Methods of stimulating appetite and / or increasing body weight in subjects having a fibrotic disease using non-naturally occurring melanocortin analogs

Abstract

Provided are methods of increasing body weight of and / or increasing food consumption in a subject having a kidney disease and / or a liver disease (e.g., chronic kidney disease, renal failure, nonalcoholic fatty liver disease (NAFLD)) using non-naturally occurring melanocortin analogs. Also provided are methods of stimulating appetite in the subject via administration of non-naturally occurring melanocortin analogs. The non-naturally occurring melanocortin analog may be present in a pharmaceutical composition and delivered via parenteral administration (e.g., subcutaneous injection). The methods improve appetite, increase food consumption, increase body weight, muscle mass, and / or fat mass of the subject.

Description

Docket No.: 146316.8006.WO00 METHODS OF STIMULATING APPETITE AND / OR INCREASING BODY WEIGHT IN SUBJECTS HAVING A FIBROTIC DISEASE USING NON- NATURALLY OCCURRING MELANOCORTIN ANALOGS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application 63 / 486,232 filed February 21, 2023, and U.S. Provisional Patent Application 63 / 541,394 filed September 29, 2023, 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_8006_WO00_SL.xml and is 1,552,278 bytes in size. BACKGROUND

[0003] Melanocortin analogs have been synthesized for the potential treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormonal secretion, and hyposecretion of many exocrine glands (e.g., Sjogren's syndrome), immuno-relevant conditions, and sexual dysfunction.

[0004] Patients suffering from kidney disease (e.g., chronic kidney disease, renal failure) and liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH)) often present with symptoms such as vomiting, decreased appetite or loss of appetite, and weight loss. Decreased appetite or loss of appetite (e.g., anorexia), if left untreated, may lead to fatigue, malnutrition, weight loss, decreased muscle mass and / or fat mass, and decline in overall physical condition. Decreased appetite and / or weight loss are also symptoms of cachexia, a wasting disease which has adverse effects on quality of life and survival of patients. The foregoing symptoms and cachexia may prevent patients from receiving appropriate therapies or may reduce duration or intensity of treatment to treat kidney disease and / or liver disease. -1- 165437951.15Docket No.: 146316.8006.WO00

[0005] Despite recent advances, there is still a need to develop more effective therapeutics for treating decreased appetite and / or weight loss in patients having kidney and / or liver disease. There is also a need for appetite stimulation methods that effectively promote appetite, increase food consumption, and increase body weight (e.g., muscle mass, fat mass) in patients having kidney and / or liver disease. Such therapeutics may render patients more likely to tolerate and benefit from therapeutics that treat kidney disease and / or liver disease. SUMMARY

[0006] In some embodiments, the present technology comprises a method of stimulating appetite and / or increasing body weight of a subject having a kidney disease and / or a liver disease, the method comprising: administering to the subject a therapeutically effective amount of a non-naturally occurring melanocortin analog comprising 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- -2- 165437951.15Docket No.: 146316.8006.WO00 leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; -3- 165437951.15Docket No.: 146316.8006.WO00 Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; 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 or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; 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; 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; -4- 165437951.15Docket No.: 146316.8006.WO00 when R3is Aba, Ata, or Aia, R6is Aia, then R4is not dNal(2’), or R4is dNal(2’) and R5is not Arg; when R4is p(Cl)dPhe, then R3is not Pro or His; when R4is p(I)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1and R7and at least one of R2and R3is Pro; when Y2-Y4are absent, then Y1is absent or is norleucine; when R2is Pro or Y2is Hyp, then R3is not Pro; when R3, R5, or R6is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1and R7or X1-X2are present and are Ac-dVal-dPro; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro- dNal(2’)-Arg-Trp-Cys (SEQ ID NO: 527),, then R1is not Ac-Nle or Y1-Y2is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R8, then R3is not His or Y1is not dVal.

[0007] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog for stimulating appetite and / or increasing body weight of a subject having a kidney disease and / or a liver disease, the non-naturally occurring melanocortin analog comprising 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, -5- 165437951.15Docket No.: 146316.8006.WO00 di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; -6- 165437951.15Docket No.: 146316.8006.WO00 R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; 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 or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; -7- 165437951.15Docket No.: 146316.8006.WO00 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; 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 R3is Aba, Ata, or Aia, R6is Aia, then R4is not dNal(2’), or R4is dNal(2’) and R5is not Arg; when R4is p(Cl)dPhe, then R3is not Pro or His; when R4is p(I)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1and R7and at least one of R2and R3is Pro; when Y2-Y4are absent, then Y1is absent or is norleucine; when R2is Pro or Y2is Hyp, then R3is not Pro; when R3, R5, or R6is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1and R7or X1-X2are present and are Ac-dVal-dPro; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys or Cys-Pro-dNal(2’)-Arg-Trp-Cys, then R1is not Ac-Nle or Y1-Y2is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R8, then R3is not His or Y1is not dVal.

[0008] In some embodiments, the N-terminus, 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.

[0009] In some embodiments, the N-terminus, if present, is modified by an acyl group.

[0010] In some embodiments, the acyl group is acetyl group. -8- 165437951.15Docket No.: 146316.8006.WO00

[0011] In some embodiments, the acyl group is formyl group.

[0012] In some embodiments, the N-terminus, if present, is modified by an imine group.

[0013] In some embodiments, the N-terminus, if present, is modified by an amide group.

[0014] In some embodiments, the amide group is a pyroglutamyl (pGlu) group.

[0015] In some embodiments, the amide group is derived from a fatty acid.

[0016] In some embodiments, the N-terminus, if present, is not modified.

[0017] In some embodiments, the C-terminus is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

[0018] In some embodiments, the C-terminus is modified by an amide group.

[0019] In some embodiments, the amide group is an -NHalkyl amide group or an - NHaryl amide group.

[0020] In some embodiments, the -NHaryl amide group is p-nitroanilide group or 7- amino-4-methylcoumarin.

[0021] In some embodiments, the C-terminus is modified by an ester group.

[0022] In some embodiments, the C-terminus is not modified.

[0023] In some embodiments, R1is absent, and R2is D-aspartic acid.

[0024] In some embodiments, X1, X2, and X3are absent.

[0025] In some embodiments, R4is D-Nal(2′).

[0026] In some embodiments, Y3- Y8are absent.

[0027] In some embodiments, Y1is D-valine and Y2is D-proline; or Y1is D-proline and Y2is D-valine.

[0028] In some embodiments, Y3is present and Y4-Y8are absent.

[0029] In some embodiments, Y1 is D-valine or D-proline; Y2 is D-valine or D-proline; and / or Y3 is D-valine or D-proline. -9- 165437951.15Docket No.: 146316.8006.WO00

[0030] In some embodiments, Y1is D-valine, Y2is D-valine, and Y3is D-proline; Y1is D-proline, Y2is D-valine, and Y3is D-valine; Y1is D-valine, Y2is D-proline, and Y3is D-valine; or Y1is D-proline, Y2is D-valine, and Y3is D-proline.

[0031] In some embodiments, Y3and Y4are present, and Y5-Y8are absent.

[0032] In some embodiments, Y1is D-valine or D-proline; Y2is D-valine or D-proline; Y3is D-valine or D-proline; and / or Y4is D-valine or D-proline.

[0033] In some embodiments, Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D- proline; Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine; or Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-proline.

[0034] 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.

[0035] 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, D-hydroxyproline, phenylalanine, and histidine; R4is histidine or dNal(2′); R5is dNal(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.

[0036] In some embodiments, the sequence of Formula (I) is linear.

[0037] In some embodiments, the non-naturally occurring melanocortin analog is present in a composition. -10- 165437951.15Docket No.: 146316.8006.WO00

[0038] In some embodiments, the composition further comprises a pharmaceutical salt.

[0039] In some embodiments, the composition further comprises a pharmaceutical carrier.

[0040] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition.

[0041] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0042] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0043] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

[0044] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0045] In some embodiments, the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0046] In some embodiments, 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.

[0047] 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.

[0048] 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. -11- 165437951.15Docket No.: 146316.8006.WO00

[0049] 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.

[0050] 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.

[0051] 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.

[0052] In some embodiments, the pharmaceutical carrier comprises water.

[0053] In some embodiments, the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further comprises fibrosis of at least a portion of the subject’s kidney, and optionally wherein the fibrotic liver disease further comprises fibrosis of at least a portion of the subject’s liver.

[0054] In some embodiments, the kidney disease is chronic kidney disease (CKD), and / or renal failure.

[0055] In some embodiments, the subject has undergone or is undergoing dialysis.

[0056] In some embodiments, the liver disease is nonalcoholic fatty liver disease (NAFLD).

[0057] In some embodiments, NAFLD is nonalcoholic steatohepatitis (NASH).

[0058] 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.

[0059] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease and / or the liver disease.

[0060] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia. -12- 165437951.15Docket No.: 146316.8006.WO00

[0061] In some embodiments, the method or the use (i) stimulates appetite of the subject; (ii) increases food consumption by 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 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.

[0062] In some embodiments, the method or the use increases body weight of and / or increases food consumption by the subject.

[0063] In some embodiments, the appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

[0064] 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.

[0065] 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 of the non-naturally occurring melanocortin analog.

[0066] In some embodiments, days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration of the non-naturally occurring melanocortin analog.

[0067] 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 of the non-naturally occurring melanocortin analog is stopped.

[0068] In some embodiments, the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety

[0069] In some embodiments, the appetite is assessed between meals.

[0070] In some embodiments, the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects. -13- 165437951.15Docket No.: 146316.8006.WO00

[0071] In some embodiments, the food consumption of the subject is increased by at least 25% to 2,000% after the administration of the non-naturally occurring melanocortin analog.

[0072] In some embodiments, the food consumption of the subject is increased by at least 50% to 500% after the administration of the non-naturally occurring melanocortin analog.

[0073] In some embodiments, the 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 of the non- naturally occurring melanocortin analog.

[0074] In some embodiments, the food consumption 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 of the non- naturally occurring melanocortin analog.

[0075] 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 of the non-naturally occurring melanocortin analog is stopped.

[0076] In some embodiments, the food consumption is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

[0077] In some embodiments, anorexia is determined by food consumption.

[0078] 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.

[0079] In some embodiments, body weight of the subject is increased by at least 5% to 25% after the administration of the non-naturally occurring melanocortin analog.

[0080] In some embodiments, body weight of the subject is increased by at least 20% to 100% after the administration of the non-naturally occurring melanocortin analog. -14- 165437951.15Docket No.: 146316.8006.WO00

[0081] 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 of the non-naturally occurring melanocortin analog is stopped.

[0082] 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.

[0083] In some embodiments, muscle mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog.

[0084] In some embodiments, muscle mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog.

[0085] 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 of the non-naturally occurring melanocortin analog is stopped.

[0086] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

[0087] In some embodiments, fat mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog.

[0088] In some embodiments, fat mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog.

[0089] In some embodiments, fat mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog.

[0090] In some embodiments, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

[0091] In some embodiments, the method or the use stimulates appetite in the subject compared to a control subject having the kidney disease or the liver disease, wherein the control subject is not administered the non-naturally occurring melanocortin analog.

[0092] In some embodiments, the control subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss. -15- 165437951.15Docket No.: 146316.8006.WO00

[0093] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease or the liver disease.

[0094] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia.

[0095] In some embodiments, the subject is a human.

[0096] In some embodiments, the subject is an animal.

[0097] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2 to 35 kg / m2.

[0098] In some embodiments, the subject has a BMI of less than 20 kg / m2.

[0099] In some embodiments, the subject has a BMI of less than 18.5 kg / m2.

[0100] In some embodiments, an appetite-regulating agent is administered to the subject.

[0101] In some embodiments, the subject does not experience an adverse event following administration of the non-naturally occurring melanocortin analog.

[0102] In some embodiments, the subject does not experience an adverse event attributable to the non-naturally occurring melanocortin analog following the administration.

[0103] In some embodiments, the subject continues to be administered with the non- naturally occurring melanocortin analog after the subject experiences the increase in appetite.

[0104] In some embodiments, the subject continues to be administered with the non- naturally occurring melanocortin analog after the subject experiences the increase in food consumption.

[0105] In some embodiments, the subject continues to be administered with the non- naturally occurring melanocortin analog after the subject experiences the increase in body weight.

[0106] In some embodiments, the subject is cachectic before the non-naturally occurring melanocortin analog is administered. -16- 165437951.15Docket No.: 146316.8006.WO00

[0107] In some embodiments, the subject is cachectic if they meet the Fearon criteria of weight loss.

[0108] In some embodiments, the Fearon criteria of weight loss comprises (1) a weight loss greater than 5% within 6 months before the administration, or (2) a weight loss greater than 2% wherein the subject has a BMI less than 20 kg / m2 or the subject has sarcopenia.

[0109] In some embodiments, the subject is no longer cachectic after the non-naturally occurring melanocortin analog is administered.

[0110] In some embodiments, the subject no longer meets the Fearon criteria of weight loss after the non-naturally occurring melanocortin analog is administered.

[0111] In some embodiments, the subject continues to be administered with the non- naturally occurring melanocortin analog after the subject is no longer cachectic.

[0112] In some embodiments, the subject continues to be administered with the non- naturally occurring melanocortin analog after the subject no longer meets the Fearon criteria of weight loss.

[0113] In some embodiments, the subject is pretreated with the non-naturally occurring melanocortin analog before the subject becomes cachectic.

