and proliferation, tumor metabolism, blood flow to the tumor and metastasis of the tumor. In some embodiments, the size of a tumor, whether by volume, weight or diameter, is reduced after the treatment by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%, relative to the tumor size before treatment. In some embodiments, the size of a tumor after treatment does not reduce but is maintained the same as the tumor size before treatment. Methods of assessing tumor size and / or presence include, but are not limited to, CT scan, MRI, DCE- MRI, and a PET scan.

[0419] In some embodiments, the subject with a cancer has previously undergone a treatment with the anti-cancer agent. In related embodiments, the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent. In some embodiments, such adverse side effects are selected from the group consisting of nausea, emesis, anorexia, weight loss, fatigue, fat mass loss, and muscle mass loss.

[0420] The subject may be any subject already with the disease or condition (e.g., cancer). In some embodiments, the subject may be a subject which does not yet experience or exhibit symptoms of the disease or condition, or a subject predisposed to the disease or condition. In some embodiments, the subject is a person who is predisposed to cancer, e.g., a person with a family history of cancer.

[0421] In some embodiments, the method of the present technology in any of its aspects (i) stimulates appetite of the subject; (ii) increases food consumption of the subject; (iii) prevents or alleviates nausea, emesis, and / or anorexia in the subject; (iv) increases or maintains body weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains muscle mass of the subject; (vii) prevents or reduces muscle mass -105- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

[0422] In any of the foregoing aspects, the anorexia may be associated with weight loss.

[0423] In any of the foregoing aspects, the subject’s mass and / or weight is not more than about 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0424] In any of the foregoing aspects, the subject’s mass and / or weight is not more than about 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0425] In any of the foregoing aspects, the muscle mass loss may be cardiac muscle mass loss, skeletal muscle mass loss, or both. In some embodiments, the cardiac muscle mass loss is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

[0426] In some embodiments, muscle mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof. For example, muscle mass of the subject is increased by at least 1% to 100%, at least 5% to 75%, at least 10% to 50%, or at least 20% to 35%, after the administration.

[0427] In some embodiments, muscle mass of the subject is increased by at least 5% to 15% after the administration. For example, muscle mass of the subject is increased by at least 5% to 15%, at least 6% to 14%, at least 7% to 12%, or at least 8% to 9%, after the administration.

[0428] In some embodiments, muscle mass of the subject is increased by at least 25% to 50% after the administration. For example, muscle mass of the subject is increased by at least 25% to 50%, at least 28% to 48%, at least 25% to 45%, or at least 30% to 40%, after the administration. -106- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0429] In some embodiments, the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0430] In some embodiments, the method prevents or reduces muscle mass loss (e.g., involuntary muscle mass loss) in the subject.

[0431] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and / or nuclear magnetic resonance (NMR).

[0432] In any of the foregoing aspects, anorexia may be determined by daily food intake, daily food consumption, and / or weekly food intake. In some embodiments, the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day. In some embodiments, the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject. In some embodiments, the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

[0433] In any of the foregoing aspects, the weight loss may be determined by daily body weight, and / or daily body weight gain.

[0434] In any of the foregoing aspects, the fat mass of the subject treated with the method may be at least 10% to 100% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog. -107- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0435] In some embodiments, fat mass of the subject is increased by at least 1% to 100% after the administration (e.g., administration of the therapeutically effective amount of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof). For example, fat mass of the subject is increased by at least 1% to 100%, at least 5% to 75%, at least 10% to 50%, or at least 20% to 35%, after the administration.

[0436] In some embodiments, fat mass of the subject is increased by at least 5% to 15% after the administration. For example, fat mass of the subject is increased by at least 5% to 15%, at least 6% to 14%, at least 7% to 12%, or at least 8% to 9%, after the administration.

[0437] In some embodiments, fat mass of the subject is increased by at least 25% to 50% after the administration. For example, fat mass of the subject is increased by at least 25% to 50%, at least 28% to 48%, at least 25% to 45%, or at least 30% to 40%, after the administration.

[0438] In some embodiments, the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0439] In some embodiments, the method prevents or reduces fat mass loss (e.g., involuntary fat mass loss) in the subject.

[0440] In some embodiments, the fat mass may be determined by the fat fold technique. In some embodiments, the fat mass changes may be assessed by using magnetic resonance imaging (MRI) and / or nuclear magnetic resonance (NMR).

[0441] In any of the foregoing aspects, the heart weight of the subject treated with the method may be at least 0.1% to 10% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0442] In any of the foregoing aspects, the daily food intake of the subject treated with the method may be at least 5% to 50% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally -108- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0443] In any of the foregoing aspects, the daily body weight of the subject treated with the method may be at least 1% to 15% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti- cancer agent without the non-naturally occurring melanocortin analog.

[0444] In some embodiments, body weight of the subject is increased by at least 5% to 200% after the administration of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof. For example, body weight of the subject is increased by at least 5% to 200%, at least 10% to 150%, at least 25% to 100%, or at least 50% to 75%, after the administration.

[0445] In some embodiments, body weight of the subject is increased by at least 5% to 25% after the administration. For example, body weight of the subject is increased by at least 5% to 25%, at least 10% to 20%, or at least 12% to 15%, after the administration.

[0446] In some embodiments, body weight of the subject is increased by at least 20% to 100% after the administration. For example, body weight of the subject is increased by at least 20% to 100%, at least 35% to 90%, at least 50% to 80%, or at least 60% to 70%, after the administration.

[0447] In some embodiments, the increased body weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0448] In some embodiments, the method prevents or reduces weight loss (e.g., involuntary weight loss) in the subject.

[0449] In some embodiments, the body weight (or weight loss) is determined by monitoring daily body weight. In some embodiments, the body weight (or weight loss) is determined by monitoring daily body weight gain (or loss). In some embodiments, the body weight (or weight loss) is determined by monitoring cumulative body weight for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months, 6 months, 1 year, or 5 years. -109- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0450] In any of the foregoing aspects, appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof. For example, appetite of the subject is increased by at least 10% to 200%, at least 20% to 175%, at least 30 to 150%, at least 40% to 125%, at least 50% to 100%, or at least 60% to 75%, after the administration.

[0451] In some embodiments, appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof. For example, appetite of the subject is increased by at least 25% to 100%, at least 30% to 90%, at least 35 to 80%, at least 40% to 70%, at least 45% to 60%, or at least 50% to 55%, after the administration.

[0452] In some embodiments, appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years during the administration.

[0453] In some embodiments, appetite is increased for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

[0454] In some embodiments, the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0455] In some embodiments, the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety. For example, the appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects rate their hunger and / or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely). In some embodiments, the appetite is assessed by the subject’s rating of feeling of hunger using a scale ranging from 0 (not all all) to 100 (extremely). In some embodiments, the appetite is assessed by the subject’s scaling of satiety (e.g., easy or hard to eat) from 0 (extremely easy to eat) to 100 (extremely hard to eat).

[0456] In some embodiments, the appetite is assessed between meals. In some embodiments, the appetite is assessed during a meal. -110- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0457] In some embodiments, the appetite is assessed after a meal, for example, 1 minute after a meal, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hour, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or 24 hours after a meal.

[0458] In some embodiments, the subject comprises two or more subjects, and the appetite is an average appetite (e.g., average rating of feeling of hunger, average scaling of satiety) of the two or more subjects. In some embodiments, the subject comprises at least 3 subjects, and the appetite is an average appetite of the at least 3 subjects. In some embodiments, the subject comprises at least 4 subjects, and the appetite is an average appetite of the at least 4 subjects. In some embodiments, the subject comprises at least 5 subjects, and the appetite is an average appetite of the at least 5 subjects. In some embodiments, the subject comprises at least 6 subjects, and the appetite is an average appetite of the at least 6 subjects. In some embodiments, the subject comprises at least 7 subjects, and the appetite is an average appetite of the at least 7 subjects. In some embodiments, the subject comprises at least 8 subjects, and the appetite is an average appetite of the at least 8 subjects. In some embodiments, the subject comprises at least 9 subjects, and the appetite is an average appetite of the at least 9 subjects. In some embodiments, the subject comprises at least 10 subjects, and the appetite is an average appetite of the at least 10 subjects. The subject may comprise e.g., at least 10, 15, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1,000, 2,500, or 5,000 subjects, and the appetite is an average appetite of the at least 10, 15, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1,000, 2,500, or 5,000 subjects.

[0459] In some embodiments, food consumption of the subject is increased by at least 25% to 2,000% after the administration (e.g., administration of the therapeutically effective amount of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof). For example, food consumption of the subject can be increased by at least at least 25% to 2,000%, at least 50% to 1,750%, at least 75% to 1,500%, at least 100% to 1,000%, at least 250% to 750%, or at least 400% to 500%, after the administration.

[0460] In some embodiments, food consumption of the subject is increased by at least 50% to 500% after the administration. For example, food consumption of the subject can be -111- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 increased by at least at least 50% to 500%, at least 60% to 400%, at least 70% to 300%, at least 80% to 250%, at least 90% to 200%, at least 100% to 175%, or at least 125% to 150%, after the administration.

[0461] In some embodiments, food consumption is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.

[0462] In some embodiments, food consumption is increased for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

[0463] In some embodiments, the increased food consumption is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0464] In some embodiments, the food consumption is determined by daily food consumption, which is total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day. In some embodiments, the food consumption is determined by weekly food consumption, which is total calories (kcal) consumed in 1 week or mass of food (grams or kilograms) consumed in 1 week. In some embodiments, the daily food consumption is determined by the daily food consumed normalized to daily body weight of the subject.

[0465] In some embodiments, the subject comprises two or more subjects, and the food consumption is an average food consumption (e.g., average daily food consumption, average weekly food consumption) of the two or more subjects. In some embodiments, the subject comprises at least 3 subjects, and the food consumption is an average food consumption of the at least 3 subjects. In some embodiments, the subject comprises at least 4 subjects, and the food consumption is an average food consumption of the at least 4 subjects. In some embodiments, the subject comprises at least 5 subjects, and the food consumption is an average food consumption of the at least 5 subjects. In some embodiments, the subject comprises at least 6 subjects, and the food consumption is an average food consumption of the at least 6 subjects. In some embodiments, the subject -112- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 comprises at least 7 subjects, and the food consumption is an average food consumption of the at least 7 subjects. In some embodiments, the subject comprises at least 8 subjects, and the food consumption is an average food consumption of the at least 8 subjects. In some embodiments, the subject comprises at least 9 subjects, and the food consumption is an average food consumption of the at least 9 subjects. In some embodiments, the subject comprises at least 10 subjects, and the food consumption is an average food consumption of the at least 10 subjects. The subject may comprise e.g., at least 10, 15, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1,000, 2,500, or 5,000 subjects, and the food consumption is an average food consumption of the at least 10, 15, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1,000, 2,500, or 5,000 subjects.

[0466] In some embodiments, the method prevents or alleviates anorexia in the subject.

[0467] In any of the foregoing aspects, anorexia is determined by food consumption. In some embodiments, anorexia is determined by daily food consumption, and / or weekly food consumption. In some embodiments, anorexia is determined by cumulative food consumption for at least 2 days, at least 5 days, at least 7 days, at least 14 days, or at least 21 days, after the administration.

[0468] In some embodiments, the method prevents or alleviates nausea, emesis, or both, in the subject.

[0469] In any of the foregoing aspects, the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent. In any of the foregoing aspects, the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non- naturally occurring melanocortin analog and / or the anti-cancer agent. In some embodiments, the method lowers the ECOG scale of the subject. In some embodiments, the method lowers the ECOG scale of the subject by at least 10%, 25%, 50%, or 100%.

[0470] In any of the foregoing aspects, the subject’s Karnofsky performance status scale is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent. In any of the foregoing aspects, the subject’s Karnofsky -113- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 performance status scale is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent. In some embodiments, the method increases the subject’s Karnofsky performance status scale. In some embodiments, the method increases the subject’s Karnofsky performance status scale by at least 10%, 25%, 50%, or 100%.

[0471] In some embodiments, a reduced or maintained Eastern Cooperative Oncology Group (ECOG) performance status score of the subject may result during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the ECOG performance status score of the subject is about grade 0, 1, 2, 3 before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the ECOG performance status score reduces by a score of about 1, 2, or 3 during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the ECOG performance status score reduces by a score of at least 1, 2, or 3 during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the ECOG performance status score reduces by a score of at least about 1, 2, or 3 during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, an increased or maintained Karnofsky Performance Status (KPS) grade of the subject may result during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the KPS grade of the subject is about grade 100, 90, 80, 70, 60, 50, 40, or 30 before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the KPS grade increases by a score of about 10, 20, 30, 40, 50, 60, or 70 during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the KPS grade increases by a score of at least 10, 20, 30, 40, 50, 60, or 70 during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the KPS grade increases by a score of at least about 10, 20, 30, 40, 50, 60, or 70 during or after administration of the non- naturally occurring melanocortin analog.

[0472] In some embodiments, the non-naturally occurring melanocortin analog is administered before the anti-cancer agent. For example, the non-naturally occurring melanocortin analog may be administered to the subject having cancer before the subject is -114- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 administered an anti-cancer agent. When administered to the subject having cancer prior to administration of an anti-cancer agent, the subject may be pretreated or preloaded with a non-naturally occurring melanocortin analog for a duration of time, including 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 12 months, or more than 12 months. By pretreating or preloading the subject with the non-naturally occurring melanocortin analog, the subject experiences mass gain (e.g., fat mass, lean muscle mass, etc.), appetite increase, ECOG score increase, KPS improvement, reduction in risk of iatrogenic injury, or other beneficial outcomes due to the non-naturally occurring melanocortin analog prior to receiving the anti- cancer agent. In these embodiments, the preloaded subject may exhibit decreased and / or delayed side-effects of the anti-cancer agent or no side-effects of the anti-cancer agent compared to a subject not preloaded with the non-naturally occurring melanocortin analog.

[0473] In some embodiments, the non-naturally occurring melanocortin analog may be administered to the subject during an anti-cancer agent therapeutic regimen where the subject has or has not received at least a first dose of the anti-cancer agent prior to administration of the non-naturally occurring melanocortin analog. In embodiments where a non-naturally occurring melanocortin analog is administered during or after administration of the anti-cancer agent therapeutic regimen, the subject may or may not be preloaded with the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is co-administered with the anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered after the anti- cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is present in a first pharmaceutical composition and the anti-cancer agent is present in a second pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog and the anti-cancer agent are present in a single pharmaceutical composition.

[0474] In some embodiments, the anti-cancer agent is administered to a subject for treating or preventing one of one or more cancers, including, but not limited to, bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, -115- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma. In some embodiments, the subject has more than one cancer, is at risk for developing more than one cancers, or has symptoms of more than one cancer.

[0475] In some embodiments, the subject has one or more or a cancer, an autoimmune disease, a hematological disorder, an immune system disorder, a need for an organ transplant, a rheumatic disease, a dermatological condition, or a rare disease, including, but not limited to: Wegener’s granulomatosis or eosinophilic granulomatosis with polyangiitis. In some embodiments, the chemotherapeutic agent is useful in treating any one of these diseases or conditions.

[0476] In some embodiments, the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis. In some embodiments, the hematological disorder is an abnormal cell proliferation or dysfunction in the blood or bone marrow, immune thrombocytopenia, or autoimmune hemolytic anemia. In some embodiments, the need for an organ transplant includes a subject receiving a transplant or undergoing conditioning for a transplant.

[0477] In some embodiments, the cancer is at risk of metastasis, has metastasized, or is metastasizing. In some embodiments, the cancer is a Stage 0 cancer, a Stage I cancer, a Stage II cancer, a Stage III cancer, or a Stage IV cancer. In some embodiments, the subject has received or is receiving radiation therapy for at least one cancer. In some embodiments, the subject has received or is receiving a surgical intervention related to at least one cancer. In some embodiments, the subject is administered an anti-cancer agent or a non-naturally occurring melanocortin analog before, during, or after radiation therapy. In some embodiments, the subject is administered an anti-cancer agent or a non-naturally occurring melanocortin analog before, during, or after a surgical intervention. In some embodiments, the subject does not receive radiation therapy. In some embodiments, the subject does not receive surgical intervention.