[0114] In some embodiments, the subject does not meet the Fearon criteria of weight loss. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] FIGS.1A-YY illustrate percent activation of the melanocortin 3 receptor (MC3R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non- naturally occurring melanocortin analogs included HS024(TFA) (FIG.1A; SEQ ID NO: 525), E1 (FIG.3B; SEQ ID NO: 15), E2 (FIG.1C; SEQ ID NO: 16), E3 (FIG.1D; SEQ ID NO: 17), E4 (FIG.1E; SEQ ID NO: 18), E5 (FIG.1F; SEQ ID NO: 19), E6 (FIG.1G; SEQ ID NO: 20), E7 (FIG.1H; SEQ ID NO: 21), E8 (FIG.1I; SEQ ID NO: 22), E9 (FIG.1J; SEQ ID NO: 23), E10 (FIG.1K; SEQ ID NO: 24), E11 (FIG.1L; SEQ ID NO: 25), E12 (FIG.1M; SEQ ID NO: -17- 165437951.15Docket No.: 146316.8006.WO00 26), E13 (FIG.1N; SEQ ID NO: 27), E14 (FIG.1O; SEQ ID NO: 28), E15 (FIG.1P; SEQ ID NO: 29), E16 (FIG.1Q; SEQ ID NO: 30), E17 (FIG.1R; SEQ ID NO: 31), E18 (FIG.1S; SEQ ID NO: 32), E19 (FIG.1T; SEQ ID NO: 35), E20 (FIG.1U; SEQ ID NO: 36), E21 (FIG.1V; SEQ ID NO: 37), F1 (FIG.1W; SEQ ID NO: 40), F2 (FIG.1X; SEQ ID NO: 41), F3 (FIG.1Y; SEQ ID NO: 42), F4 (FIG.1Z; SEQ ID NO: 43), F5 (FIG.1AA; SEQ ID NO: 44), F6 (FIG. 1BB; SEQ ID NO: 50), F7 (FIG.1CC; SEQ ID NO: 51), F8 (FIG.1DD; SEQ ID NO: 52), F9 (FIG.1EE; SEQ ID NO: 53), F10 (FIG.1FF; SEQ ID NO: 54), F11 (FIG.1GG; SEQ ID NO: 55), F12 (FIG.1HH; SEQ ID NO: 56), F13 (FIG.1II; SEQ ID NO: 57), F14 (FIG.1AJJ; SEQ ID NO: 58), F15 (FIG.1KK; SEQ ID NO: 59), F16 (FIG.1LL; SEQ ID NO: 60), F17 (FIG. 1MM; SEQ ID NO: 61), F18 (FIG.1NN; SEQ ID NO: 62), F19 (FIG.1OO; SEQ ID NO: 63), F20 (FIG.1PP; SEQ ID NO: 64), F21 (FIG.1QQ; SEQ ID NO: 65), F22 (FIG.1RR; SEQ ID NO: 45), F23 (FIG.1SS; SEQ ID NO: 46), F24 (FIG.1TT; SEQ ID NO: 47), F25 (FIG.1UU; SEQ ID NO: 48), F26 (FIG.1VV; SEQ ID NO: 49), F28 (FIG.1WW; SEQ ID NO: 67), F29 (FIG.1XX; SEQ ID NO: 68), and F30 (FIG.30YY; SEQ ID NO: 69).

[0116] FIGS.2A-OO illustrate percent activation of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included G5 (FIG. 2A; SEQ ID NO: 77), G6 (FIG.2B; SEQ ID NO: 78), G7 (FIG.2C; SEQ ID NO: 75), G8 (FIG. 2D; SEQ ID NO: 74), G9 (FIG.2E; SEQ ID NO: 79), G10 (FIG.2F; SEQ ID NO: 80), G11 (FIG.2G; SEQ ID NO: 81), G12 (FIG.2H; SEQ ID NO: 82), G13 (FIG.2I; SEQ ID NO: 83), G15 (FIG.2J; SEQ ID NO: 85), G17 (FIG.2K; SEQ ID NO: 211), G18 (FIG.2L; SEQ ID NO: 212), G19 (FIG.2M; SEQ ID NO: 213), G 20 (FIG.2N; SEQ ID NO: 214), H1 (FIG.2O; SEQ ID NO: 97), H2 (FIG.2P; SEQ ID NO: 98), H3 (FIG.2Q; SEQ ID NO: 99), H4 (FIG.2R; SEQ ID NO: 100), H5 (FIG.2S; SEQ ID NO: 101), H6 (FIG.2T; SEQ ID NO: 102), H7 (FIG.2U; SEQ ID NO: 103), H8 (FIG.2V; SEQ ID NO: 104), H9 (FIG.2W; SEQ ID NO: 105), H10 (FIG.2X; SEQ ID NO: 106), H11 (FIG.2Y; SEQ ID NO: 107), H12 (FIG.2Z; SEQ ID NO: 108), H13 (FIG.2AA; SEQ ID NO: 109), H14 (FIG.2BB; SEQ ID NO: 110), H15 (FIG.2CC; SEQ ID NO: 111), I1 (FIG.2DD; SEQ ID NO: 112), I2 (FIG.2EE; SEQ ID NO: 113), I3 (FIG. 2FF; SEQ ID NO: 119), I4 (FIG.2GG; SEQ ID NO: 115), I5 (FIG.2HH; SEQ ID NO: 120), I6 (FIG.2II; SEQ ID NO: 121), I7 (FIG.2JJ; SEQ ID NO: 116), I8 (FIG.2KK; SEQ ID NO: 117), -18- 165437951.15Docket No.: 146316.8006.WO00 I9 (FIG.2LL; SEQ ID NO: 122), I10 (FIG.2MM; SEQ ID NO: 123), I11 (FIG.2NN; SEQ ID NO: 118), and I12 (FIG.2OO; SEQ ID NO: 124).

[0117] FIGS.3A-ZZ illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included J1 (FIG. 3A; SEQ ID NO: 126), J4 (FIG.3B; SEQ ID NO: 129), J5 (FIG.3C; SEQ ID NO: 130), J6 (FIG.3D; SEQ ID NO: 131), J7 (FIG.3E; SEQ ID NO: 132), J8 (FIG.3F; SEQ ID NO: 133), J9 (FIG.3G; SEQ ID NO: 134), J10 (FIG.3H; SEQ ID NO: 135), J11 (FIG.3I; SEQ ID NO: 136), J12 (FIG.3J; SEQ ID NO: 137), J13 (FIG.3K; SEQ ID NO: 138), J14 (FIG.3L; SEQ ID NO: 139), J15 (FIG.3M; SEQ ID NO: 140), J16 (FIG.3N; SEQ ID NO: 141), J17 (FIG. 3O; SEQ ID NO: 142), J18 (FIG.3P; SEQ ID NO: 143), J19 (FIG.3Q; SEQ ID NO: 144), J20 (FIG.3R; SEQ ID NO: 145), J21 (FIG.3S; SEQ ID NO: 146), J22 (FIG.3T; SEQ ID NO: 147), J23 (FIG.3U; SEQ ID NO: 148), J24 (FIG.3V; SEQ ID NO: 149), J25 (FIG.3W; SEQ ID NO: 150), J26 (FIG.3X; SEQ ID NO: 151), J27 (FIG.3Y; SEQ ID NO: 152), J28 (FIG.3Z; SEQ ID NO: 153), J29 (FIG.3AA; SEQ ID NO: 154), J30 (FIG.3BB; SEQ ID NO: 155), J31 (FIG.3CC; SEQ ID NO: 156), J32 (FIG.3DD; SEQ ID NO: 157), J33 (FIG.3EE; SEQ ID NO: 158), J34 (FIG.3FF; SEQ ID NO: 159), J35 (FIG.3GG; SEQ ID NO: 160), J36 (FIG. 3HH; SEQ ID NO: 161), J37 (FIG.3II; SEQ ID NO: 126; SEQ ID NO: 162), J38 (FIG.3JJ; SEQ ID NO: 163), J39 (FIG.3KK; SEQ ID NO: 164), J40 (FIG.3LL; SEQ ID NO: 165), J41 (FIG.3MM; SEQ ID NO: 166), J42 (FIG.3NN; SEQ ID NO: 167), J43 (FIG.3OO; SEQ ID NO: 168), J44 (FIG.3PP; SEQ ID NO: 169), J45 (FIG.3QQ; SEQ ID NO: 170), J46 (FIG. 3RR; SEQ ID NO: 171), J47 (FIG.3SS; SEQ ID NO: 172), J48 (FIG.3TT; SEQ ID NO: 173), J49 (FIG.3UU; SEQ ID NO: 174), J60 (FIG.3VV; SEQ ID NO: 185), J63 (FIG.3WW; SEQ ID NO: 188), J65 (FIG.3XX; SEQ ID NO: 190), J68 (FIG.3YY; SEQ ID NO: 193), and J69 (FIG.3ZZ; SEQ ID NO: 194).

[0118] FIGS.4A-SS illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included K2 (FIG. -19- 165437951.15Docket No.: 146316.8006.WO00 4A; SEQ ID NO: 394), K3 (FIG.4B; SEQ ID NO: 396), K4 (FIG.4C; SEQ ID NO: 398), K5 (FIG.4D; SEQ ID NO: 399), K6 (FIG.4E; SEQ ID NO: 392), K7 (FIG.4F; SEQ ID NO: 393), K8 (FIG.4G; SEQ ID NO: 395), K9 (FIG.4H; SEQ ID NO: 397), K10 (FIG.4I; SEQ ID NO: 400), K13 (FIG.4J; SEQ ID NO: 403), K16 (FIG.4K; SEQ ID NO: 376), K17 (FIG.4L; SEQ ID NO: 377), K18 (FIG.4M; SEQ ID NO: 378), K20 (FIG.4N; SEQ ID NO: 380), K23 (FIG. 4O; SEQ ID NO: 388), L4 (FIG.4P; SEQ ID NO: 217), M1 (FIG.4Q; SEQ ID NO: 225), M2 (FIG.4R; SEQ ID NO: 234), M3 (FIG.4S; SEQ ID NO: 226), M4 (FIG.4T; SEQ ID NO: 235), M5 (FIG.4U; SEQ ID NO: 227), M6 (FIG.4V; SEQ ID NO: 228), M7 (FIG.4W; SEQ ID NO: 229), M8 (FIG.4X; SEQ ID NO: 230), M9 (FIG.4Y; SEQ ID NO: 231), M11 (FIG.4Z; SEQ ID NO: 233), N1 (FIG. AA; SEQ ID NO: 236), N2 (FIG.4BB; SEQ ID NO: 237), N3 (FIG. 4CC; SEQ ID NO: 240), N4 (FIG.4DD; SEQ ID NO: 241), N5 (FIG.4EE; SEQ ID NO: 242), N6 (FIG.4FF; SEQ ID NO: 243), N7 (FIG.4GG; SEQ ID NO: 244), N8 (FIG.4HH; SEQ ID NO: 245), O1 (FIG.4II; SEQ ID NO: 246), O2 (FIG.4JJ; SEQ ID NO: 247), O3 (FIG.4KK; SEQ ID NO: 248), O4 (FIG.4LL; SEQ ID NO: 249), O5 (FIG.4MM; SEQ ID NO: 250), O6 (FIG.4NN; SEQ ID NO: 255), O7 (FIG.4OO; SEQ ID NO: 256), O9 (FIG.4PP; SEQ ID NO: 258), O10 (FIG.4QQ; SEQ ID NO: 259), O11 (FIG.4RR; SEQ ID NO: 260), and TCMCB07 (FIG.4SS; SEQ ID NO: 3).

[0119] FIGS. 5A-DDD illustrate percent activation of the melanocortin 4 receptor (MC4R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included HS024(TFA) (FIG.5A; SEQ ID NO: 525), E1 (FIG.5B; SEQ ID NO: 15), E2 (FIG.5C; SEQ ID NO: 16), E3 (FIG.5D; SEQ ID NO: 17), E4 (FIG.5E; SEQ ID NO: 18), E5 (FIG.5F; SEQ ID NO: 19), E6 (FIG.5G; SEQ ID NO: 20), E7 (FIG.5H; SEQ ID NO: 21), E8 (FIG.5I; SEQ ID NO: 22), E9 (FIG.5J; SEQ ID NO: 23), E10 (FIG.5K; SEQ ID NO: 24), E11 (FIG.5L; SEQ ID NO: 25), E12 (FIG. 5M; SEQ ID NO: 26), E13 (FIG.5N; SEQ ID NO: 27), E14 (FIG.5O; SEQ ID NO: 28), E15 (FIG.5P; SEQ ID NO: 29), E16 (FIG.5Q; SEQ ID NO: 30), E17 (FIG.5R; SEQ ID NO: 31), E18 (FIG.5S; SEQ ID NO: 32), E20 (FIG.5T; SEQ ID NO: 36), E21 (FIG.5U; SEQ ID NO: 37), E22 (FIG.5V; SEQ ID NO: 195), E23 (FIG.5W; SEQ ID NO: 196), E24 (FIG.5X; SEQ ID NO: 197), F1 (FIG.5Y; SEQ ID NO: 40), F2 (FIG.5Z; SEQ ID NO: 41), F3 (FIG.5AA; SEQ ID NO: 42), F4 (FIG.5BB; SEQ ID NO: 43), F5 (FIG.5CC; SEQ ID NO: 44), F6 (FIG. -20- 165437951.15Docket No.: 146316.8006.WO00 5DD; SEQ ID NO: 50), F7 (FIG.5EE; SEQ ID NO: 51), F8 (FIG.5FF; SEQ ID NO: 52), F9 (FIG.5GG; SEQ ID NO: 53), F10 (FIG.5HH; SEQ ID NO: 54), F11 (FIG.5II; SEQ ID NO: 55), F12 (FIG.5JJ; SEQ ID NO: 56), F13 (FIG.5KK; SEQ ID NO: 57), F14 (FIG.5LL; SEQ ID NO: 58), F15 (FIG.5MM; SEQ ID NO: 59), F16 (FIG.5NN; SEQ ID NO: 60), F17 (FIG. 5OO; SEQ ID NO: 61), F18 (FIG.5PP; SEQ ID NO: 62), F19 (FIG.5QQ; SEQ ID NO: 63), F20 (FIG.5RR; SEQ ID NO: 64), F21 (FIG.5SS; SEQ ID NO: 65), F22 (FIG.5TT; SEQ ID NO: 45), F23 (FIG.5UU; SEQ ID NO: 46), F24 (FIG.5VV; SEQ ID NO: 47), F25 (FIG.5WW; SEQ ID NO: 48), F26 (FIG.5XX; SEQ ID NO: 49), F27 (FIG.5YY; SEQ ID NO: 66), F28 (FIG.5ZZ; SEQ ID NO: 67), F29 (FIG.5AAA; SEQ ID NO: 68), F30 (FIG.5BBB; SEQ ID NO: 69), F31 (FIG.5CCC; SEQ ID NO: 201), and F32 (FIG.5DDD; SEQ ID NO: 205).