[0478] In some embodiments, the subject has received or is receiving nutritive therapy or a nutrition supplement. In some embodiments, the subject has received or is receiving an -116- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 antiemetic. In some embodiments, the antiemetic is ondansetron, granisetron, dolasetron, palonosetron, metoclopramide, prochlorperazine, promethazine, droperidol, dimenhydrinate, cyclizine, meclizine, scopolamine, aprepitant, fosaprepitant, netupitant, olanzapine, dexamethasone, lorazepam, ginger, dronabinol, marijuana, and tetrahydrocannabinol. In some embodiments, the subject has received or is receiving a therapeutic for preventing cancer associated wasting. In some embodiments, the therapeutic for preventing cancer associated wasting is a corticosteroid, testosterone, testosterone cypionate, etanercept, formoterol, formoterol fumarate, dronabinol, Marinol, medroxyprogesterone, medroxyprogesterone acetate, Megace ES, megesterol, megesterol acetate suspension, oxandrolone, prednisone, ghrelin receptor agonists, a selective androgen receptor modulator (SARM), a selective androgen receptor degraders (SARD), anamorelin, omega-3 fatty acids, thalidomide, pentoxifylline, a nonsteroidal anti- inflammatory drug (NSAID), cyproheptadine, progestogens, metformin, branched-chain amino acids, eicosapentaenoic acid (EPA), coenzyme Q10, melatonin, dexamethasone, and creatine. In some embodiments, the subject has failed or is failing to response adequately to a nutritive therapy, a nutrition supplement, an antiemetic, or a therapeutic for preventing cancer associated wasting.

[0479] In some embodiments, administration of the anti-cancer agent is associated with one or more side effects. In some embodiments, the administration of the anti-cancer agent and the non-naturally occurring melanocortin analog reduces one or more of these side effects. Nonlimiting examples of the one or more side effects may include nausea, emesis (i.e., vomiting), anorexia (e.g., decreasing food intake, decreasing appetite), cachexia, weight loss, fatigue, fat mass loss, and muscle mass loss. Other side effects include, but are not limited to, cytopenia (e.g., anemia (low red blood cell counts), myelosuppression, infection, mucositis, alopecia (hair loss), easy bruising and bleeding, cutaneous complications, such as pruritis, urticaria, and angioedema, constipation, diarrhea, neurological complications (e.g., chemo brain, mood changes), pulmonary and cardiac complications (e.g., cardiac toxicity) especially in patients receiving chemotherapy and / or radiation, and reproductive and endocrine complications. Cachexia may include, but is not limited to, one or more of the foregoing side effects and one or more of the foregoing side- effects may occur in the absence of cachexia. -117- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0480] In any of the foregoing aspects, the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent. In some embodiments, the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog. In some embodiments, the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

[0481] In any of the foregoing aspects, the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti- cancer agent. In some embodiments, the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0482] In any of the foregoing aspects, the subject may have been administered or is being administered an antiemetic. In other aspects, the subject has not received an antiemetic. In certain aspects, the subject received an antiemetic but failed to respond adequately. In some embodiments, the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

[0483] In some embodiments, the baseline or control is the subject before receiving the non-naturally occurring melanocortin analog. In some embodiments, the baseline or control is a subject receiving an anti-cancer agent without administration of the non-naturally occurring melanocortin analog. In some embodiments, the baseline or control is a subject after receiving an anti-cancer agent without administration of the non-naturally occurring melanocortin analog. In some embodiments, the baseline or control is a second subject that -118- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 has not received the non-naturally occurring melanocortin analog. In some embodiments, the second subject has received or is receiving an anti-cancer agent.

[0484] In some embodiments, the subject administered the non-naturally occurring melanocortin analog prior to, during administration of, and / or after administration of the anti- cancer agent exhibits one or more of (a) an increase in body weight compared to baseline or control; (b) an increase in muscle mass compared to baseline or control; (c) an increase in fat mass compared to baseline or control; (d) an increase in cardiac mass compared to baseline or control; (e) an increase in bone density compared to baseline or control; (f) an increase in appetite compared to baseline or control; (g) a reduction in fatigue compared to baseline or control; (h) a reduction in vomiting compared to baseline or control; and (i) a reduction in diarrhea compared to baseline or control.

[0485] In some embodiments, the subject administered the non-naturally occurring melanocortin analog and the anti-cancer agent exhibits one or more of (a) an increase in body weight by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline or control; (b) an increase in muscle mass by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (c) an increase in fat mass by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline or control; -119- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (d) an increase in cardiac mass by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline or control; (e) an increase in bone density by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to baseline or control; (f) an increase in appetite as measured by an increased food intake (by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline or control; (g) a reduction in fatigue compared to baseline or control; (h) a reduction in vomiting compared to baseline or control; (i) a reduction in diarrhea compared to baseline or control; (j) a decrease in tumor size by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to control; (k) a decrease in cancer metastasis as measured by a decrease in cancer cell proliferation by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to control; (l) a maintenance in ECOG score or a reduction in ECOG score by about 1, 2, or 3 compared to baseline or control; and (m) a maintenance in KPS score or an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

[0486] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell -120- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.

[0487] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

[0488] In some embodiments, the cancer is breast cancer, and the chemotherapy is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the taxane is paclitaxel.

[0489] In some embodiments, the cancer is lung cancer, and the chemotherapy is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin- bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.

[0490] In some embodiments, the cancer is prostate cancer, and the chemotherapy is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.

[0491] In some embodiments, the chemotherapy is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0492] In some embodiments, the subject is receiving radiation therapy, and the chemotherapy is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

[0493] In some embodiments, the subject is not receiving radiation therapy, and the chemotherapy is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.

[0494] In some embodiments, the cancer is melanoma, and the chemotherapy is dacarbazine and / or temozolomide. -121- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0495] In some embodiments, the cancer is non-Hodgkin's lymphoma, and the chemotherapy is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin. Cisplatin

[0496] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent is a platinum-based chemotherapy. In some embodiments, the platinum-based chemotherapy is cisplatin.

[0497] In some embodiments, cisplatin is administered hourly, daily, weekly, biweekly, monthly, or bimonthly. In some embodiments, cisplatin is administered through continuous infusion. In some embodiments, cisplatin is administered per cycle at a dose of about 5 mg / m IV to about 1000 mg / m IV. In some embodiments, cisplatin is administered per cycle at a dose of at least 5 mg / m IV to at least 1000 mg / m IV. In some embodiments, cisplatin is administered per cycle at a dose of at least about 5 mg / m IV to at least about 1000 mg / m IV. In some embodiments, cisplatin is administered at a dose of about 0.5 mg / m2per cycle to about 1000 mg / m2per cycle. In some embodiments, cisplatin is administered at a dose of at least 0.5 mg / m2per cycle to at least 1000 mg / m2per cycle. In some embodiments, cisplatin is administered at a dose of at least about 0.5 mg / m2per cycle to at least about 1000 mg / m2per cycle.

[0498] In some embodiments, cisplatin is administered a dose of about 20 mg / m IV daily for 5 days per cycle. In some embodiments, cisplatin is administered at a dose of 75 to 100 mg / m IV per cycle once every 4 weeks. In some embodiments, cisplatin is administered at a dose of 600 mg / m IV once every 4 weeks. In some embodiments, cisplatin is administered at a dose of 100 mg / m IV per cycle once every 4 weeks. In some embodiments, cisplatin is administered at a dose of 50 to 70 mg / m IV per cycle once every 3 to 4 weeks. In some embodiments, cisplatin is administered at a dose of 50 mg / m per cycle repeated every 4 weeks. -122- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0499] In some embodiments, administration of cisplatin is associated with one or more symptoms selected from the group consisting of vomiting, nausea, anorexia, fatigue, diarrhea, weight loss, fat mass loss, muscle mass loss, cardiac muscle loss, and general weakness. In some embodiments, nausea or vomiting may begin within 1 minute to 24 hours after administration of cisplatin. In some embodiments, nausea or vomiting lasts up to 1 hour to one week after administration of cisplatin. In some embodiments, nausea or vomiting beings or persists 1 minute to one week after administration of cisplatin. In some embodiments, the administration of cisplatin and a non-naturally occurring melanocortin analog reduces or prevents one or more of these symptoms.

[0500] In some embodiments, nausea or vomiting may begin within 1 to 4 hours after administration of cisplatin. In some embodiments, nausea or vomiting lasts up to 24 to 28 hours after administration of cisplatin. In some embodiments, nausea or vomiting begins or persists 24 hours or more after administration of cisplatin. In some embodiments, various degrees of vomiting, nausea and / or anorexia may persist for a week after administration of cisplatin. In some embodiments, the administration of cisplatin and a non-naturally occurring melanocortin analog reduces or prevents one or more of these symptoms.

[0501] In some embodiments, cisplatin is administered before, during, or after administration of a non-naturally occurring melanocortin analog. In some embodiments, cisplatin is administered at a dose of about 0.5 mg / m2per cycle to about 1000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog.

[0502] In some embodiments, cisplatin is administered at a dose of at least 0.5 mg / m2per cycle to at least 1000 mg / m2per cycle before, during, or after administration of the non- naturally occurring melanocortin analog.

[0503] In some embodiments, cisplatin is administered at a dose of at least about 0.5 mg / m2per cycle to at least about 1000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog.

[0504] In some embodiments, cisplatin is administered at a dose of about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, -123- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 600, 650, 700, 750, 800, 850, 900, or mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog.

[0505] In some embodiments, cisplatin is administered at a dose of at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog.

[0506] In some embodiments, cisplatin is administered at a dose of at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or 1000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog.

[0507] In some embodiments, the cisplatin is administered hourly, daily, every 2 days, every 3 days, every 4 days, every 5 days, once a week, once every 2 weeks, once every 3 weeks, or once every four weeks.

[0508] In some embodiments, the cisplatin is administered by continuous 1-hour, 2- hour, 3-hour, 4-hour, 5-hour, 6-hour, 7-hour, 8-hour, 9-hour, 10-hour, 12-hour, 14-hour, 16- hour, 18-hour, 20-hour, 22-hour, 24-hour, 36-hour, or 72-hour infusion.

[0509] In some embodiments, the subject has received one or more of a nutritive therapy, a nutritional supplement, an antiemetic, or a therapeutic for preventing cancer associated wasting before during, or after administration of cisplatin or the non-naturally occurring melanocortin analog.

[0510] In some embodiments, the subject administered the non-naturally occurring melanocortin analog before, during, or after administration of the cisplatin exhibits one or more of a reduction in vomiting or nausea compared to baseline or control, a reduction in gastrointestinal side effects that are not vomiting or nausea compared to baseline or control, a reduction in asthenia compared to baseline or control, a reduction in anorexia compared to baseline or control, an increase in appetite compared to baseline or control, a reduction in fatigue compared to baseline or control, a reduction in diarrhea compared to baseline or control, an increase in body weight compared to baseline or control, a reduced rate of weight loss compared to baseline or control, an increase in skeletal muscle mass compared to -124- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 baseline or control, a reduced rate of loss of skeletal muscle mass compared to baseline or control, an increase in cardiac muscle mass compared to baseline or control, a reduced rate of loss of cardiac muscle mass compared to baseline or control, an increase in fat mass compared to baseline or control, a reduced rate of loss of fat mass compared to baseline or control, an increase in bone density compared to baseline or control, a reduction in rate of loss of bone density compared to baseline or control, a reduction in general weakness compared to baseline or control, a reduction of ECOG performance score compared to baseline or control, a maintenance in ECOG performance score, an increase in KPS score compared to baseline or control, a maintenance in KPS score, no titration of cisplatin treatment, a reduced titration of cisplatin treatment compared to baseline or control, or a reduction in iatrogenic injury.

[0511] In some embodiments, the subject administered the non-naturally occurring melanocortin analog before, during, or after administration of the cisplatin exhibits one or more of (a) a reduction in the onset of vomiting or nausea compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; (b) a reduction in the duration of vomiting or nausea compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 48 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days after cisplatin administration; (c) a reduction in the onset of abdominal discomfort or pain compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; (d) a reduction in the duration of abdominal discomfort or pain compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, -125- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 48 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days after cisplatin administration; (e) a reduction in the onset of hemorrhagic colitis compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; (f) a reduction in the duration of hemorrhagic colitis compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; (g) a reduction in asthenia compared to baseline or control compared to control within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after cisplatin administration; (h) a reduction in general physical deterioration to baseline or control compared to control measured by an increase in body mass index by about 0.25, 0.5, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.26, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, or 10 or more; (i) a reduction in the onset of influenza-like illness or chills about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; (j) a reduction in the duration of influenza-like illness or chills about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after cisplatin administration; -126- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (k) a reduction in anorexia compared to baseline or control measured by an increase in body mass index by about 0.25, 0.5, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.26, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, or 10 or more; (l) an increase in appetite compared to baseline or control, which may be measured by an increase in calorie consumption by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more; (m) a reduction in fatigue compared to baseline or control, which may be measured by an increase in perceived energy or reduced energy expenditure about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after cisplatin administration; (n) a reduction in diarrhea compared to baseline or control about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after cisplatin administration; (o) an increase in body weight compared to baseline or control measured by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (p) a reduced rate of weight loss compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; -127- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (q) an increase in skeletal mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (r) a reduction in rate of loss of skeletal mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (s) an increase in cardiac mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (t) a reduction in rate of loss of cardiac mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (u) an increase in fat mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (v) a reduction in rate of loss of fat mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (w) an increase in bone density compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (x) a reduction in rate of loss of bone density compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (y) a reduction in general weakness compared to baseline or control as measured by an increase perceived or exerted force without increased energy expenditure about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 -128- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after administration of cisplatin; (z) a maintenance in ECOG performance score or a reduction in ECOG performance score compared to baseline or control by about 1, 2, or 3; (aa) a maintenance in KPS score or an increase in KPS score compared to baseline or control by about 100, 90, 80, 70, 60, 50, 40, or 30; (bb) a reduction in titration of cisplatin treatment by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to baseline or control; (cc) an increase in tolerance of administered dose of cisplatin treatment compared to baseline or control by about 1 mg / m2, 2 mg / m2, 5 mg / m2, 10 mg / m2, 25 mg / m2, 50 mg / m2, 75 mg / m2, 100 mg / m2, 150 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 350 mg / m2, 400 mg / m2, 450 mg / m2, 500 mg / m2, 600 mg / m2, 700 mg / m2, 800 mg / m2, 900 mg / m2, 1000 mg / m2; (dd) an increase in frequency of administration of cisplatin treatment compared to baseline or control by about 1 hour, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months; and (ee) a reduction in iatrogenic injury by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to baseline or control.

[0512] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent is a platinum-based chemotherapy. In some embodiments, the platinum-based chemotherapy is carboplatin.

[0513] In some embodiments, carboplatin is administered hourly, daily, weekly, biweekly, monthly, or bimonthly. In some embodiments, carboplatin is administered through continuous infusion. In some embodiments, carboplatin is administered per cycle at a dose of about 5 mg / m IV to about 2000 mg / m IV. In some embodiments, carboplatin is administered per cycle at a dose of at least 5 mg / m IV to at least 2000 mg / m IV. In some -129- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 embodiments, carboplatin is administered per cycle at a dose of at least about 5 mg / m IV to at least about 2000 mg / m IV. In some embodiments, carboplatin is administered at a dose of about 0.5 mg / m2per cycle to about 2000 mg / m2per cycle. In some embodiments, carboplatin is administered at a dose of at least 0.5 mg / m2per cycle to at least 2000 mg / m2per cycle. In some embodiments, carboplatin is administered at a dose of at least about 0.5 mg / m2per cycle to at least about 2000 mg / m2per cycle.

[0514] In some embodiments, carboplatin is administered a dose of about 200 mg / m2, 250 mg / m2, 300 mg / m2, 360 mg / m2. In some embodiments, the carboplatin is administered every 4 weeks. In some embodiments, the carboplatin is administered every 4 weeks for 6 cycles. In some embodiments, carboplatin is administered more than once when the neutrophil count of the subject is at least about 2,000 or the platelet count is at least about 100,000. In some embodiments, the carboplatin is administered with carboplatin or cyclophosphamide.