[0120] FIGS.6A-ZZ illustrate percent activation of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included G1 (FIG.6A; SEQ ID NO: 71), G2 (FIG.6B; SEQ ID NO: 72), G3 (FIG. 6C; SEQ ID NO: 73), G4 (FIG.6D; SEQ ID NO: 76), G5 (FIG.6E; SEQ ID NO: 77), G6 (FIG. 6F; SEQ ID NO: 78), G7 (FIG.6G; SEQ ID NO: 75), G8 (FIG.6H; SEQ ID NO: 74), G9 (FIG. 6I; SEQ ID NO: 79), G10 (FIG.6J; SEQ ID NO: 80), G11 (FIG.6K; SEQ ID NO: 81), G12 (FIG.6L; SEQ ID NO: 82), G13 (FIG.6M; SEQ ID NO: 83), G14 (FIG.6N; SEQ ID NO: 84), G15 (FIG.6O; SEQ ID NO: 85), G16 (FIG.6P; SEQ ID NO: 86), G17 (FIG.6Q; SEQ ID NO: 211), G18 (FIG.6R; SEQ ID NO: 212), G19 (FIG.6S; SEQ ID NO: 213), G20 (FIG.6T; SEQ ID NO: 214), G21 (FIG.6U; SEQ ID NO: 215), G22 (FIG.6V; SEQ ID NO: 202), G23 (FIG. 6W; SEQ ID NO: 203), G24 (FIG.6X; SEQ ID NO: 204), H1 (FIG.6Y; SEQ ID NO: 97), H2 (FIG.6Z; SEQ ID NO: 98), H3 (FIG.6AA; SEQ ID NO: 99), H4 (FIG.6BB; SEQ ID NO: 100), H5 (FIG.6CC; SEQ ID NO: 101), H6 (FIG.6DD; SEQ ID NO: 102), H7 (FIG.6EE; SEQ ID NO: 103), H8 (FIG.6FF; SEQ ID NO: 104), H9 (FIG.6GG; SEQ ID NO: 105), H10 (FIG. 6HH; SEQ ID NO: 106), H11 (FIG.6II; SEQ ID NO: 107), H12 (FIG.6JJ; SEQ ID NO: 108), H13 (FIG.6KK; SEQ ID NO: 109), H14 (FIG.6LL; SEQ ID NO: 110), H15 (FIG.6MM; SEQ ID NO: 111), I1 (FIG.6NN; SEQ ID NO: 112), I2 (FIG.6OO; SEQ ID NO: 113), I3 (FIG.6PP; SEQ ID NO: 119), I4 (FIG.6QQ; SEQ ID NO: 115), I5 (FIG.6RR; SEQ ID NO: 120), I6 (FIG. 6SS; SEQ ID NO: 121), I7 (FIG.6TT; SEQ ID NO: 116), I8 (FIG.6UU; SEQ ID NO: 117), I9 -21- 165437951.15Docket No.: 146316.8006.WO00 (FIG.6VV; SEQ ID NO: 122), I10 (FIG.6WW; SEQ ID NO: 123), I11 (FIG.6XX; SEQ ID NO: 118), I12 (FIG.6YY; SEQ ID NO: 124), and I13 (FIG.6ZZ; SEQ ID NO: 200).

[0121] FIGS. 7A-RRR illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included J1 (FIG.7A; SEQ ID NO: 126), J2 (FIG.7B; SEQ ID NO: 127), J3 (FIG.7C; SEQ ID NO: 128), J4 (FIG.7D; SEQ ID NO: 129), J5 (FIG.7E; SEQ ID NO: 130), J6 (FIG.7F; SEQ ID NO: 131), J7 (FIG.7G; SEQ ID NO: 132), J8 (FIG.7H; SEQ ID NO: 133), J9 (FIG.7I; SEQ ID NO: 17), J10 (FIG.7J; SEQ ID NO: 135), J11 (FIG.7K; SEQ ID NO: 136), J12 (FIG.7L; SEQ ID NO: 137), J13 (FIG.7M; SEQ ID NO: 138), J14 (FIG.7N; SEQ ID NO: 139), J15 (FIG.7O; SEQ ID NO: 140), J16 (FIG.7P; SEQ ID NO: 141), J17 (FIG.7Q; SEQ ID NO: 142), J18 (FIG.7R; SEQ ID NO: 143), J19 (FIG.7S; SEQ ID NO: 144), J20 (FIG.7T; SEQ ID NO: 145), J21 (FIG.7U; SEQ ID NO: 146), J22 (FIG. 7V; SEQ ID NO: 147), J23 (FIG.7W; SEQ ID NO: 148), J24 (FIG.7X; SEQ ID NO: 149), J25 (FIG.7Y; SEQ ID NO: 150), J26 (FIG.7Z; SEQ ID NO: 151), J27 (FIG.7AA; SEQ ID NO: 152), J28 (FIG.7BB; SEQ ID NO: 153), J29 (FIG.7CC; SEQ ID NO: 154), J30 (FIG. 7DD; SEQ ID NO: 155), J31 (FIG.7EE; SEQ ID NO: 156), J32 (FIG.7FF; SEQ ID NO: 157), J33 (FIG.7GG; SEQ ID NO: 158), J34 (FIG.7HH; SEQ ID NO: 159), J35 (FIG.7II; SEQ ID NO: 160), J36 (FIG.7JJ; SEQ ID NO: 161), J37 (FIG.7KK; SEQ ID NO: 126; SEQ ID NO: 162), J38 (FIG.7LL; SEQ ID NO: 163), J39 (FIG.7MM; SEQ ID NO: 164), J40 (FIG.7NN; SEQ ID NO: 165), J41 (FIG.7OO; SEQ ID NO: 166), J42 (FIG.7PP; SEQ ID NO: 167), J43 (FIG.7QQ; SEQ ID NO: 168), J44 (FIG.7RR; SEQ ID NO: 169), J45 (FIG.7SS; SEQ ID NO: 170), J46 (FIG.7TT; SEQ ID NO: 171), J47 (FIG.7UU; SEQ ID NO: 172), J48 (FIG. 7VV; SEQ ID NO: 173), J49 (FIG.7WW; SEQ ID NO: 174), J50 (FIG.7XX; SEQ ID NO: 175), J51 (FIG.7YY; SEQ ID NO: 176), J52 (FIG.7ZZ; SEQ ID NO: 177), J53 (FIG.7AAA; SEQ ID NO: 178), J54 (FIG.7BBB; SEQ ID NO: 179), J55 (FIG.7CCC; SEQ ID NO: 180), J56 (FIG.7DDD; SEQ ID NO: 181), J57 (FIG.7EEE; SEQ ID NO: 182), J58 (FIG.7FFF; SEQ ID NO: 183), J59 (FIG.7GGG; SEQ ID NO: 184), J60 (FIG.7HHH; SEQ ID NO: 185), J61 (FIG.7III; SEQ ID NO: 186), J62 (FIG.7JJJ; SEQ ID NO: 187), J63 (FIG.7KKK; SEQ ID NO: 188), J64 (FIG.7LLL; SEQ ID NO: 189), J65 (FIG.7MMM; SEQ ID NO: 190), J66 -22- 165437951.15Docket No.: 146316.8006.WO00 (FIG.7NNN; SEQ ID NO: 191), J67 (FIG.7OOO; SEQ ID NO: 192), J68 (FIG.7PPP; SEQ ID NO: 193), J69 (FIG.7QQQ; SEQ ID NO: 194), and J70 (FIG.7RRR; SEQ ID NO: 206).

[0122] FIGS. 8A-GGG illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included K1 (FIG.8A; SEQ ID NO: 391), K2 (FIG.8B; SEQ ID NO: 394), K3 (FIG.8C; SEQ ID NO: 396), K4 (FIG.8D; SEQ ID NO: 398), K5 (FIG.8E; SEQ ID NO: 399), K6 (FIG.8F; SEQ ID NO: 392), K7 (FIG.8G; SEQ ID NO: 393), K8 (FIG.8H; SEQ ID NO: 395), K9 (FIG. 8I; SEQ ID NO: 397), K10 (FIG.8J; SEQ ID NO: 400), K11 (FIG.8K; SEQ ID NO: 401), K12 (FIG.8L; SEQ ID NO: 402), K13 (FIG.8M; SEQ ID NO: 403), K14 (FIG.8N; SEQ ID NO: 406), K15 (FIG.8O; SEQ ID NO: 375), K16 (FIG.8P; SEQ ID NO: 376), K17 (FIG.8Q; SEQ ID NO: 377), K18 (FIG.8R; SEQ ID NO: 378), K19 (FIG.8S; SEQ ID NO: 379), K20 (FIG. 8T; SEQ ID NO: 380), K21 (FIG.8U; SEQ ID NO: 381), K22 (FIG.8V; SEQ ID NO: 125), K23 (FIG.8W; SEQ ID NO: 388), L1 (FIG.8X; SEQ ID NO: 198), L2 (FIG.8Y; SEQ ID NO: 199), L3 (FIG.8Z; SEQ ID NO: 216), L4 (FIG.8AA; SEQ ID NO: 217), L5 (FIG.8BB; SEQ ID NO: 220), M1 (FIG.8CC; SEQ ID NO: 225), M2 (FIG.8DD; SEQ ID NO: 234), M3 (FIG. 8EE; SEQ ID NO: 226), M4 (FIG.8FF; SEQ ID NO: 237), M5 (FIG.8GG; SEQ ID NO: 227), M6 (FIG.8HH; SEQ ID NO: 228), M7 (FIG.8II; SEQ ID NO: 229), M8 (FIG.8JJ; SEQ ID NO: 230), M9 (FIG.8KK; SEQ ID NO: 231), M10 (FIG.8LL; SEQ ID NO: 232), M11 (FIG. 8MM; SEQ ID NO: 233), N1 (FIG.8NN; SEQ ID NO: 236), N2 (FIG.8OO; SEQ ID NO: 237), N3 (FIG.8PP; SEQ ID NO: 239), N4 (FIG.8QQ; SEQ ID NO: 241), N5 (FIG.8RR; SEQ ID NO: 242), N6 (FIG.8SS; SEQ ID NO: 243), N7 (FIG.8TT; SEQ ID NO: 244), N8 (FIG.8UU; SEQ ID NO: 245), O1 (FIG.8VV; SEQ ID NO: 246), O2 (FIG.8WW; SEQ ID NO: 247), O3 (FIG.8XX; SEQ ID NO: 248), O4 (FIG.8YY; SEQ ID NO: 249), O5 (FIG.8ZZ; SEQ ID NO: 250), O6 (FIG.8AAA; SEQ ID NO: 255), O7 (FIG.8BBB; SEQ ID NO: 256), O8 (FIG.8CCC; SEQ ID NO: 257), O9 (FIG.8DDD; SEQ ID NO: 258), O10 (FIG.8EEE; SEQ ID NO: 259), O11 (FIG.8FFF; SEQ ID NO: 260), and TCMCB07 (FIG.8GGG; SEQ ID NO: 3).

[0123] FIGS.9A-G show that subcutaneous administration of TCMCB07 ameliorates anorexia, body weight loss, and lean mass loss in rats with CKD induced cachexia. FIG.9A -23- 165437951.15Docket No.: 146316.8006.WO00 is a graph depicting design of an in vivo renal failure model (5 / 6 nephrectomy model) in rats using one or more compositions of the present technology. FIG.9B is a graph comparing the daily body weights in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 9A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG.9C is a graph comparing the daily food intakes in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 9A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG.9D is a bar graph depicting fat mass gain in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 9A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 9E is a graph showing body weight gain (%, net gain normalized to baseline) post-nephrectomy and post-treatment. FIG.9F is a graph showing cumulative food intake post-treatment. FIG. 9G is a graph showing lean mass were determined by MR pre- (day 14) and post- (day 28) treatment, and gain (%) was calculated (net gain normalized to baseline). All data are expressed as mean ± SEM for each group. Two-way ANOVA in (9B-9E), Unpaired Student’s t-Test in (9D and 9G), * & # p < 0.05, ## p < 0.01, ***& ### p < 0.001 and **** p < 0.0001. Stars in (9B and 9C): Neph / saline group versus Sham / saline group, and red pounds in (9B and 9C): Neph / TCMCB07 group versus Neph / saline group.

[0124] FIGS.10A-F show the effect of continued treatment with TCMCB07 in the CKD model of FIGS.9A-G after the rat meets the equivalence point, where the weight of the rat treated with TCMCB07 is no different from a sham rat. FIG.10A shows a schematic diagram of the experimental method. FIG.10B shows daily body weight of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG.10C shows daily body weight gain compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG.10D shows body weight gain, measured as % of initial weight compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG.10E shows body weight gain, measured as % of initial weight compared to day 14 of CKD model rats treated with TCMCB07 with a change in dosing at -24- 165437951.15Docket No.: 146316.8006.WO00 the equivalence point. FIG.10F shows the cumulative food intake of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point.

[0125] FIGS.11A-F show the body compositions of CKD model rats of FIGS.12A-G treated with TCMCB07 with a change in dosing at the equivalence point. FIG.11A shows the fat mass; FIG. 11B shows the lean mass; FIG. 11C shows the fluid mass; FIG. 11D shows the fat mass gained; FIG.11E shows the lean mass gained; and FIG.11F shows the fluid mass gained.

[0126] FIGS.12A-D show the tissue weight and length of the CKD model rats of FIGS. 12A-G treated with TCMCB07 with a change in dosing at the equivalence point. FIG.12A shows heart weight; FIG.12B shows gastrocnemii weight; FIG.12C shows spleen weight; and FIG.12D shows body length.

[0127] FIGS.13A and 13B show serum creatinine and urea of the CKD model rats of FIGS.9A-G treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 13A shows serum creatinine and FIG.13B shows serum blood urea nitrogen (BUN).

[0128] FIG.14 shows high performance liquid chromatograms of plasma from the CKD model rats of FIGS.9A-G. Time points are pre-intravenous administration and 2 minutes post administration of 750 nmol / kg TCMCB07. Concentration of TCMCB07 in plasma 2 minutes post-intravenous administration is 7 nmol / mL.

[0129] FIG. 15 shows high performance liquid chromatograms of cerebrospinal fluid from the CKD model rats of FIGS.9A-G. Time points: pre administration, 5 and 30 minutes post administration of intravenous TCMCB07 (750 nmol / kg). The small peak at the 12.9- minute retention time in the pre-administration sample represents a co-eluting component of cerebrospinal fluid. Inserted graph (upper left) shows the increased cerebrospinal fluid concentration (represented as peak height) of the proposed TCMCB07 metabolite over time.

[0130] FIGS.16A-C show a mass spectrometry analysis of the collected eluent from the peak with a retention time of 12.9 minutes. Arrows indicate the occurrence of a peptide in the post-injection samples, but not in the pre-injection sample. Peak has an atomic weight of 1,209 Daltons, 21 Daltons less than cyclized TCMCB07, at 1,230 Da. -25- 165437951.15Docket No.: 146316.8006.WO00 DETAILED DESCRIPTION

[0131] The present technology comprises methods of promoting appetite and / or increasing body weight of a subject having a kidney disease and / or a liver disease via administering a non-naturally occurring melanocortin analog to the subject. In some embodiments, promoting appetite includes stimulating appetite. The non-naturally occurring melanocortin analog may be present in a pharmaceutical composition and delivered via parenteral administration (e.g., subcutaneous injection). The appetite promoting methods may lead to increased food consumption, increased body weight, increased muscle mass, and / or increased fat mass of the subject. The methods may also prevent or alleviate nausea, emesis, and / or anorexia in the subject. The subject may have a kidney disease which is chronic kidney disease (CKD), and / or renal failure (e.g., chronic renal failure). Alternatively, or additionally, the subject may have a liver disease which is nonalcoholic fatty liver disease (NAFLD), e.g., nonalcoholic steatohepatitis (NASH). The kidney and / or liver disease may be fibrotic.