[0515] In some embodiments, administration of carboplatin is associated with one or more symptoms selected from the group consisting of vomiting, nausea, gastrointestinal side effects that are not vomiting or nausea, electrolyte loss in one or more electrolytes, asthenia, anorexia, fatigue, diarrhea, weight loss, fat mass loss, muscle mass loss, cardiac muscle loss, and general weakness. In some embodiments, nausea or vomiting may begin within 1 minute to 24 hours after administration of carboplatin. In some embodiments, nausea or vomiting lasts up to 1 hour to one week after administration of carboplatin. In some embodiments, nausea or vomiting beings or persists 1 minute to one week after administration of carboplatin. In some embodiments, the administration of carboplatin and a non-naturally occurring melanocortin analog reduces or prevents one or more of these symptoms.

[0516] In some embodiments, nausea or vomiting may begin within 1 to 24 hours after administration of carboplatin. In some embodiments, nausea or vomiting lasts up to 1 hour to 24 hours after administration of carboplatin. In some embodiments, nausea or vomiting begins or persists 24 hours or more after administration of carboplatin. In some embodiments, the administration of carboplatin and a non-naturally occurring melanocortin analog reduces or prevents one or more of these symptoms. -130- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00

[0517] In some embodiments, carboplatin is administered before, during, or after administration of a non-naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of about 5 mg / m2per cycle to about 2000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of at least 5 mg / m2per cycle to at least 2000 mg / m2per cycle before, during, or after administration of the non- naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of at least about 5 mg / m2per cycle to at least about 2000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, carboplatin is administered at a dose of at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or 1000 mg / m2per cycle before, during, or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the carboplatin is administered hourly, daily, every 2 days, every 3 days, every 4 days, every 5 days, once a week, once every 2 weeks, once every 3 weeks, or once every four weeks. In some embodiments, the carboplatin is administered by continuous 1-hour, 2-hour, 3-hour, 4-hour, 5-hour, 6-hour, 7-hour, 8-hour, 9-hour, 10-hour, 12-hour, 14-hour, 16-hour, 18-hour, 20- hour, 22-hour, 24-hour, 36-hour, or 72-hour infusion. In some embodiments, carboplatin is administered by daily pulse doses. In some embodiments, the subject has received one or more of a nutritive therapy, a nutritional supplement, an antiemetic, or a therapeutic for preventing cancer associated wasting before during, or after administration of carboplatin or the non-naturally occurring melanocortin analog.

[0518] In some embodiments, the subject administered the non-naturally occurring melanocortin analog before, during, or after administration of the carboplatin exhibits one or -131- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 more of a reduction in vomiting or nausea compared to baseline or control, a reduction in gastrointestinal side effects that are not vomiting or nausea compared to baseline or control, a reduction in asthenia compared to baseline or control, a reduction in anorexia compared to baseline or control, an increase in appetite compared to baseline or control, a reduction in fatigue compared to baseline or control, a reduction in diarrhea compared to baseline or control, an increase in body weight compared to baseline or control, a reduced rate of weight loss compared to baseline or control, an increase in skeletal muscle mass compared to baseline or control, a reduced rate of loss of skeletal muscle mass compared to baseline or control, an increase in cardiac muscle mass compared to baseline or control, a reduced rate of loss of cardiac muscle mass compared to baseline or control, an increase in fat mass compared to baseline or control, a reduced rate of loss of fat mass compared to baseline or control, an increase in bone density compared to baseline or control, a reduction in rate of loss of bone density compared to baseline or control, a reduction in general weakness compared to baseline or control, a reduction of ECOG performance score compared to baseline or control, a maintenance in ECOG performance score, an increase in KPS score compared to baseline or control, a maintenance in KPS score, no titration of carboplatin treatment, A reduced titration of carboplatin treatment compared to baseline or control, or a reduction in iatrogenic injury.

[0519] In some embodiments, the subject administered the non-naturally occurring melanocortin analog before, during, or after administration of the carboplatin exhibits one or more of (a) a reduction in the onset of vomiting or nausea compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (b) a reduction in the duration of vomiting or nausea compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 48 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days after carboplatin administration; -132- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (c) a reduction in the onset of abdominal discomfort or pain compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (d) a reduction in the duration of abdominal discomfort or pain compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 48 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days after carboplatin administration; (e) a reduction in the onset of hemorrhagic colitis compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (f) a reduction in the duration of hemorrhagic colitis compared to baseline or control about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (g) a reduction in asthenia compared to baseline or control compared to control within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after carboplatin administration; (h) a reduction in general physical deterioration to baseline or control compared to control measured by an increase in body mass index by about 0.25, 0.5, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.26, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, or 10 or more; (i) a reduction in the onset of influenza-like illness or chills about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, -133- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (j) a reduction in the duration of influenza-like illness or chills about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours after carboplatin administration; (k) a reduction in anorexia compared to baseline or control measured by an increase in body mass index by about 0.25, 0.5, 1.0, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.26, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, or 10 or more; (l) an increase in appetite compared to baseline or control, which may be measured by an increase in calorie consumption by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more; (m) an reduction in fatigue compared to baseline or control, which may be measured by an increase in perceived energy or reduced energy expenditure about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after carboplatin administration; (n) a reduction in diarrhea compared to baseline or control about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after carboplatin administration; -134- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (o) an increase in body weight compared to baseline or control measured by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (p) a reduced rate of weight loss compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (q) an increase in skeletal mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (r) a reduction in rate of loss of skeletal mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (s) an increase in cardiac mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (t) a reduction in rate of loss of cardiac mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (u) an increase in fat mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (v) a reduction in rate of loss of fat mass compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (w) an increase in bone density compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; -135- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 (x) a reduction in rate of loss of bone density compared to baseline or control by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%; (y) a reduction in general weakness compared to baseline or control as measured by an increase perceived or exerted force without increased energy expenditure about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, or about 2 weeks after administration of carboplatin; (z) a maintenance in ECOG performance score or a reduction in ECOG performance score compared to baseline or control by about 1, 2, or 3; (aa) a maintenance in KPS score or an increase in KPS score compared to baseline or control by about 100, 90, 80, 70, 60, 50, 40, or 30; (bb) a reduction in titration of carboplatin treatment by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to baseline or control; (cc) an increase in tolerance of administered dose of carboplatin treatment compared to baseline or control by about 1 mg / m2, 2 mg / m2, 5 mg / m2, 10 mg / m2, 25 mg / m2, 50 mg / m2, 75 mg / m2, 100 mg / m2, 150 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 350 mg / m2, 400 mg / m2, 450 mg / m2, 500 mg / m2, 600 mg / m2, 700 mg / m2, 800 mg / m2, 900 mg / m2, 1000 mg / m2, 1250 mg / m2, 1500 mg / m2, 1750 mg / m2, or 2000 mg / m2or more; (dd) an increase in frequency of administration of cisplatin treatment compared to baseline or control by about 1 hour, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months; and (ee) a reduction iatrogenic injury by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to baseline or control. -136- 146316.8005.WO00\165317095.7Attorney Docket No.146316.8005.WO00 Cyclophosphamide

[0520] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent is an antineoplastic. In some embodiments, the antineoplastic is cyclophosphamide.

[0521] In some embodiments, cyclophosphamide is administered hourly, daily, weekly, biweekly, monthly, or bimonthly. In some embodiments, cyclophosphamide is administered per cycle at a dose of about 0.5 mg / kg to about 20 mg / kg per day. In some embodiments, cyclosphosphamide is administered per cycle at a dose of at least 0.5 mg / kg to at least 20 mg / kg. In some embodiments, cyclophosphamide is administered per cycle at a dose of at least about 0.5 mg / kg to at least about 20 mg / kg.

[0522] In some embodiments, cyclophosphamide is administered a dose of about 1 mg / kg per day.1.5 mg / kg per day, 2 mg / kg per day, 2.5 mg / kg per day, 3 mg / kg per day, 3.5 mg / kg per day, 4 mg / kg per day, 4.5 mg / kg per day, 5 mg / kg per day, 10 mg / kg per day, 15 mg / kg per day, or 20 mg / kg per day or more. In some embodiments, the cyclophosphamide is administered once daily. In some embodiments, the cyclophosphamidei s administered once daily for 8 to 12 weeks. In some embodiments, cyclophosphamide is administered at a maximum cumulative dose of 168 mg / kg. In some embodiments, cyclophosphamide is administered to a subject having neutrophils ≤1,500 / mm or platelets <50,000 / mm prior to administration of cyclophosphamide.

[0523] In some embodiments, administration of cyclophosphamide is associated with one or more symptoms selected from the group consisting of vomiting, nausea, abdominal discomfort or pain, hemorrhagic colitis, asthenia, general physical deterioration, influenza- like illness, cardiac function, anorexia, fatigue, diarrhea, weight loss, fat mass loss, muscle mass loss, cardiac muscle loss, and general weakness. In some embodiments, nausea or vomiting may begin within 1 minute to 24 hours after administration of cyclophosphamide. In some embodiments, nausea or vomiting lasts up to 1 hour to one week after administration of cyclosphosphamide. In some embodiments, nausea or vomiting beings or persists 1 minute to one week ...

Claims

AMENDED CLAIMS received by the International Bureau on 07 November 2024 (07.11 .2024) l / We claim:

1. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

2. A method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

3. A method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

4. The method of claim 2 or 3, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

5. A method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring360AMENDED SHEET (ARTICLE 19)melanocortin analog to the subject prior to, during, and / or after administration of the anticancer agent.

6. The method of claim 5, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

7. A method of preventing, reducing, or restoring weight loss induced by an anticancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

8. The method of claim 7, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

9. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

10. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.361AMENDED SHEET (ARTICLE 19)11 . The method of claim 10, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

12. A method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non- naturally occurring melanocortin analog to the subject.

13. A method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

14. A method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and / or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and a non- naturally occurring melanocortin analog to the subject.

15. The method of claim 14, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.

16. The method of claim 14, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

17. The method of claim 1 , wherein the method maintains or increases lean body mass, fat body mass, and / or weight of the subject.

18. The method of claim 5, wherein the method maintains or increases lean body mass, fat body mass, and / or body weight of the subject.362AMENDED SHEET (ARTICLE 19)19. The method of claim 9, wherein the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

20. The method of claim 10, wherein the nutritional intervention further comprises nutritional supplementation.

21. The method of claim 12, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

22. The method of claim 13, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

23. The method of claim 14, wherein the ECOG score and / or KPS score is improved, maintained, and / or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

24. The method of any one of claims 1-10, wherein the subject has a cancer.

25. The method of any one of claims 1-14, wherein the anti-cancer agent comprises a chemotherapy.

26. The method of claim 25, wherein the method reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject.363AMENDED SHEET (ARTICLE 19)27. The method of claim 25, wherein the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject.

28. The method of any one of claims 1 -14, wherein the anorexia is associated with weight loss.

29. The method of any one of claims 1-14, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

30. The method of claim 29, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

31. The method of claim 29, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

32. The method of any one of claims 1-14, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent.

33. The method of claim 32, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin364AMENDED SHEET (ARTICLE 19)analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

34. The method of any one of claims 1-14, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

35. The method of claim 34, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by a cancer.

36. The method of claim 34, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

37. The method of any one of claims 1-14, wherein the subject is receiving an antiemetic.

38. The method of claim 37, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

39. The method of any one of claims 1-14, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

40. The method of any one of claims 1-14, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

41. The method of claim 1 , wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

42. The method of claim 2, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing365AMENDED SHEET (ARTICLE 19)anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

43. The method of claim 3, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

44. The method of claim 5, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject.

45. The method of claim 7, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.

46. The method of claim 9, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment.

47. The method of claim 10, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention.

48. The method of claim 12, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject.

49. The method of claim 13, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject.366AMENDED SHEET (ARTICLE 19)50. The method of claim 14, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and / or Karnofsky performance status score of the subject.

51. The method of any one of claims 1-14, wherein the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

52. The method of any one of claims 1-14, wherein the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and / or the anti-cancer agent.

53. The method of any one of claims 1 -14, wherein the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

54. The method of any one of claims 1 -14, wherein the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

55. The method of claim 53 or 54, wherein the method lowers the ECOG scale of the subject.

56. The method of any one of claims 1-14, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

57. The method of any one of claims 1-14, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.367AMENDED SHEET (ARTICLE 19)58. The method of claim 56 or 57, wherein the method increases the subject’s KPS score.

59. The method of any one of claims 1-58, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine,368AMENDED SHEET (ARTICLE 19)para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;R10is absent or is lysine;R11-R20are absent;X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;369AMENDED SHEET (ARTICLE 19)Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine;370AMENDED SHEET (ARTICLE 19)provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.

60. The method of any one of claims 1-59, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.

61. The method of any one of claims 1-59, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

62. The method of claim 25, wherein the chemotherapy comprises at least one chemotherapeutic agent.

63. The method of claim 62, wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.371AMENDED SHEET (ARTICLE 19)64. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.

65. The method of claim 63, wherein the at least one chemotherapeutic agent comprises an antimetabolite.

66. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

67. The method of claim 63, wherein the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.

68. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.

69. The method of claim 64, wherein the platinum-coordination complex is carboplatin and / or cisplatin.

70. The method of claim 65, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.71 . The method of claim 66, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

72. The method of claim 67, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine,372AMENDED SHEET (ARTICLE 19)cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

73. The method of claim 68, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

74. The method of claim 64, wherein the platinum-coordination complex is cisplatin.

75. The method of claim 74, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

76. The method of claim 65, wherein the antimetabolite is 5-fluorouracil (5-FU).

77. The method of claim 76, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

78. The method of claim 66, wherein the tubulin binding agent or the plant alkaloid is vincristine.

79. The method of claim 67, wherein the alkylating antineoplastic agent is cyclophosphamide.

80. The method of claim 68, wherein the cytotoxic antibiotic is doxorubicin.

81. The method of claim 80, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.373AMENDED SHEET (ARTICLE 19)82. The method of any one of claims 12-14, or 24, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.

83. The method of any one of claims 12-14, or 24, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

84. The method of any one of claims 12-14, or 24, wherein the cancer is breast cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.

85. The method of claim 84, wherein the anthracycline is doxorubicin.

86. The method of claim 84, wherein the taxane is paclitaxel.

87. The method of any one of claims 12-14, or 24, wherein the cancer is lung cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.

88. The method of any one of claims 12-14, or 24, wherein the cancer is prostate cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.374AMENDED SHEET (ARTICLE 19)89. The method of any one of claims 1 -88, wherein the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

90. The method of any one of claims 1-88, wherein the subject is receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

91. The method of any one of claims 1-88, wherein subject is not receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.

92. The method of any one of claims 1-88, wherein the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and / or temozolomide.

93. The method of any one of claims 12-14, or 24, wherein the cancer is nonHodgkin's lymphoma, and wherein the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.

94. The method of any one of claims 1-93, wherein the method does not reduce efficacy of the anti-cancer agent.

95. The method of any one of claims 1-94, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.375AMENDED SHEET (ARTICLE 19)96. The method of claim 95, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

97. The method of any one of claims 1-96, wherein the subject is a human.

98. The method of any one of claims 1-96, wherein the subject is an animal.

99. The method of any one of claims 1-3, 8-10, 21 -23, 42, 43, or 96, wherein the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.

100. The method of claim 99, wherein the cardiac muscle mass loss is determined by measuring change in heart weight.101 . The method of claim 99, wherein the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

102. The method of any one of claims 1-3, 9, 10, 21-23, 42, 43, 74, or 96, wherein anorexia is determined by daily food intake, daily food consumption, and / or weekly food intake.

103. The method of claim 102, wherein the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

104. The method of claim 102, wherein the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.

105. The method of claim 102, wherein the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.376AMENDED SHEET (ARTICLE 19)106. The method of any one of claims 1-3, 8-10, 21 -23, 42, 43, or 96, wherein the weight loss is determined by daily body weight, and / or daily body weight gain.

107. The method of any one of claims 1-106, wherein the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non- naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

108. The method of any one of claims 1 -106, wherein the heart weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non- naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

109. The method of any one of claims 1-106, wherein the gastrocnemius tissue weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

110. The method of any one of claims 1-106, wherein the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

111. The method of any one of claims 1 -106, wherein the daily body weight of the subject treated with the method is at least 1 % to 15% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of377AMENDED SHEET (ARTICLE 19)the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

112. The method of any one of claims 1-106, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

113. The method of any one of claims 1-106, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

114. The method of claim 112 or 113, wherein appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.

115. The method of claim 112 or 113, wherein appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

116. The method of any one of claims 112-115, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

117. The method of any one of claims 112-116, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

118. The method of claim 117, wherein the appetite is assessed between meals.

119. The method of any one of claims 112-117, wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.378AMENDED SHEET (ARTICLE 19)120. The method of any one of claims 1-23, wherein anorexia is determined by food consumption.