[0132] The methods of the present technology use non-naturally occurring melanocortin receptor antagonist analogs, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, referred to herein collectively as melanocortin antagonists. Some of the melanocortin antagonists may bind only the melanocortin 3 receptor or the melanocortin 4 receptor. Other melanocortin antagonists may bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, whereas other melanocortin antagonists may bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. Certain melanocortin antagonists may bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0133] Each of the non-naturally occurring melanocortin analogs may have one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, D-Hyp, Pro, D-Pro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and / or β-turn structures in the peptide. Additionally, D-Met and disulfide bridges (cyclization via a disulfide bridge) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. Pro-Gly and Gly-Gly linkers may also induce and / or stabilize beta- -26- 165437951.15Docket No.: 146316.8006.WO00 turns. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. The non-naturally occurring melanocortin analogs include D-valine-D- proline (dV-dP) or D-proline-D-valine (dP-dV) chain as their C-terminus, which may provide enhanced transport and resistance to degradation. The non-naturally occurring melanocortin analogs may be linear or optionally cyclized via a disulfide bridge or a lactam bond at various positions of the peptide chain. Each of the non-naturally occurring melanocortin analogs may include one or more of the foregoing features.

[0134] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. 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. 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.

[0135] Furthermore, the detailed description of various embodiments herein refers 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, 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 step or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0136] 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 present technology belongs. For the purposes of the present technology, the following terms are defined below. -27- 165437951.15Docket No.: 146316.8006.WO00

[0137] 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.

[0138] 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.

[0139] The terms “administering” or “administer” include delivery of non-naturally occurring melanocortin analogs (also referred to herein as peptides) 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. Administering includes pre-administration of a non-naturally occurring melanocortin analog before the onset of symptoms.

[0140] “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 -28- 165437951.15Docket No.: 146316.8006.WO00 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.

[0141] 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.

[0142] “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.

[0143] 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.

[0144] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like. -29- 165437951.15Docket No.: 146316.8006.WO00

[0145] 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.

[0146] 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 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.

[0147] 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.

[0148] “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 -30- 165437951.15Docket No.: 146316.8006.WO00 generally Synthetic Peptides: 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 described generally in Synthetic Peptides: 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.

[0149] 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.

[0150] 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.

[0151] 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; -31- 165437951.15Docket No.: 146316.8006.WO00 “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 tyrosine; 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” or “lPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D- phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / lPhe” 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 norleucine; “Nal” is naphthylalanine; “D-Nal” is D-naphthylalanine; D-Nal(2′) or DNal(2’) is D-2′- naphthylalanine; L-Nal(2') or LNal(2’) is L-2′-naphthylalanine; L-Nal(1') is L-1′- naphthylalanine; D-Nal(1') or DNal(1’) is D-1′-naphthylalanine; Tle is tert-Leucine; Nva is norvaline; Orn is ornithine; Bip is biphenyl amino acid; and so on.

[0152] 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).

[0153] 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). -32- 165437951.15Docket No.: 146316.8006.WO00

[0154] Further, β-amino acids may have L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D- isomer, or a combination thereof.

[0155] 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.

[0156] 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 —NH2 moiety on the C-terminus of a peptide indicates an amidated C- terminus. In addition, the following abbreviations are used herein: Harg is Homo arginine; Hlys is Homo lysine.

[0157] Additional abbreviations are used as follows: tBu is tert-butyl; Hyp(Bzl) is benzyl-L-hydroxy-proline; Mamb is 3-aminomethyl-benzoic acid; 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; 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, F – fluoro, CF3 – trifluoromethyl); and p(Cl)dPhe is para-chloro-D-phenylalanine (I – iodo, Br- bromo, F – fluoro, CF3– trifluoromethyl).

[0158] 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. -33- 165437951.15Docket No.: 146316.8006.WO00

[0159] 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.

[0160] 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.

[0161] The term “alkynyl” 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, propynyl, butynyl, and the like.

[0162] 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.

[0163] The term “aliphatic” includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0164] 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.”

[0165] 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.

[0166] 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. -34- 165437951.15Docket No.: 146316.8006.WO00

[0167] 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.

[0168] 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.

[0169] An “amine” includes compounds that contain an amine group (—NH2).

[0170] 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.

[0171] An “imine” includes compounds that have a carbon-nitrogen double bond, with the nitrogen also attached to a hydrogen (NH═CH—R).

[0172] An “imide” includes compounds containing an imido group (—OC—NH—CO—).

[0173] A “nitrile” includes compounds that are carboxylic acid derivatives and contain a (—CN) group bound to an organic group.

[0174] 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 —CF3and the like.

[0175] 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, -35- 165437951.15Docket No.: 146316.8006.WO00 or structures designed to mimic amino acids (peptide mimetics), and the like, including all the foregoing, are sometimes referred to herein as “residues.”

[0176] 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.

[0177] “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 displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0178] 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. The term “active ingredient,” as used herein, refers one or more of the non-naturally occurring melanocortin analogs of the present technology in any of their embodiments, e.g., the non-naturally occurring melanocortin analog comprising a sequence according to Formula (I). In some embodiments, other active ingredients in addition to the non-naturally occurring melanocortin analogs may be incorporated into the pharmaceutical composition, for example, an additional active ingredient (e.g., an appetite-promoting agent) which is chemically distinct from the non- naturally occurring melanocortin analogs.

[0179] As used herein, a “pharmaceutically acceptable carrier and / or excipient” of the 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” -36- 165437951.15Docket No.: 146316.8006.WO00 encompasses any 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. An “excipient” of the pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound.

[0180] 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.

[0181] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof 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. Unless otherwise specified, durations of time encompassed by “after administration” may include seconds, minutes, hours, days, weeks, months, and years“

[0182] "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 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). -37- 165437951.15Docket No.: 146316.8006.WO00

[0183] “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.

[0184] “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.

[0185] 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.

[0186] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or non-naturally occurring 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).

[0187] 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. -38- 165437951.15Docket No.: 146316.8006.WO00

[0188] 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 loss of appetite, nausea, emesis, anorexia, or cachexia.

[0189] 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.

[0190] As used herein, "kidney dysfunction" includes abnormal function of the kidney that may be caused, in whole or in part, by a kidney disease, kidney injury, or both kidney disease and kidney injury. Kidney dysfunction may also include abnormal kidney function that is caused by a disease or condition of an organ other than the kidney. Kidney dysfunction may also include abnormal function of the kidney that is caused, in whole or in part, by kidney injury-induced kidney disease. Kidney dysfunction may also include abnormal function of the kidney that is caused, in whole or in part, by kidney disease-induced kidney injury. Kidney dysfunction may also include abnormalities in kidney function such as glomerulosclerosis, tubular necrosis, edema of proximal tubules, or tubular fibrosis. Kidney dysfunction may also include abnormal kidney function that occurs after a medical procedure, including, but not limited to, cardiac surgery or kidney transplants. In some embodiments, kidney dysfunction is associated with increased inflammation in the kidney.

[0191] As used herein, the term "kidney disease" includes chronic kidney diseases (CKD), renal failure, kidney failure, other kidney diseases, including, but not limited to, tubular disease, vascular disease, interstitial disease, proteinuric kidney disease, diabetic kidney disease, acute tubular necrosis, acquired cystic kidney disease, kidney amyloidosis, ectopic kidney, glomerular diseases, Goodpasture's disease, kidney dysplasia, kidney infection, kidney stones, lupus nephritis, medullary sponge kidney, nephrotic syndrome, -39- 165437951.15Docket No.: 146316.8006.WO00 polycystic kidney disease, renal artery stenosis, renal tubular acidosis, simple kidney cysts, or solitary or single functioning kidneys.

[0192] As used herein, the term "kidney injury" (e.g., kidney cell injury, renal cell injury, or acute kidney injury) includes minor loss in kidney function, major loss in kidney function, or complete loss of kidney function that is caused by a disease or condition of the kidney or of other organs. For example, kidney injury may be caused by reduced blood flow to the kidneys due to, for example, dehydration, heart failure, sepsis, or certain medications. Kidney injury may also be caused by kidney hypoxia. Kidney injury may also be caused by diseases or conditions of the kidney including, for example, inflammation of the kidney or a portion of the kidney, glomerulonephritis, or vasculitis. Kidney injury may also be caused by medications, such as antibiotics, blood pressure medicines, chemotherapy agents, or dyes used during imaging procedures. For example, kidney injury may be caused by gentamicin. Kidney injury may be measured by various symptoms and characteristics, such as glomerulosclerosis, tubular necrosis, edema of proximal tubules, and / or tubular fibrosis. Kidney injury may be prerenal, intrinsic renal, or postrenal kidney injury.

[0193] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties, including but not limited to U.S. Patent Nos.8,541,545 and 9,534,018. Non-naturally Occurring Melanocortin Analogs

[0194] In some aspects, the present technology provides a non-naturally occurring melanocortin analog. 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 trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), trans-4-guanidinyl- proline (transPro(guan)), cis-4-guanidinyl-proline (cisPro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl -40- 165437951.15Docket No.: 146316.8006.WO00 tyrosine (Dmt), 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 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 (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D- tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, cysteine, D-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), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-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), 7-amino-7,8- dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6- tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2- carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline- 3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 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), dBip, glycine, -41- 165437951.15Docket No.: 146316.8006.WO00 proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D- lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-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, D-histidine, cysteine, Nal(1’), D- Nal(1’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), ornithine, D-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, D-proline, 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, -42- 165437951.15Docket No.: 146316.8006.WO00 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, acetylated D- arginine, acetylated L-arginine, acetylated D-valine, 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, D-tert-leucine, L-tert- leucine, norleucine, 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; 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, D-tert-leucine, L-tert-leucine, norleucine, 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-cysteine, L-cysteine, D-threonine, L-threonine, D-alanine, L-alanine, D-lysine, L-lysine, D-proline, L-proline, D- -43- 165437951.15Docket No.: 146316.8006.WO00 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-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: 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, D-lysine, Dap, D-ornithine, or ornithine; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; 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; a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; and -44- 165437951.15Docket No.: 146316.8006.WO00 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.

[0195] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), 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 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 glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-asprtic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, 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), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, -45- 165437951.15Docket No.: 146316.8006.WO00 isoleucine, tryptophan, D-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), 7-amino-7,8- dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6- tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2- carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline- 3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 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), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D- lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-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, D-histidine, cysteine, Nal(1’), D- Nal(1’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), ornithine, D-ornithine, Pen, dPen, and tetrahydro- isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine or arginine; R9is absent or is tryptophan; -46- 165437951.15Docket No.: 146316.8006.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, D-proline, 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, acetylated D- arginine, acetylated L-arginine, acetylated D-valine, 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, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; -47- 165437951.15Docket No.: 146316.8006.WO00 Y2is absent or is selected from the group consisting of D-proline, L-proline, D- valine, L-valine, D-tert-leucine, 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-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: 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, Dap, 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, D-lysine, D-ornithine, or ornithine; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; -48- 165437951.15Docket No.: 146316.8006.WO00 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; X1X2X3represents an optionally present N-terminus; and Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus.

[0196] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated cysteine, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated 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 glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, 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), transPro(guan), cisPro(guan), -49- 165437951.15Docket No.: 146316.8006.WO00 alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-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), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4- phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 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), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D- lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1’), D-Nal(1’), Aia, D- phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D- alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), ornithine, D-ornithine, Pen, dPen, and tetrahydro- isoquinoline-3-carboxylic acid (Tic); -50- 165437951.15Docket No.: 146316.8006.WO00 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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, 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, D-tert-leucine, L-tert-leucine, norleucine, 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, D-tert-leucine, 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-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; -51- 165437951.15Docket No.: 146316.8006.WO00 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, Dap, 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, D-lysine, D-ornithine, or ornithine; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; 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 -52- 165437951.15Docket No.: 146316.8006.WO00 when Y1is dPro, Y2is dVal, Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified.

[0197] 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; -53- 165437951.15Docket No.: 146316.8006.WO00 R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; 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 or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; -54- 165437951.15Docket No.: 146316.8006.WO00 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; 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; 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 R3is Aba, Ata, or Aia, R6is Aia, then R4is not dNal(2’), or R4is dNal(2’) and R5is not Arg; when R4is p(Cl)dPhe, then R3is not Pro or His; when R4is p(I)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1and R7and at least one of R2and R3is Pro; when Y2-Y4are absent, then Y1is absent or is norleucine; when R2is Pro or Y2is Hyp, then R3is not Pro; when R3, R5, or R6is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1and R7or X1-X2are present and are Ac-dVal-dPro; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys or Cys-Pro-dNal(2’)-Arg-Trp-Cys, then R1is not Ac-Nle or Y1-Y2is not dVal-dPro, dVal-dVal, dPro-dPro; and -55- 165437951.15Docket No.: 146316.8006.WO00 when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R8, then R3is not His or Y1is not dVal.

[0198] 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; -56- 165437951.15Docket No.: 146316.8006.WO00 R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; 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 or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; -57- 165437951.15Docket No.: 146316.8006.WO00 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 139); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-c(Asp-Aba-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 207); Ac-Nle-c(Asp-Aia-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 208); Ac-Nle-c(Asp-Ata-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 209), Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 192); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 193); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dPro-NH2(SEQ ID NO: 190); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 396); Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO: 376); -58- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 392); Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO: 137); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 127); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 129); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO: 131); Ac-Nle-c(Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 198); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 401); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO: 114); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3; B07); Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13; A1); Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 71); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c(Asp-Pro-dNal(2’)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Lys)-dVal-dPro-NH2(SEQ ID NO: 112); Ac-Nle-c(Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 5; D1); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 8; D2); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 286); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 287); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 288); -59- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 289); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 292); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 420); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 424); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 425); and Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 426).

[0199] 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 D-proline, L-proline, hydroxyproline, D-hydroxyproline, D-alanine, D-methionine, D-valine, prolylglycine (Pro- Gly), glycine, transPro(guan), cisPro(guan), provides 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, provides the β-hairpin and / or β- turn structures of the non-naturally occurring melanocortin analog.

[0200] 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.

[0201] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments, the -60- 165437951.15Docket No.: 146316.8006.WO00 acyl group is acetyl In some embodiments, the acylgroup is formyl ).

[0202] Inof the non-naturally occurring melanocortin analog, if present, is modified by an imine group.

[0203] 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 embodiments, the amide group (e.g.,).are not limited to,

[0205] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified. -61- 165437951.15Docket No.: 146316.8006.WO00

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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, -62- 165437951.15Docket No.: 146316.8006.WO00 Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23, and Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23Y24, etc., wherein Y9-Y24, if present, are each independently D-proline or D-valine.

[0211] 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.

[0212] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of Formula (I), a non-naturally occurring modified byan amide may be represented by a terminal -NH2, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2(SEQ ID NO: 126). In some embodiments, the amide group is an N-alkyl amide group ,aryl amide group. In some embodiments, the N-aryl amidegroup is p-nitroanilide 7-amino-4-).-63- 165437951.15Docket No.: 146316.8006.WO00

[0213] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an ester group ,. embodiments, the C-terminus of the non-naturally occurringmelanocortin analog is modified by an aldehyde ).