121. The method of any one of claims 1-120, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

122. The method of claim 121 , wherein the pharmaceutical composition further comprises a pharmaceutical salt.

123. The method of claim 121 , wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

124. The method of claim 121 , wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the pharmaceutical composition.

125. The method of claim 124, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition.

126. The method of claim 125, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the pharmaceutical composition.

127. The method of claim 126, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

128. The method of any one of claims 1-14, wherein the non-naturally occurring379AMENDED SHEET (ARTICLE 19)melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

129. The method of any one of claims 121-127, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

130. The method of any one of claims 121-127, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

131. The method of any one of claims 1-130, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

132. The method of claim 123, wherein the pharmaceutical carrier comprises water.

133. The method of any one of claims 1-132, wherein the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.

134. The method of any one of claims 1-132, wherein the non-naturally occurring melanocortin analog is administered to a subject with a meal.

135. The method of any one of claims 1-134, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

136. The method of any one of claims 135, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.380AMENDED SHEET (ARTICLE 19)137. The method of any one of claims 1-134, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

138. The method of any one of claims 1-134, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

139. The method of claim 138, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

140. The method of claim 138, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

141. The method of any one of claims 1-140, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

142. The method of any one of claims 1-140, wherein the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

143. The method of any one of claims 1-142, wherein the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.381AMENDED SHEET (ARTICLE 19)144. The method of claim 143, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the single composition.

145. The method of claim 144, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the single composition.

146. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the single composition.

147. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg / mL, relative to a total volume of the single composition.

148. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

149. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

150. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5382AMENDED SHEET (ARTICLE 19)times, or 10 times per day.

151. The method of any one of claims 148-150, wherein the administration is performed once per day.

152. The method of any one of claims 1-142, wherein: the anti-cancer agent is present in a first pharmaceutical composition; and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.

153. The method of claim 152, wherein the first and the second pharmaceutical compositions are different and are administered sequentially.

154. The method of claim 152, wherein the first and the second pharmaceutical compositions are different and are administered simultaneously but separately.

155. The method of any one of claims 152-154, wherein the second pharmaceutical composition is administered subcutaneously.

156. The method of any one of claims 152-155, wherein anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1 ,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

157. The method of claim 156, wherein the chemotherapy is cisplatin, and cisplatin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

158. The method of claim 156, wherein the chemotherapy is 5-FU, and 5-FU is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the first pharmaceutical composition.383AMENDED SHEET (ARTICLE 19)159. The method of claim 156, wherein the chemotherapy is doxorubicin, and doxorubicin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50, relative to a total volume of the first pharmaceutical composition.

160. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the second pharmaceutical composition.

161. The method of claim 160, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the second pharmaceutical composition.

162. The method of claim 161 , wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the second pharmaceutical composition.

163. The method of claim 161 , wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the second pharmaceutical composition.

164. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

165. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is384AMENDED SHEET (ARTICLE 19)performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

166. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

167. The method of any one of claims 164-166, wherein the administration is performed once per day.

168. The method of claim 152, wherein the anti-cancer agent comprises cisplatin, and wherein cisplatin is administered orally and / or intraperitoneally.

169. The method of claim 152, wherein the anti-cancer agent comprises 5-FU, and wherein 5-FU is administered orally and / or intraperitoneally.

170. The method of claim 152, wherein the anti-cancer agent comprises doxorubicin, and wherein doxorubicin is administered intraperitoneally.

171. The method of claim 152, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

172. The method of any one of claims 152-171 , wherein a therapeutically effective amount of the anti-cancer agent is administered at least once per week.

173. The method of claim 172, wherein the anti-cancer agent comprises cisplatin, and the therapeutically effective amount of cisplatin is from 0.01 mg / kg to 25 mg / kg per body weight of the subject.

174. The method of claim 173, wherein the therapeutically effective amount of cisplatin is about 2.5 mg / kg per body weight of the subject.385AMENDED SHEET (ARTICLE 19)175. The method of claim 172, wherein the anti-cancer agent comprises 5-FU, and the therapeutically effective amount of 5-FU is from 0.1 mg / kg to 700 mg / kg per body weight of the subject.

176. The method of claim 175, wherein the therapeutically effective amount of 5- FU is about 70 mg / kg per body weight of the subject.

177. The method of claim 172, wherein the anti-cancer agent comprises doxorubicin, and the therapeutically effective amount of doxorubicin is from 0.005 mg / kg to 50mg / kg per body weight of the subject.

178. The method of claim 177, wherein the therapeutically effective amount of doxorubicin is about 2 mg / kg per body weight of the subject.

179. The method of any one of claims 172-178, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

180. The method of any one of claims 172-178, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

181. The method of claim 152, wherein the anti-cancer agent comprises cisplatin, and cisplatin is administered at a dose of 0.01 mg / kg to 25 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.

182. The method of claim 152, wherein the anti-cancer agent comprises 5-FU, and 5-FU is administered at a dose of 0.1 mg / kg to 700 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.386AMENDED SHEET (ARTICLE 19)183. The method of claim 152, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at a daily dose of 0.001 mg / kg to 25 mg / kg per body weight of the subject.

184. Use of a non-naturally occurring melanocortin analog to treat, prevent, or reduce one or more side effects associated with an anti-cancer agent in a subject, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, wherein the non- naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the anti-cancer agent185. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

186. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

187. The use of claim 185 or 186, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.387AMENDED SHEET (ARTICLE 19)188. Use of a non-naturally occurring melanocortin analog to maintain or increase muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent.

189. The use of claim 188, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

190. Use of a non-naturally occurring melanocortin analog to maintain or increase bone density in a subject prior to, during, and / or after administration of an anti-cancer agent.

191. The use of claim 190, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

192. Use of a non-naturally occurring melanocortin analog to stimulate appetite or reduce loss of appetite induced by an anti-cancer agent in a subject.

193. The use of claim 192, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

194. Use of a non-naturally occurring melanocortin analog for preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject.

195. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, the one or more side effects are selected from388AMENDED SHEET (ARTICLE 19)the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

196. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

197. Use of a non-naturally occurring melanocortin analog for preventing or reducing an anti-cancer agent induced side effect in a subject having cancer.

198. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer.

199. Use of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving ECOG score and / or KPS score of a subject having cancer relative to a baseline or a control.

200. The use of claim 199, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.

201. The use of claim 199, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

202. The use of claim 184, wherein the use maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.389AMENDED SHEET (ARTICLE 19)203. The use of claim 192, wherein the use maintains or increases lean body mass, fat body mass, and / or body weight of the subject relative to a baseline or a control.

204. The use of claim 195, wherein the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

205. The use of claim 196, wherein the nutritional intervention further comprises nutritional supplementation.

206. The use of claim 197, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.

207. The use of claim 198, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

208. The use of claim 199, wherein the improvement, maintenance, or prevented reduction of ECOG score and / or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

209. The use of any one of claims 184-208, wherein the subject has a cancer.

210. The use of any one of claims 184-209, wherein the anti-cancer agent comprises a chemotherapy.390AMENDED SHEET (ARTICLE 19)211. The use of claim 210, wherein the use reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

212. The use of claim 210, wherein the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the use reduces mass loss and / or wasting in the subject relative to a baseline or a control.

213. The use of any one of claims 184-199, wherein the anorexia is associated with weight loss.

214. The use of any one of claims 184-213, wherein the subject has not previously received an anti-cancer agent.

215. The use of any one of claims 184-213, wherein the subject has previously received an anti-cancer agent.

216. The use of any one of claims 184-213, wherein the subject is receiving an anticancer agent.

217. The use of any one of claims 184-216, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

218. The use of claim 217, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.391AMENDED SHEET (ARTICLE 19)219. The use of claim 217, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

220. The use of any one of claims 184-219, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.221 . The use of claim 220, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

222. The use of any one of claims 184-221 , wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

223. The use of claim 222, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by a cancer.

224. The use of claim 222, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

225. The use of any one of claims 184-224, wherein the subject is receiving or has received an antiemetic.

226. The use of claim 225, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.392AMENDED SHEET (ARTICLE 19)227. The use of any one of claims 184-226, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

228. The use of any one of claims 184-226, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

229. The use of claim 184, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

230. The use of claim 185, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

231. The use of claim 186, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

232. The use of claim 192, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.

233. The use of claim 194, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject relative to a baseline or a control.

234. The use of claim 195, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject393AMENDED SHEET (ARTICLE 19)who failed to respond clinically and / or therapeutically to an antiemetic treatment, relative to a baseline or a control.

235. The use of claim 196, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention, relative to a baseline or a control.

236. The use of claim 197, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject, relative to a baseline or a control.

237. The use of claim 198, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject, relative to a baseline or a control.

238. The use of claim 199, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and / or KPS score of the subject, relative to a baseline or a control.

239. The use of any one of claims 184-199, wherein the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

240. The use of any one of claims 184-199, wherein the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and / or the anti-cancer agent.241 . The use of any one of claims 184-240, wherein the subject has an ECOG score of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.394AMENDED SHEET (ARTICLE 19)242. The use of any one of claims 184-240, wherein the subject has an ECOG score of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

243. The use of claim 241 or 242, wherein the use lowers the ECOG score of the subject, relative to a baseline or a control.

244. The use of any one of claims 184-243, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

245. The use of any one of claims 184-243, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

246. The use of claim 244 or 245, wherein the use increases the subject’s KPS score relative to a baseline or control.

247. The use of any one of claims 184-246, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;395AMENDED SHEET (ARTICLE 19)R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;R10is absent or is lysine;396AMENDED SHEET (ARTICLE 19)R11-R20are absent;X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Y8is absent or is D-proline or D-valine;397AMENDED SHEET (ARTICLE 19)the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent398AMENDED SHEET (ARTICLE 19)248. The use of any one of claims 184-199, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.

249. The use of any one of claims 184-199, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

250. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

251. Use of a non-naturally occurring melanocortin analog for maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering the non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

252. Use of a non-naturally occurring melanocortin analog for maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering the non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.399AMENDED SHEET (ARTICLE 19)253. The use of claim 251 or 252, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

254. Use of a non-naturally occurring melanocortin analog for stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

255. The use of claim 254, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

256. Use of a non-naturally occurring melanocortin analog preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

257. The use of claim 256, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

258. A use of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side400AMENDED SHEET (ARTICLE 19)effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

259. A use of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

260. The use of claim 259, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

261. Use of a non-naturally occurring melanocortin analog preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.

262. Use of a non-naturally occurring melanocortin analog treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.

263. Use of a non-naturally occurring melanocortin analog preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and / or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.401AMENDED SHEET (ARTICLE 19)264. The use of claim 263, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.

265. The use of claim 263, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

266. The use of claim 250, wherein the use maintains or increases lean body mass, fat body mass, and / or weight of the subject.

267. The use of claim 254, wherein the use maintains or increases lean body mass, fat body mass, and / or body weight of the subject.

268. The use of claim 258, wherein the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

269. The use of claim 259, wherein the nutritional intervention further comprises nutritional supplementation.

270. The use of claim 261 , wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.271 . The use of claim 262, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

272. The use of claim 263, wherein the ECOG score and / or KPS score is improved, maintained, and / or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.402AMENDED SHEET (ARTICLE 19)273. The use of any one of claims 250-259, wherein the subject has a cancer.

274. The use of any one of claims 250-263, wherein the anti-cancer agent comprises a chemotherapy.

275. The use of claim 274, wherein the use reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject.

276. The use of claim 274, wherein the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the use reduces mass loss and / or wasting in the subject.

277. The use of any one of claims 250-263, wherein the anorexia is associated with weight loss.

278. The use of any one of claims 250-263, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

279. The use of claim 278, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

280. The use of claim 278, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.403AMENDED SHEET (ARTICLE 19)281 . The use of any one of claims 250-263, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent.

282. The use of claim 281 , wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

283. The use of any one of claims 250-263, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

284. The use of claim 283, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by a cancer.

285. The use of claim 283, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

286. The use of any one of claims 250-263, wherein the subject is receiving an antiemetic.

287. The use of claim 286, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

288. The use of any one of claims 250-263, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.404AMENDED SHEET (ARTICLE 19)289. The use of any one of claims 250-263, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

290. The use of claim 250, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

291. The use of claim 251 , wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

292. The use of claim 252, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

293. The use of claim 254, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject.

294. The use of claim 256, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.

295. The use of claim 258, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment.405AMENDED SHEET (ARTICLE 19)296. The use of claim 259, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention.

297. The use of claim 261 , wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject.

298. The use of claim 262, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject.

299. The use of claim298, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and / or Karnofsky performance status score of the subject.

300. The use of any one of claims 250-263, wherein the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

301. The use of any one of claims 250-263, wherein the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and / or the anti-cancer agent.

302. The use of any one of claims 250-263, wherein the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

303. The use of any one of claims 250-263, wherein the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.406AMENDED SHEET (ARTICLE 19)304. The use of claim 302 or 303, wherein the use lowers the ECOG scale of the subject.

305. The use of any one of claims 250-263, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

306. The use of any one of claims 250-263, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

307. The use of claim 305 or 306, wherein the use increases the subject’s KPS score.

308. The use of any one of claims 250-307, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine,407AMENDED SHEET (ARTICLE 19)arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;R10is absent or is lysine;R11-R20are absent;408AMENDED SHEET (ARTICLE 19)X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Y8is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:409AMENDED SHEET (ARTICLE 19)a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5- R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.410AMENDED SHEET (ARTICLE 19)309. The use of any one of claims 250-308, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.

310. The use of any one of claims 250-308, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

311. The use of claim 274, wherein the chemotherapy comprises at least one chemotherapeutic agent.

312. The use of claim 311 , wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.

313. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.

314. The use of claim 312, wherein the at least one chemotherapeutic agent comprises an antimetabolite.

315. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

316. The use of claim 312, wherein the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.

317. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.411AMENDED SHEET (ARTICLE 19)318. The use of claim 313, wherein the platinum-coordination complex is carboplatin and / or cisplatin.

319. The use of claim 314, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

320. The use of claim 315, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

321. The use of claim 316, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

322. The use of claim 317, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

323. The use of claim 313, wherein the platinum-coordination complex is cisplatin.

324. The use of claim 323, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

325. The use of claim 314, wherein the antimetabolite is 5-fluorouracil (5-FU).

326. The use of claim 325, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.412AMENDED SHEET (ARTICLE 19)327. The use of claim 315, wherein the tubulin binding agent or the plant alkaloid is vincristine.

328. The use of claim 316, wherein the alkylating antineoplastic agent is cyclophosphamide.

329. The use of claim 317, wherein the cytotoxic antibiotic is doxorubicin.

330. The use of claim 329, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.331 . The use of any one of claims 261 -263 and 273, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.

332. The use of any one of claims 261-263 and 273, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

333. The use of any one of claims 261-263 and 273, wherein the cancer is breast cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.

334. The use of claim 333, wherein the anthracycline is doxorubicin.413AMENDED SHEET (ARTICLE 19)335. The use of claim 333, wherein the taxane is paclitaxel.

336. The use of any one of claims 261-263 and 273, wherein the cancer is lung cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.

337. The use of any one of claims 261 -263 and 273, wherein the cancer is prostate cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.

338. The use of any one of claims 250-337, wherein the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

339. The use of any one of claims 250-337, wherein the subject is receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

340. The use of any one of claims 250-337, wherein subject is not receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.341 . The use of any one of claims 250-337, wherein the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and / or temozolomide.

342. The use of any one of claims 261-263 and 273, wherein the cancer is nonHodgkin's lymphoma, and wherein the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide,414AMENDED SHEET (ARTICLE 19)prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.

343. The use of any one of claims 250-342, wherein the use does not reduce efficacy of the anti-cancer agent.

344. The use of any one of claims 250-343, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

345. The use of claim 344, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

346. The use of any one of claims 250-345, wherein the subject is a human.

347. The use of any one of claims 250-346, wherein the subject is an animal.415AMENDED SHEET (ARTICLE 19)

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