[0215] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of Formula (I), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro- OH (SEQ ID NO: 127) or by the absence of a C-terminal group, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 2; B07a). 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-dNal2’-Arg-Trp-Lys)- dVal-dPro (SEQ ID NO: 2).

[0216] In some embodiments, R1is absent, and R2is D-aspartic acid. In some embodiments, R1is acetylated norleucine, and R2is D-aspartic acid.

[0217] In some embodiments, X1, X2, and X3are absent. In some embodiments, X1is present and X2and X3are absent.

[0218] 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.

[0219] In some embodiments, the non-naturally occurring melanocortin analog of the present technology is cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide -64- 165437951.15Docket No.: 146316.8006.WO00 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 cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1and any of R5-8when R1is aspartic acid and any of R5-8are lysine; a side-chain lactam bridge between R1and R6when R1is lysine and R6is aspartic acid; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side- chain lactam bridge between R2and R7when R2is glutamic acid, aspartic acid, or CO-cis- CH═CH—CO, and R7is lysine, Dap, or ornithine; a side-chain lactam bridge between R2and R8when R2is glutamic acid or aspartic acid, R8is lysine, and R7is glycine, proline or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2or R4is 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 / or a lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino-propionic acid. Cyclization may also occur from any of the X residues (optional stabilizing N-terminus residues). For example, X2may be an aspartic acid that may be used for cyclization.

[0220] 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 D-hydroxyproline, R4is D-Nal(2′), R5is arginine, R6is D-tryptophan or L-tryptophan, R7is lysine, Y1is D-valine, and / or Y2is D-proline.

[0221] 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; D3), wherein c represents cyclization through R2and R7via a lactam bond.

[0222] 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, D-hydroxyproline, phenylalanine, and histidine, R4is histidine or dNal(2′), R5is dNal(2′) or arginine, R6is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan, R7is tryptophan or proline, R8is lysine, Y1is -65- 165437951.15Docket No.: 146316.8006.WO00 selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y2is D- proline.

[0223] 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; D1); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 6; D1γ); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2(SEQ ID NO: 7; D1δ); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 8; D2); Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 9; D4); and Ac-Nle-c(Asp-Pro-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5), wherein c represents cyclization through R2and R8via a lactam bond.

[0224] 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: 11; D1α), wherein c represents cyclization through R2and R10via a lactam bond.

[0225] 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: 12; D1β), wherein c represents cyclization through R4and R10via a lactam bond.

[0226] 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: 13; A1). In some embodiments, the sequence of Formula (I) is Ac- Nle-Pro-dNal(2’)-Arg-Trp-dVal-dPro-NH2(SEQ ID NO: 14; A2).

[0227] In some embodiments of the sequence of Formula (I), R1is acetylated norleucine. Alternatively, in some embodiments, R1is an acetylated amino acid other than -66- 165437951.15Docket No.: 146316.8006.WO00 acetylated norleucine. In some embodiments, R1is a non-acetylated amino acid. 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: 15); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dIle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dLeu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 18); Ac-dVal-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 19); Ac-dAla-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Ala-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Tle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 22); Ac-dTle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-dNle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nva-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 25); Ac-Gly-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dPro-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dCys-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 28); Ac-dPhe-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 29); Ac-dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dGln-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 31); Ac-dAsn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 32); Ac-transPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-cisPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 36); -67- 165437951.15Docket No.: 146316.8006.WO00 Dmt-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 39), wherein c represents cyclization through R2and R7via a lactam bond.

[0228] In some embodiments, when the sequence of Formula (I) is cyclized through R2and R7, then R2is Asp and R7is Lys. Alternatively, in some embodiments, when the sequence of Formula (I) is cyclized through R2and R7, then R2is an amino acid capable of forming a linkage to the residue at R7other than Asp and R7is an amino acid capable of forming a linkage to the residue at R2other than Lys. For example, when R2is an amino acid other than Arg and R7is an amino acid other than Lys, the residue at R2may be capable of forming a linkage such as a lactam bond or a disulfide bond with the residue at R7. 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: 40); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 43); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 44); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 46); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 47); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 50); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 51); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 52); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 53); -68- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 56); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 59); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 60); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 63); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 66); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 69);and Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO: 70), wherein c represents cyclization through R2and R6or R7via a lactam bond or a disulfide bond.

[0229] In some embodiments of the sequence of Formula (I), R3is Pro. Alternatively, in some embodiments, R3is absent or an amino acid other than Pro. 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: 71); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 73); -69- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 76); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 79); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 80); Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c(Asp-dIle-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 86); Ac-Nle-c(Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 87); Ac-Nle-c(Asp-cisPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 88); Ac-Nle-c(Asp-Val-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 89); Ac-Nle-c(Asp-Ile-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 90); Ac-Nle-c(Asp-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 91); Ac-Nle-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 92); Ac-Nle-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 93); Ac-Nle-c(Asp-dLeu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 95); and Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 96), wherein c represents cyclization through R2and R7via a lactam bond. -70- 165437951.15Docket No.: 146316.8006.WO00

[0230] In some embodiments of the sequence of Formula (I), R5is Arg. Alternatively, in some embodiments, R5is absent or an amino acid other than Arg. 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: 97); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 99); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 100); Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 103); Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 106); Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 107); Ac-Nle-c(Asp-Pro-dNal(2’)-dHis-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2’)-dAla-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2’)-dAsp-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2’)-dGlu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 111), wherein c represents cyclization through R2and R7via a lactam bond.

[0231] In some embodiments of the sequence of Formula (I), R6is Trp. Alternatively, in some embodiments, R6is absent or an amino acid other than Trp. 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: 112); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 113); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 114); -71- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 115); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 116); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2(SEQ ID NO: 117); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dPhe-Lys)-dVal-dPro-NH2(SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(2’)-Lys)-dVal-dPro-NH2(SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dAla-Lys)-dVal-dPro-NH2(SEQ ID NO: 124), wherein c represents cyclization through R2and R7via a lactam bond.

[0232] In some embodiments of the sequence of Formula (I), R4is dNal(2’). Alternatively, in some embodiments, R4is an amino acid other than dNal(2’). For example, in some embodiments, when R4is an amino acid other than dNal(2’), R4is Bip. In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal- dPro-NH2(SEQ ID NO: 125), wherein c represents cyclization through R2and R7via a lactam bond.

[0233] In some embodiments of the sequence of Formula (I), Y1is dVal and Y2is dPro. Alternatively, in some embodiments, Y1is an amino acid other than dVal and Y2is an amino acid other than dPro. In some embodiments, Y1is dVal and Y2is an amino acid other than dPro. In some embodiments, Y1is an amino acid other than dVal and Y2is dPro.

[0234] In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is an amino acid other than dVal, Y2is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is dVal, Y2is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is an amino acid other than dVal, Y2is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is unmodified. -72- 165437951.15Docket No.: 146316.8006.WO00

[0235] In embodiments of Formula (I) when Y1is an amino acid other than dVal, then Y1is selected from dPro, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle. In embodiments of Formula (I) when Y2is an amino acid other than dPro, then Y2or selected from dVal, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. 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: 126); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 127); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 129); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 130); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2 (SEQ ID NO: 131); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-dHyp-NH2(SEQ ID NO: 132); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-dVal-NH2 (SEQ ID NO: 133); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-dVal-NH2 (SEQ ID NO: 134); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO: 135); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO: 136); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2 (SEQ ID NO: 137); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO: 138); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO: 139); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-NH2 (SEQ ID NO: 141); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO: 142); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-NH2 (SEQ ID NO: 143); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-NH2 (SEQ ID NO: 144); -73- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-NH2 (SEQ ID NO: 145); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-NH2 (SEQ ID NO: 146); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO: 147); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-Ala-NH2 (SEQ ID NO: 148); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Gly-Gly-NH2 (SEQ ID NO: 149); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO: 150); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO: 151); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asn-NH2 (SEQ ID NO: 152); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsp-NH2 (SEQ ID NO: 153); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ ID NO: 154); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsn-NH2 (SEQ ID NO: 155); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO: 157); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-dPro-NH2 (SEQ ID NO: 158); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-dPro-NH2 (SEQ ID NO: 159); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO: 160); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO: 161); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-NH2 (SEQ ID NO: 162); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO: 163); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO: 164); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-NH2 (SEQ ID NO: 165); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-NH2 (SEQ ID NO: 166); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO: 167); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2 (SEQ ID NO: 168); -74- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2 (SEQ ID NO: 169); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2 (SEQ ID NO: 170); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO: 171); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2 (SEQ ID NO: 172); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2 (SEQ ID NO: 173); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO: 174); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2(SEQ ID NO: 175); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 176); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 177); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2(SEQ ID NO: 178); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 179); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 180); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2(SEQ ID NO: 181); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-NH2(SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-NH2(SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID NO: 186); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dVal-NH2(SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dTle-NH2(SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dTle-NH2 (SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

[0236] In some embodiments of the sequence of Formula (I) when Y3is present and Y4-8are absent, then each of Y1, Y2, and Y3are independently selected form dVal and dPro. -75- 165437951.15Docket No.: 146316.8006.WO00 In some embodiments of the sequence of Formula (I) when Y3and Y4are present and Y5-8are absent, then each of Y1, Y2, Y3, and Y4are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y5are present and Y6-8are absent, then each of Y1-Y5are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y6are present and Y7-8are absent, then each of Y1-Y6are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y7are present and Y8is absent, then each of Y1-Y7are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y8are present, then each of Y1-Y8are independently selected form dVal and dPro. 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)-dVal-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2(SEQ ID NO: 191); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 193); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 194), wherein c represents cyclization through R2and R7via a lactam bond.

[0237] In some embodiments of the sequence of Formula (I), 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: 195); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 196); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 197), wherein c represents cyclization through R2and R7via a lactam bond. -76- 165437951.15Docket No.: 146316.8006.WO00

[0238] As described above, some of the non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor and the melanocortin 4 receptor with the same or generally similar affinity. Other non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor. In some embodiments, when the non-naturally occurring melanocortin analog of the present technology binds the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, then 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: 198); Ac-Nle-c(Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 199); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 200); c(CO-cis-CH = CH-CO-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 201); Ac-Nle-c(Asp-β-Ala-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 202); Ac-Nle-c(Asp-Mamb-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 203); Ac-Nle-c(Asp-Acpc-dNal(2′) Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 204); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2(SEQ ID NO: 205); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Trp-NH2(SEQ ID NO: 206); Ac-Nle-c(Asp-Aba-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 207); Ac-Nle-c(Asp-Aia-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 208); and Ac-Nle-c(Asp-Ata-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 209), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond or through R2and R5via a disulfide bond.

[0239] Some non-naturally occurring melanocortin analog comprising the sequence of Formula (I) may bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. In some embodiments, when the non-naturally occurring melanocortin analog binds the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor, then the sequence of Formula (I) is selected from the group consisting of: -77- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Aic-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 210); Ac-Nle-c(Asp-Cpe-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 211); Ac-Nle-c(Asp-Che-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 212); Ac-Nle-c(Asp-Oic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 213); Ac-Nle-c(Asp-Ioc-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 214); Ac-Nle-c(Asp-Tic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle-c(Asp-His-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c(Asp-His-dNal(2’)-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 219); Ac-Nle-c(Asp-Pro-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c(Asp-Pro-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 221); Ac-Nle-c(Asp-Pro-dNal(2’)-cisPro(guan) -Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 222); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 224); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 225); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 226); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 228); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 229); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 230); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 231); Ac-Glu-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2(SEQ ID NO: 232); and -78- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 233),

[0240] wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0241] In some embodiments of the sequence of Formula (I), when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond or a disulfide bond between R1and any one of R5-8. In some embodiments, when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1and R6. In some embodiments, when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1and R7. In some embodiments, Y1and Y2are present and are dVal and dPro, respectively, and Y3-Y8are absent. In some embodiments, Y1-Y8are absent. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 235); Ac-Nle-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 236); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 238); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 239); Ac-dArg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 240); Ac-Arg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 241); Ac-dArg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 242); Ac-Nle-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Arg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 244); Ac-dArg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 245); Ac-Nle-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c(Asp-Pro-Trp-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 248); -79- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 249); Ac-Nle-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH2(SEQ ID NO: 251); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 254), wherein c represents cyclization through R1and any one of R5-8via a lactam bond or a disulfide bond.

[0242] In some embodiments of the sequence of Formula (I), when X1and X2are present and X3is absent, the sequence of Formula (I) is cyclized through a lactam bond between R1and R6. In such embodiments, X1and X2are each independently selected from dVal and dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-NH2 (SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-Nle-NH2(SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-Nle-NH2(SEQ ID NO: 258); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO: 260), wherein c represents cyclization through R2and R7via a lactam bond.

[0243] In some embodiments of the sequence of Formula (I), R1is Nle and one or more of X1and X2are present. In some embodiments, R1is Nle X1is present, and X2is absent. In some embodiments, R1is Nle, and X1and X2are present. In some embodiments, the sequence of Formula (I) is: Ac-dVal-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 262), -80- 165437951.15Docket No.: 146316.8006.WO00 wherein c represents cyclization through R2and R7via a lactam bond.

[0244] In some embodiments of the sequence of Formula (I), R1is Ac-Glu. In some embodiments, R1is Ac-Glu, R2is Asp, R3is Glu, His, or Arg, R4is dNal(2’), R5is Arg, R6is Trp, and R7is Lys. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 263); Ac-Glu-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R2and R7via a lactam bond.

[0245] In some embodiments of the sequence of Formula (I), R5is His. In some embodiments, when R5is His, then R3is His and the sequence of Formula (I) is cyclized via a lactam bond through R1or R2and R7. In some embodiments, X1is Ac-Arg or absent, R1is Ac-Nle, Asp or absent, R2is Asp or Pro, R3is His, R4is dNal(2’), R5is His, R6is Trp, and R7is Lys or Dap. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 269); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 270); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 273); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 276); -81- 165437951.15Docket No.: 146316.8006.WO00 Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 277); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO: 279); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281); wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0246] In some embodiments of the sequence of Formula (I), R1is Ac-Nle, R2is Asp and dAsp, R3is Pro or His, R4is dNal(2’), R5is Arg, R6is Trp, and R7is Lys and dLys. In such embodiments, Y1, Y2, and Y3are varied. 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-NH2 (SEQ ID NO: 282); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 283); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 284); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 285); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 286); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 287); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO: 288); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 289); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 290); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 291); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO: 294); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β2Val-NH2 (SEQ ID NO: 295); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β3Val-NH2 (SEQ ID NO: 296); -82- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2 (SEQ ID NO: 297); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2 (SEQ ID NO: 298); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO: 299); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2 (SEQ ID NO: 300); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β2Val-β3Pro-NH2 (SEQ ID NO: 301); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Val-β3Pro-NH2(SEQ ID NO: 302); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO: 303); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2 (SEQ ID NO: 304); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2 (SEQ ID NO: 305); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO: 306); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-β3Pro-β3Pro-NH2 (SEQ ID NO: 307); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 308); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2(SEQ ID NO: 309); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 310); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2 (SEQ ID NO: 311); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO: 312); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2(SEQ ID NO: 313); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO: 314); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 315); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 316); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO: 317); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO: 318); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO: 319); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 320); -83- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 321); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 322); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 323); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 324); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 325); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 326); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 327); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 328); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 329); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 330); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 331); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO: 333); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 335); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO: 336); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO: 337); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 338); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO: 339); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO: 340); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2 (SEQ ID NO: 341); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2 (SEQ ID NO: 342); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2(SEQ ID NO: 343); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO: 344); -84- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO: 345); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO: 346); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2(SEQ ID NO: 347); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 348); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 349); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2(SEQ ID NO: 350) Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 351); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 352); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 353); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 354); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 356); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO: 357); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 359); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 360); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 361); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 362); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO: 363); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO: 364); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 365); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO: 367); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 368); -85- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 369); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 370); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 371); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 372); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 373); and Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 374), wherein c represents cyclization through R1and R7via a lactam bond.

[0247] 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-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375); Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-Nle-c(Asp-His-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-Nle-c(Asp-Pro-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c(Asp-Arg-Pro-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO: 380); Ac-Nle-c(Asp-Arg-Pro-dBip-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO: 381); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c(Asp-Aia-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 383); Ac-Nle-c(Asp-Ata-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 384); Ac-Nle-c(Asp-Aba-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 385); Ac-Nle-c(Asp-Aia-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 386); Ac-Nle-c(Asp-Ata-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 387); Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 388); -86- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 391); Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 392); Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 393); Ac-Nle-c(Asp-Pro-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 394); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 395); Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 396); Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 398); Ac-Nle-c(Asp-His-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 399); Ac-Nle-c(Asp-His-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 400); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 401); Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 402); Ac-Nle-c(Asp-His-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 403); Ac-Nle-c(Asp-His-dPhe-transPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 404); Ac-Nle-c(Asp-His-dPhe-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 405); Ac-Nle-c(Asp-Pro-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 406); Ac-Nle-c(Asp-Pro-dPhe-transPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 407); Ac-Nle-c(Asp-Pro-dPhe-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 408); Ac-Nle-c(Asp-Pro-dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 409); Ac-Nle-c(Asp-Pro-dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 410); Ac-Nle-c(Asp-Pro-dPhe-Arg-Ata-Lys)-dVal-dPro-NH2(SEQ ID NO: 411); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 412); -87- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 414); and Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH2(SEQ ID NO: 415), wherein c represents cyclization through R1and R7or R8via a lactam bond.

[0248] 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: 416); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 417); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 418); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dlys)-dThr-dPro-dThr (SEQ ID NO: 419); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 420); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 422); Ac-Nle-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 423); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 425); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 426); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 427); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO: 428); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO: 429); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βPro-βVal-NH2 (SEQ ID NO: 430); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βPro-βVal-NH2 (SEQ ID NO: 431); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO: 432); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2 (SEQ ID NO: 433); -88- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βVal-βPro-NH2 (SEQ ID NO: 434); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-βVal-βPro-NH2 (SEQ ID NO: 435); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO: 436); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2 (SEQ ID NO: 437); Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-dLys)-βPro-βPro-NH2 (SEQ ID NO: 438); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-βPro-βPro-NH2(SEQ ID NO: 439); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO: 440); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2 (SEQ ID NO: 441); Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-dLys)-βVal-βVal-NH2 (SEQ ID NO: 442); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βVal-βVal-NH2(SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 444); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 445); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βVal-NH2(SEQ ID NO: 446); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO: 448); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 449); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 450); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 452); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 453); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βThr-βPro-βThr (SEQ ID NO: 454); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βThr-βPro-βThr (SEQ ID NO: 455); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 456); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 457); -89- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 458); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 460); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 462); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO: 463); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO: 464); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2 (SEQ ID NO: 465); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βPro-βAla-NH2 (SEQ ID NO: 466); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βPro-βAla-NH2(SEQ ID NO: 467); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2 (SEQ ID NO: 468); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2 (SEQ ID NO: 469); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βAla-βPro-NH2(SEQ ID NO: 470); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βAla-βPro-NH2 (SEQ ID NO: 471); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2 (SEQ ID NO: 472); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO: 473); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-βVal-βAla-NH2(SEQ ID NO: 474); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-βVal-βAla-NH2 (SEQ ID NO: 475); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 476); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 477); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO: 478); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 479); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 480); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 481); -90- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO: 482); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 483); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 484); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 485); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO: 487); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 488); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 489); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 490); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 491); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 492); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 493); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO: 494); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 495); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 496); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO: 497); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO: 498); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 499); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 500); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 501); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 502); and Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 503), wherein c represents cyclization through R1and R7via a lactam bond. -91- 165437951.15Docket No.: 146316.8006.WO00

[0249] In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor antagonist, such as a melanocortin 3 receptor and / or a melanocortin 4 receptor antagonist. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor agonist, such as a melanocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, and / or melanocortin 5 receptor agonist. For example, in some embodiments, the melanocortin analog has agonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as the melanocortin 1 and melanocortin 5 receptors. In other embodiments, the melanocortin analog has antagonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as agonist activity at the melanocortin 1 and melanocortin 5 receptors.

[0250] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the of the present technology. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-374. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 2-281. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 3, 20, 29-32, 67-70, 99-102, 127-130, 159, 163-166, 187-190, 391, 394, 396, 398, and 399. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 128, 182-189, 212-281, 394 and 399.

[0251] 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: -92- 165437951.15Docket No.: 146316.8006.WO00Formulations

[0252] The compositions comprising the carriers and / or excipients of the present technology facilitate delivery of the non-naturally occurring melanocortin analog in any of its embodiments to a subject.

[0253] In some embodiments, the non-naturally occurring melanocortin analog is present in a composition.

[0254] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0255] In some embodiments, the non-naturally occurring melanocortin analog comprises TCMCB07, and the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog comprising TCMCB07 is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, 10 -93- 165437951.15Docket No.: 146316.8006.WO00 mg / mL to 75 mg / mL, 15 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, or 25 mg / mL to 30 mg / mL, relative to a total volume of the composition. In some embodiments, the non- naturally occurring melanocortin analog comprising TCMCB07 is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0256] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0257] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises the non-naturally occurring melanocortin analog of formula (I) at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises TCMCB07.

[0258] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject.

[0259] 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 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.

[0260] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2to 25 kg / m2. In some embodiments, the subject has a BMI of less than 20 kg / m2. In some embodiments, the subject has a BMI of less than 18.5 kg / m2. -94- 165437951.15Docket No.: 146316.8006.WO00

[0261] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of “normal” BMI (e.g., 18.5 kg / m2).

[0262] The compositions comprising the carriers and / or excipients of the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analogs to a subject. Other purposes of the compositions comprising the carriers and / or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.

[0263] The carriers and / or excipients of the composition may generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0264] In some embodiments, the carrier and / or excipient is isotonic.

[0265] To achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0266] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.

[0267] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection. -95- 165437951.15Docket No.: 146316.8006.WO00

[0268] In some embodiments, the composition includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0269] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0270] In some embodiments, sodium acetate is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.1 mg / mL, 7.5 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0271] In some embodiments, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0272] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0273] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, -96- 165437951.15Docket No.: 146316.8006.WO00 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0274] In some embodiments, Tris is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.3 mg / mL, 7.6 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0275] In some embodiments, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition.

[0276] In some embodiments, Tris is present in the composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM, relative to a total volume of the composition.

[0277] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0278] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0279] In some embodiments, a weight ratio of sodium acetate to Tris is 1:4 to 4:1, 2:7 to 7:2, 1:3 to 3:1, 2:5 to 5:2, 1:2 to 2:1, 2:3 to 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1. -97- 165437951.15Docket No.: 146316.8006.WO00

[0280] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[0281] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0282] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m- cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0283] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0284] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0285] In some embodiments, the composition has a pH ranging from 6.5 to 8.5. In some embodiments, the composition has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0286] In some embodiments, the composition is basic and has a pH of about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the -98- 165437951.15Docket No.: 146316.8006.WO00 composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the composition has a pH of 7.3 or 7.4.

[0287] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0288] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP.

[0289] The compositions of the present technology may be formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0290] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers. -99- 165437951.15Docket No.: 146316.8006.WO00

[0291] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0292] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises sodium acetate at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.

[0293] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises Tris at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0294] The compositions of the present technology may be formulated for intranasal delivery. In some embodiments, the intranasal composition comprises a non-naturally occurring melanocortin analog of the present technology and a carrier and / or excipient.

[0295] The carriers and / or excipients of the composition may generally include one or more of the following components: (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and / or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition. -100- 165437951.15Docket No.: 146316.8006.WO00

[0296] In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0297] To achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some aspects, the salt is sodium chloride at a concentration of 0.9% wt.

[0298] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises sodium acetate, Tris, and / or a phosphate buffer.

[0299] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0300] In some embodiments, the composition includes water (e.g., water for injection) in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0301] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0302] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0303] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, -101- 165437951.15Docket No.: 146316.8006.WO00 Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0304] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0305] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0306] In some embodiments, sodium phosphate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0307] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m- cresol, benzyl alcohol, benzalkonium chloride, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben. -102- 165437951.15Docket No.: 146316.8006.WO00

[0308] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0309] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0310] In some embodiments, the composition has a pH approximating the normal pH range of the nasal fluid. In some embodiments, the composition has a pH ranging from 5.5 to 6.5. In some embodiments, the composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0311] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0312] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP. -103- 165437951.15Docket No.: 146316.8006.WO00

[0313] In some embodiments, the composition comprises one or more antioxidants. For example, the composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0314] In some embodiments, the composition comprises a surfactant, such as a sorbitan ester.

[0315] In some embodiments, the composition comprises a flavoring or scent, such as an aromatic oil.

[0316] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0317] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. In some embodiments, the solvent or vehicle is purified water, ethyl alcohol, propylene glycol. The composition may comprise between 0.03% wt and 1% wt melanocortin solubilized or suspended in a solvent or vehicle. The composition may comprise about 0.03% wt, 0.05% wt, 0.1% wt, 0.15% wt, 0.2% wt, 0.25% wt, 0.3% wt, 0.35% wt, 0.4% wt, 0.45% wt, 0.5% wt, 0.55% wt, 0.6% wt, 0.65% wt 0.7% wt, 0.75% wt, 0.8% wt, 0.85% wt, 0.9% wt, 0.95% wt, or 1% wt of the non-naturally occurring melanocortin analog.

[0318] In some embodiments, the composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0319] The composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be -104- 165437951.15Docket No.: 146316.8006.WO00 formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, or nebulizer. In some embodiments, the composition includes a propellant, such as hydrofluoroalkane.

[0320] In some embodiments, the composition may be configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1ug to 100ug per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1ug to 100ug, 5ug to 90ug, 10ug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray. Additional Embodiments of Non-Naturally Occurring Melanocortin Analogs

[0321] Additional aspects of non-naturally occurring melanocortin analogs that may be used in the methods of the present technology are described below.

[0322] Cyclized melanocortin analogs have shown improved efficacy and stability. See Balse-Srinivasan et al., J. Med. Chem.46(17): 3728-3733 (2003) and Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001); Kavarana, et al., J. Med. Chem.45(12): 2644-2650 (2002). In one aspect, the non-naturally occurring melanocortin analog represented by Formula I is cyclized. The following represents a non-limiting list of examples of how the non-naturally occurring melanocortin analog represented by Formula I may be cyclized:

[0323] In Formula I, disulfide bond between R1or R2and R7or Y1, when R1or R2is cysteine and R7or Y1is cysteine as described in Balse-Srinivasan et al., J. Med. Chem., 2003, 46(23): 4965-4973. When Y1is cysteine, Y2is not absent, but is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring.

[0324] A lactam bridge between R1and R7, when R1is norleucine and R7is glutamic acid, as described in Mayorov et al. J. Med. Chem.49: 1946-1952 (2006) and Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001).

[0325] A side-chain lactam bridge between R2and R7, when R2is glutamic acid or aspartic acid and R7is lysine, as described in Bednarek et al., Biochem. Biophys. Res. Com. 286(3): 641-645 (2001). -105- 165437951.15Docket No.: 146316.8006.WO00

[0326] A lactam bridge between R1and R7, when R1is succinic acid or o-pthalic acid and R7is lysine, as described in Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641- 645 (2001) and Kavarana et al., J. Med. Chem.45(12): 2644-2650 (2002).

[0327] A lactam bridge between R2or R3and R7, when R2or R3is succinic acid and R7is 2,3-diamino-propionic acid as described in Bednarek et al., Biochem. Biophys. Res. Com. 286(3): 641-645 (2001).

[0328] A “backbone” cyclized peptide is formed by covalent bond formation between the C- and / or N-terminus of a linear peptide of interest. An example of this is described in the bonding of two amide nitrogens via a bridge consisting of alkyl groups and an amide, as described by Hess et al., J. Med. Chem.50: 6201-6211 (2007). Peptide Synthesis

[0329] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology.

[0330] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.

[0331] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to -106- 165437951.15Docket No.: 146316.8006.WO00 the general principles of solid phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem.24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980).

[0332] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0333] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0334] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.

[0335] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-((R,S)-α-(1-(9H-fluor-en-9-yl)-methoxyformamido)-2,4- dimethyloxybenzyl)-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker-BHA resin supports are commercially -107- 165437951.15Docket No.: 146316.8006.WO00 available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20- 40% v / v) in N,N-dimethylformamide (DMF) may be used for this purpose.

[0336] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0337] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0338] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N′-dicyclohexylcarbodiimide / 1- -108- 165437951.15Docket No.: 146316.8006.WO00 hydroxybenzotriazole (DCCl / HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).

[0339] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like. Salt Forms of Peptides

[0340] The non-naturally occurring melanocortin analog peptides of the present technology may be in the form of any salt. The term “pharmaceutically acceptable salts” refers to salts prepared from non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0341] When the peptides of the present technology are basic, acid addition salts may be prepared from non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, -109- 165437951.15Docket No.: 146316.8006.WO00 mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Acid addition salts of the peptides of the present technology are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides of the present technology include an acidic moiety, suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts. Pharmacokinetics and Pharmacodynamics

[0342] The non-naturally occurring melanocortin analogs of the present technology exhibit pharmacokinetic (pK) and / or pharmacodynamic (pD) parameters. Such pK and / or pD may be expressed or otherwise determined relative to a control, which, in some instances, may be a non-naturally occurring melanocortin analog lacking one or more features of the non-naturally occurring melanocortin analogs of the present technology.

[0343] In some embodiments, the pK and / or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and / or temporal measurements (e.g., Tfinal, Cmax, T ½ (h)), AUC, or Tmax.In some embodiments, the non-naturally occurring melanocortin analogs have reduced clearance and / or metabolism, increased uptake, absorption, and / or stability, relative to a control. Clearance

[0344] “Clearance” may refer to the elimination, absorption, and / or metabolism of the non-naturally occurring melanocortin analogs in the subject’s plasma. Clearance may be assessed as volume of plasma cleared of the non-naturally occurring melanocortin analogs over time (e.g., mL / min, L / hr, or L / day) and / or may be normalized to body weight of the subject (e.g., mL / min / kg). Reduced clearance may also be represented by an increase in half-life or volume of distribution (Vd). In some embodiments, measuring clearance comprises measuring a terminal elimination rate constant (λz) or an inter-compartmental clearance (Q). -110- 165437951.15Docket No.: 146316.8006.WO00

[0345] In some embodiments, the reduction in clearance comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0346] In some embodiments, the reduction in clearance comprises a measurement during administration of the non-naturally occurring melanocortin analogs. In some embodiments, the reduction in clearance comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Concentration

[0347] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, and / or serum concentration relative to a control. “Concentration” may comprise a measurement reflecting one or more of the absolute amounts of the non-naturally occurring melanocortin analogs, the absorption of the non-naturally occurring melanocortin analogs, the metabolism of non-naturally occurring melanocortin analogs, or the elimination of non-naturally occurring melanocortin analogs.

[0348] The increased tissue, plasma, and / or serum concentration may be an increase in concentration of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The concentration may be measured at an intermediate time point or a final time point and may be measured as a mean residence time (MRT), an average concentration (Cavg), a trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (CT).

[0349] In some embodiments, the increased concentration is reflected by an increase in peak plasma concentration (Cmax). An increase in Cmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmaxcomprises a dose normalized Cmax (DNCmax). -111- 165437951.15Docket No.: 146316.8006.WO00

[0350] In some embodiments, the increased concentration is reflected by an increase in minimum plasma concentration (Cmin). An increase in Cmin may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmin comprises a dose normalized Cmin (DNCmin).

[0351] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax(Tmax). A reduced Tmaxmay suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0352] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinal). An increased Tfinal may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0353] In some embodiments, the increased concentration is reflected by an increase in area under the curve (AUC). An increase in AUC may signify increased exposure to the non-naturally occurring melanocortin analogs and / or may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. The AUC measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0354] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non- naturally occurring melanocortin analogs.

[0355] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non- naturally occurring melanocortin analogs. -112- 165437951.15Docket No.: 146316.8006.WO00

[0356] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0357] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0358] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at the completion of administration of the non- naturally occurring melanocortin analogs. Distribution

[0359] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control. The increased distribution may be an increase in distribution of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The distribution may be measured at an intermediate time point or a final time point.

[0360] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vdor Vdß), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd,Vdß, Vz, and / or Vssmay suggest large distribution beyond the tissue, plasma, and / or serum compartment, relative to the control.

[0361] In some embodiments, the increase in distribution comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs. -113- 165437951.15Docket No.: 146316.8006.WO00

[0362] In some embodiments, the increase in distribution comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0363] In some embodiments, the increase in distribution comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0364] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0365] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Additional pD and pK Embodiments

[0366] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following: (a) an increase in half-life relative to a control; (b) a reduction in clearance relative to a control; (c) an increase in tissue concentration relative to a control; (d) an increase in plasma concentration relative to a control; (e) an increase in serum concentration relative to a control; (f) an increase in distribution relative to a control; (g) an increase in an AUC measurement relative to a control; (h) an increase in a DNAUC measurement relative to a control; (i) an increase in Tfinal relative to a control; (j) an increase in Cmax relative to a control; (k) an increase in Cminrelative to a control; -114- 165437951.15Docket No.: 146316.8006.WO00 (l) an increase in DNCmin relative to a control; (m) an increase in MRT relative to a control; (n) an increase in Cavgrelative to a control; (o) an increase in Ctrough relative to a control; (p) an increase in CT relative to a control; (q) an increase in Vdrelative to a control; (r) a reduction in Tmaxrelative to a control; or (s) a reduction in Q relative to a control.

[0367] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; (c) an increase in tissue concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (d) an increase in plasma concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (e) an increase in serum concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (f) an increase in distribution by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -115- 165437951.15Docket No.: 146316.8006.WO00 (g) an increase in an AUC by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% measurement relative to a control; (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (i) an increase in Tfinalby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (j) an increase in Cmaxby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (k) an increase in Cminby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (l) an increase in DNCminby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (m) an increase in MRT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (n) an increase in Cavg by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (o) an increase in Ctrough by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -116- 165437951.15Docket No.: 146316.8006.WO00 (p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (q) an increase in Vd by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (r) a reduction in Tmaxby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or (s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control. Associated Methods

[0368] The present technology provides methods of stimulating appetite and / or increasing body weight of a subject suffering from a kidney disease and / or a liver disease. The methods include administering to the subject a therapeutically effective amount of a non-naturally occurring melanocortin analog. 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, emesis, and symptoms associated with hypermetabolic immunoinflammatory syndrome in the subjects of the present technology (e.g., a subject having a kidney disease and / or a liver disease). Subject Features Kidney and Liver Disease:

[0369] The subject of the present technology may have or be at risk of developing a kidney disease and / or a liver disease. The kidney and / or liver disease applicable to the methods of the present technology may be any kidney and / or liver disease known to a person of ordinary skill in the art. For example, the kidney disease may comprise chronic kidney disease (CKD), and / or renal failure (e.g., chronic renal failure). The liver disease may comprise nonalcoholic fatty liver disease (NAFLD), e.g., nonalcoholic steatohepatitis -117- 165437951.15Docket No.: 146316.8006.WO00 (NASH). The kidney disease and / or the liver disease may be fibrotic. In some embodiments, the kidney and / or liver disease may cause fatigue, weakness, nausea, anorexia, cachexia, loss of appetite, reduced appetite, decreased food consumption, and / or weight loss.

[0370] In some embodiments, the subject has a kidney disease. In some embodiments, the kidney disease comprises CKD and / or renal failure.

[0371] In some embodiments, the subject has undergone or is undergoing dialysis. Non-limiting examples of dialysis include peritoneal- and hemodialysis. In some embodiments, the subject has undergone or is undergoing renal transplantation.

[0372] In some embodiments, the subject may have kidney dysfunction and / or kidney injury in addition to, or in lieu of the kidney disease of the present technology.

[0373] In some embodiments, the subject has a liver disease. Non-limiting examples of liver disease include NAFLD, NASH, alcoholic liver disease, viral hepatitis, hemochromatosis, drug-induced hepatitis, Wilson's disease, sclerosing cholangitis, primary biliary cirrhosis, Budd-Chiari syndrome, venoocclusive disease, autoimmune hepatitis, steatohepatitis, partial hepatectomy, or Reye's syndrome. In some embodiments, the liver disease is NAFLD. In some embodiments, NAFLD is NASH. BMI, weight, appetite, and associated features:

[0374] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2to 35 kg / m2. In some embodiments, the subject has a BMI of less than 20 kg / m2. In some embodiments, the subject has a BMI of less than 18.5 kg / m2.

[0375] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of "normal" BMI (e.g., 18.5 kg / m2).

[0376] 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 1% per month, 2% per month, 5% per month, or 10% per month 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. -118- 165437951.15Docket No.: 146316.8006.WO00

[0377] In some embodiments, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration.

[0378] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease and / or the liver disease.

[0379] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia.

[0380] In some embodiments, the subject is cachectic if they meet the Fearon criteria for weight loss. Whether a subject meets the Fearon criteria may be determined using methods known to one of ordinary skill in the art. In some embodiments, the Fearon criteria of weight loss comprise (1) a weight loss greater than 5% in the previous 6 month, or (2) a weight loss greater than 2% wherein the subject has a BMI less than 20 kg / m2or the subject has sarcopenia. Whether the subject has sarcopenia may be determined using methods known to one of skill in the art. Additional Subject Features:

[0381] 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 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. Dosing

[0382] In general, the actual quantity of pharmaceutical compositions administered to a subject may vary between wide ranges depending upon the mode of administration, the formulation used, and the response desired. The dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect. Thus, a therapeutically effective amount includes an amount of a peptide, such as the non-naturally occurring melanocortin analogs (e.g., non- naturally occurring melanocortin analogs) of the present technology, or pharmaceutical composition that is sufficient to increase body weight and / or increase food consumption in -119- 165437951.15Docket No.: 146316.8006.WO00 a metabolically unchallenged subject. In some embodiments, therapeutically effective amount includes an amount of a peptide, such as the non-naturally occurring melanocortin analogs (e.g., non-naturally occurring melanocortin analogs) of the present technology, or pharmaceutical composition alleviates a feeding disorder in a patient, or to prevent or delay onset or recurrence of the feeding disorder, or for the management of the feeding disorder in patients with diseases or syndromes associated with cachexia, including secondary to immune disorders and cancer, or other diseases and conditions of the present technology.

[0383] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog (e.g., to stimulate appetite of a subject, in terms of mg of the non-naturally occurring melanocortin analog per body weight of the subject (kg), ranges from about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 90 mg / kg, about 0.1 mg / kg to about 80 mg / kg, about 0.5 mg / kg to about 70 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1.2 mg / kg to about 50 mg / kg, about 1.4 mg / kg to about 40 mg / kg, about 1.6 mg / kg to about 30 mg / kg, about 1.8 mg / kg to about 20 mg / kg, about 2 mg / kg to about 10 mg / kg, about 2.2 mg / kg to about 5 mg / kg, about 2.4 mg / kg to about 3 mg / kg, or about 2.5 mg / kg.

[0384] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog ranges from at least 0.001 mg / kg to at least 100 mg / kg, at least 0.01 mg / kg to at least 90 mg / kg, at least 0.1 mg / kg to at least 80 mg / kg, at least 0.5 mg / kg to at least 70 mg / kg, at least 1 mg / kg to at least 60 mg / kg, at least 1.2 mg / kg to at least 50 mg / kg, at least 1.4 mg / kg to at least 40 mg / kg, at least 1.6 mg / kg to at least 30 mg / kg, at least 1.8 mg / kg to at least 20 mg / kg, at least 2 mg / kg to at least 10 mg / kg, at least 2.2 mg / kg to at least 5 mg / kg, at least 2.4 mg / kg to at least 3 mg / kg, or at least 2.5 mg / kg.

[0385] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog ranges from at least about 0.001 mg / kg to at least about 100 mg / kg, at least about 0.01 mg / kg to at least about 90 mg / kg, at least about 0.1 mg / kg to at least about 80 mg / kg, at least about 0.5 mg / kg to at least about 70 mg / kg, at least about 1 mg / kg to at least about 60 mg / kg, at least about 1.2 mg / kg to at least about 50 mg / kg, at least about 1.4 mg / kg to at least about 40 mg / kg, at least about 1.6 mg / kg to at least about 30 mg / kg, at least about 1.8 mg / kg to at least about 20 mg / kg, at least about 2 mg / kg to at -120- 165437951.15Docket No.: 146316.8006.WO00 least about 10 mg / kg, at least about 2.2 mg / kg to at least about 5 mg / kg, at least about 2.4 mg / kg to at least about 3 mg / kg, or at least about 2.5 mg / kg.

[0386] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from about 0.001 mg / kg to about 25 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from about 0.001 mg / kg to about 25 mg / kg, about 0.005 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.05 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, or about 0.5 mg / kg to about 1 mg / kg, per body weight of the subject.

[0387] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least 0.001 mg / kg to at least 25 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least 0.001 mg / kg to at least 25 mg / kg, at least 0.005 mg / kg to at least 20 mg / kg, at least 0.01 mg / kg to at least 15 mg / kg, at least 0.05 mg / kg to at least 10 mg / kg, at least 0.1 mg / kg to at least 5 mg / kg, or at least 0.5 mg / kg to at least 1 mg / kg, per body weight of the subject.

[0388] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least about 0.001 mg / kg to at least about 25 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non- naturally occurring melanocortin analog is from at least about 0.001 mg / kg to at least about 25 mg / kg, at least about 0.005 mg / kg to at least about 20 mg / kg, at least about 0.01 mg / kg to at least about 15 mg / kg, at least about 0.05 mg / kg to at least about 10 mg / kg, at least about 0.1 mg / kg to at least about 5 mg / kg, or at least about 0.5 mg / kg to at least about 1 mg / kg, per body weight of the subject.

[0389] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from about 0.5 mg / kg to about 10 mg / kg, about 0.75 mg / kg to about 9 mg / kg, about 1 mg / kg to about 8 mg / kg, about 1.5 mg / kg to about 7 mg / kg, about 2 mg / kg to about 6 mg / kg, or about 3 mg / kg to about 5 mg / kg, per body weight of the subject. -121- 165437951.15Docket No.: 146316.8006.WO00

[0390] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least 0.5 mg / kg to at least 10 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least 0.5 mg / kg to at least 10 mg / kg, at least 0.75 mg / kg to at least 9 mg / kg, at least 1 mg / kg to at least 8 mg / kg, at least 1.5 mg / kg to at least 7 mg / kg, at least 2 mg / kg to at least 6 mg / kg, or at least 3 mg / kg to at least 5 mg / kg, per body weight of the subject.

[0391] In some embodiments, the therapeutically effective amount of the non- naturally occurring melanocortin analog is from at least about 0.5 mg / kg to at least about 10 mg / kg per body weight of the subject. For example, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from at least about 0.5 mg / kg to at least about 10 mg / kg, at least about 0.75 mg / kg to at least about 9 mg / kg, at least about 1 mg / kg to at least about 8 mg / kg, at least about 1.5 mg / kg to at least about 7 mg / kg, at least about 2 mg / kg to at least about 6 mg / kg, or at least about 3 mg / kg to at least about 5 mg / kg, per body weight of the subject.

[0392] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of the non-naturally occurring melanocortin analog, which is about 0.001 nmol, about 0.005 nmol, about 0.01 nmol, about 0.02 nmol, about 0.03 nmol, about 0.04 nmol, about 0.05 nmol, about 0.06 nmol, about 0.07 nmol, about 0.08 nmol, about 0.09 nmol, about 0.1 nmol, about 0.2 nmol, about 0.3 nmol, about 0.4 nmol, about 0.5 nmol, about 0.6 nmol, about 0.7 nmol, about 0.8 nmol, about 0.9 nmol, about 1.0 nmol, about 1.1 nmol, about 1.2 nmol, about 1.3 nmol, about 1.4 nmol, about 1.5 nmol, about 1.6 nmol, about 1.7 nmol, about 1.8 nmol, about 1.9 nmol, about 2 nmol, about 3 nmol, about 4 nmol, about 5 nmol, about 6 nmol, about 7 nmol, about 8 nmol, about 9 nmol, about 10 nmol, about 11 nmol, about 12 nmol, about 13 nmol, about 14 nmol, about 15 nmol, about 16 nmol, about 17 nmol, about 18 nmol, about 19 nmol, about 20 nmol, about 21 nmol, about 22 nmol, about 23 nmol, about 24 nmol, about 25 nmol, about 26 nmol, about 27 nmol, about 28 nmol, about 29 nmol, about 30 nmol, about 31 nmol, about 32 nmol, about 33 nmol, about 34 nmol, about 35 nmol, about 36 nmol, about 37 nmol, about 38 nmol, about 39 nmol, about 40 nmol, about 41 nmol, about 42 nmol, about 43 nmol, about -122- 165437951.15Docket No.: 146316.8006.WO00 44 nmol, about 45 nmol, about 46 nmol, about 47 nmol, about 48 nmol, about 49 nmol, about 50 nmol, about 51 nmol, about 52 nmol, about 53 nmol, about 54 nmol, about 55 nmol, about 56 nmol, about 57 nmol, about 58 nmol, about 59 nmol, about 60 nmol, about 61 nmol, about 62 nmol, about 63 nmol, about 64 nmol, about 65 nmol, about 66 nmol, about 67 nmol, about 68 nmol, about 69 nmol, about 70 nmol, about 61 nmol, about 72 nmol, about 73 nmol, about 74 nmol, about 75 nmol, about 76 nmol, about 77 nmol, about 78 nmol, about 79 nmol, about 80 nmol, about 81 nmol, about 82 nmol, about 83 nmol, about 84 nmol, about 85 nmol, about 86 nmol, about 87 nmol, about 88 nmol, about 89 nmol, about 90 nmol, about 91 nmol, about 92 nmol, about 93 nmol, about 94 nmol, about 95 nmol, about 96 nmol, about 97 nmol, about 98 nmol, about 99 nmol, about 100 nmol, about 110 nmol, about 120 nmol, about 130 nmol, about 140 nmol, about 150 nmol, about 160 nmol, about 170 nmol, about 180 nmol, about 190 nmol, about 200 nmol, about 210 nmol, about 220 nmol, about 230 nmol, about 240 nmol, about 250 nmol, about 260 nmol, about 270 nmol, about 280 nmol, about 290 nmol, about 300 nmol, about 310 nmol, about 320 nmol, about 330 nmol, about 340 nmol, about 350 nmol, about 360 nmol, about 370 nmol, about 380 nmol, about 390 nmol, about 400 nmol, about 410 nmol, about 420 nmol, about 430 nmol, about 440 nmol, about 450 nmol, about 460 nmol, about 470 nmol, about 480 nmol, about 490 nmol, about 500 nmol, about 510 nmol, about 520 nmol, about 530 nmol, about 540 nmol, about 550 nmol, about 660 nmol, about 770 nmol, about 880 nmol, about 990 nmol, about 600 nmol, about 610 nmol, about 620 nmol, about 630 nmol, about 640 nmol, about 650 nmol, about 660 nmol, about 670 nmol, about 680 nmol, about 690 nmol, about 700 nmol, about 710 nmol, about 720 nmol, about 730 nmol, about 740 nmol, about 750 nmol, about 760 nmol, about 770 nmol, about 780 nmol, about 790 nmol, about 800 nmol, about 810 nmol, about 820 nmol, about 830 nmol, about 840 nmol, about 850 nmol, about 860 nmol, about 870 nmol, about 880 nmol, about 890 nmol, about 900 nmol, about 910 nmol, about 920 nmol, about 930 nmol, about 940 nmol, about 950 nmol, about 960 nmol, about 970 nmol, about 980 nmol, about 990 nmol, about 1000 nmol, or more.

[0393] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of the non-naturally occurring melanocortin analog, which is at least 0.001 nmol, at least 0.005 nmol, at least 0.01 nmol, at least 0.02 nmol, at least 0.03 nmol, at least 0.04 nmol, at least 0.05 nmol, at -123- 165437951.15Docket No.: 146316.8006.WO00 least 0.06 nmol, at least 0.07 nmol, at least 0.08 nmol, at least 0.09 nmol, at least 0.1 nmol, at least 0.2 nmol, at least 0.3 nmol, at least 0.4 nmol, at least 0.5 nmol, at least 0.6 nmol, at least 0.7 nmol, at least 0.8 nmol, at least 0.9 nmol, at least 1.0 nmol, at least 1.1 nmol, at least 1.2 nmol, at least 1.3 nmol, at least 1.4 nmol, at least 1.5 nmol, at least 1.6 nmol, at least 1.7 nmol, at least 1.8 nmol, at least 1.9 nmol, at least 2 nmol, at least 3 nmol, at least 4 nmol, at least 5 nmol, at least 6 nmol, at least 7 nmol, at least 8 nmol, at least 9 nmol, at least 10 nmol, at least 11 nmol, at least 12 nmol, at least 13 nmol, at least 14 nmol, at least 15 nmol, at least 16 nmol, at least 17 nmol, at least 18 nmol, at least 19 nmol, at least 20 nmol, at least 21 nmol, at least 22 nmol, at least 23 nmol, at least 24 nmol, at least 25 nmol, at least 26 nmol, at least 27 nmol, at least 28 nmol, at least 29 nmol, at least 30 nmol, at least 31 nmol, at least 32 nmol, at least 33 nmol, at least 34 nmol, at least 35 nmol, at least 36 nmol, at least 37 nmol, at least 38 nmol, at least 39 nmol, at least 40 nmol, at least 41 nmol, at least 42 nmol, at least 43 nmol, at least 44 nmol, at least 45 nmol, at least 46 nmol, at least 47 nmol, at least 48 nmol, at least 49 nmol, at least 50 nmol, at least 51 nmol, at least 52 nmol, at least 53 nmol, at least 54 nmol, at least 55 nmol, at least 56 nmol, at least 57 nmol, at least 58 nmol, at least 59 nmol, at least 60 nmol, at least 61 nmol, at least 62 nmol, at least 63 nmol, at least 64 nmol, at least 65 nmol, at least 66 nmol, at least 67 nmol, at least 68 nmol, at least 69 nmol, at least 70 nmol, at least 61 nmol, at least 72 nmol, at least 73 nmol, at least 74 nmol, at least 75 nmol, at least 76 nmol, at least 77 nmol, at least 78 nmol, at least 79 nmol, at least 80 nmol, at least 81 nmol, at least 82 nmol, at least 83 nmol, at least 84 nmol, at least 85 nmol, at least 86 nmol, at least 87 nmol, at least 88 nmol, at least 89 nmol, at least 90 nmol, at least 91 nmol, at least 92 nmol, at least 93 nmol, at least 94 nmol, at least 95 nmol, at least 96 nmol, at least 97 nmol, at least 98 nmol, at least 99 nmol, at least 100 nmol, at least 110 nmol, at least 120 nmol, at least 130 nmol, at least 140 nmol, at least 150 nmol, at least 160 nmol, at least 170 nmol, at least 180 nmol, at least 190 nmol, at least 200 nmol, at least 210 nmol, at least 220 nmol, at least 230 nmol, at least 240 nmol, at least 250 nmol, at least 260 nmol, at least 270 nmol, at least 280 nmol, at least 290 nmol, at least 300 nmol, at least 310 nmol, at least 320 nmol, at least 330 nmol, at least 340 nmol, at least 350 nmol, at least 360 nmol, at least 370 nmol, at least 380 nmol, at least 390 nmol, at least 400 nmol, at least 410 nmol, at least 420 nmol, at least 430 nmol, at least 440 nmol, at least 450 nmol, at least 460 nmol, at least 470 nmol, at least 480 nmol, at least -124- 165437951.15Docket No.: 146316.8006.WO00 490 nmol, at least 500 nmol, at least 510 nmol, at least 520 nmol, at least 530 nmol, at least 540 nmol, at least 550 nmol, at least 660 nmol, at least 770 nmol, at least 880 nmol, at least 990 nmol, at least 600 nmol, at least 610 nmol, at least 620 nmol, at least 630 nmol, at least 640 nmol, at least 650 nmol, at least 660 nmol, at least 670 nmol, at least 680 nmol, at least 690 nmol, at least 700 nmol, at least 710 nmol, at least 720 nmol, at least 730 nmol, at least 740 nmol, at least 750 nmol, at least 760 nmol, at least 770 nmol, at least 780 nmol, at least 790 nmol, at least 800 nmol, at least 810 nmol, at least 820 nmol, at least 830 nmol, at least 840 nmol, at least 850 nmol, at least 860 nmol, at least 870 nmol, at least 880 nmol, at least 890 nmol, at least 900 nmol, at least 910 nmol, at least 920 nmol, at least 930 nmol, at least 940 nmol, at least 950 nmol, at least 960 nmol, at least 970 nmol, at least 980 nmol, at least 990 nmol, at least 1000 nmol, or more.

[0394] In some embodiments, the pharmaceutical composition is administered parenterally (e.g., subcutaneously) at a therapeutically effective dose of the non-naturally occurring melanocortin analog, which is at least about 0.001 nmol, at least about 0.005 nmol, at least about 0.01 nmol, at least about 0.02 nmol, at least about 0.03 nmol, at least about 0.04 nmol, at least about 0.05 nmol, at least about 0.06 nmol, at least about 0.07 nmol, at least about 0.08 nmol, at least about 0.09 nmol, at least about 0.1 nmol, at least about 0.2 nmol, at least about 0.3 nmol, at least about 0.4 nmol, at least about 0.5 nmol, at least about 0.6 nmol, at least about 0.7 nmol, at least about 0.8 nmol, at least about 0.9 nmol, at least about 1.0 nmol, at least about 1.1 nmol, at least about 1.2 nmol, at least about 1.3 nmol, at least about 1.4 nmol, at least about 1.5 nmol, at least about 1.6 nmol, at least about 1.7 nmol, at least about 1.8 nmol, at least about 1.9 nmol, at least about 2 nmol, at least about 3 nmol, at least about 4 nmol, at least about 5 nmol, at least about 6 nmol, at least about 7 nmol, at least about 8 nmol, at least about 9 nmol, at least about 10 nmol, at least about 11 nmol, at least about 12 nmol, at least about 13 nmol, at least about 14 nmol, at least about 15 nmol, at least about 16 nmol, at least about 17 nmol, at least about 18 nmol, at least about 19 nmol, at least about 20 nmol, at least about 21 nmol, at least about 22 nmol, at least about 23 nmol, at least about 24 nmol, at least about 25 nmol, at least about 26 nmol, at least about 27 nmol, at least about 28 nmol, at least about 29 nmol, at least about 30 nmol, at least about 31 nmol, at least about 32 nmol, at least about 33 nmol, at least about 34 nmol, at least about 35 nmol, at least about 36 nmol, at least about 37 nmol, at least -125- 165437951.15Docket No.: 146316.8006.WO00 about 38 nmol, at least about 39 nmol, at least about 40 nmol, at least about 41 nmol, at least about 42 nmol, at least about 43 nmol, at least about 44 nmol, at least about 45 nmol, at least about 46 nmol, at least about 47 nmol, at least about 48 nmol, at least about 49 nmol, at least about 50 nmol, at least about 51 nmol, at least about 52 nmol, at least about 53 nmol, at least about 54 nmol, at least about 55 nmol, at least about 56 nmol, at least about 57 nmol, at least about 58 nmol, at least about 59 nmol, at least about 60 nmol, at least about 61 nmol, at least about 62 nmol, at least about 63 nmol, at least about 64 nmol, at least about 65 nmol, at least about 66 nmol, at least about 67 nmol, at least about 68 nmol, at least about 69 nmol, at least about 70 nmol, at least about 61 nmol, at least about 72 nmol, at least about 73 nmol, at least about 74 nmol, at least about 75 nmol, at least about 76 nmol, at least about 77 nmol, at least about 78 nmol, at least about 79 nmol, at least about 80 nmol, at least about 81 nmol, at least about 82 nmol, at least about 83 nmol, at least about 84 nmol, at least about 85 nmol, at least about 86 nmol, at least about 87 nmol, at least about 88 nmol, at least about 89 nmol, at least about 90 nmol, at least about 91 nmol, at least about 92 nmol, at least about 93 nmol, at least about 94 nmol, at least about 95 nmol, at least about 96 nmol, at least about 97 nmol, at least about 98 nmol, at least about 99 nmol, at least about 100 nmol, at least about 110 nmol, at least about 120 nmol, at least about 130 nmol, at least about 140 nmol, at least about 150 nmol, at least about 160 nmol, at least about 170 nmol, at least about 180 nmol, at least about 190 nmol, at least about 200 nmol, at least about 210 nmol, at least about 220 nmol, at least about 230 nmol, at least about 240 nmol, at least about 250 nmol, at least about 260 nmol, at least about 270 nmol, at least about 280 nmol, at least about 290 nmol, at least about 300 nmol, at least about 310 nmol, at least about 320 nmol, at least about 330 nmol, at least about 340 nmol, at least about 350 nmol, at least about 360 nmol, at least about 370 nmol, at least about 380 nmol, at least about 390 nmol, at least about 400 nmol, at least about 410 nmol, at least about 420 nmol, at least about 430 nmol, at least about 440 nmol, at least about 450 nmol, at least about 460 nmol, at least about 470 nmol, at least about 480 nmol, at least about 490 nmol, at least about 500 nmol, at least about 510 nmol, at least about 520 nmol, at least about 530 nmol, at least about 540 nmol, at least about 550 nmol, at least about 660 nmol, at least about 770 nmol, at least about 880 nmol, at least about 990 nmol, at least about 600 nmol, at least about 610 nmol, at least about 620 nmol, at least about 630 nmol, -126- 165437951.15Docket No.: 146316.8006.WO00 at least about 640 nmol, at least about 650 nmol, at least about 660 nmol, at least about 670 nmol, at least about 680 nmol, at least about 690 nmol, at least about 700 nmol, at least about 710 nmol, at least about 720 nmol, at least about 730 nmol, at least about 740 nmol, at least about 750 nmol, at least about 760 nmol, at least about 770 nmol, at least about 780 nmol, at least about 790 nmol, at least about 800 nmol, at least about 810 nmol, at least about 820 nmol, at least about 830 nmol, at least about 840 nmol, at least about 850 nmol, at least about 860 nmol, at least about 870 nmol, at least about 880 nmol, at least about 890 nmol, at least about 900 nmol, at least about 910 nmol, at least about 920 nmol, at least about 930 nmol, at least about 940 nmol, at least about 950 nmol, at least about 960 nmol, at least about 970 nmol, at least about 980 nmol, at least about 990 nmol, at least about 1000 nmol, or more.

[0395] In some embodiments, at least one individual dose of the non-naturally occurring melanocortin analog is no more than about 1000 nmol, about 990 nmol, about 980 nmol, about 970 nmol, about 960 nmol, about 950 nmol, about 940 nmol, about 930 nmol, about 920 nmol, about 910 nmol, about 900 nmol, about 890 nmol, about 880 nmol, about 870 nmol, about 860 nmol, about 850 nmol, about 840 nmol, about 830 nmol, about 820 nmol, about 810 nmol, about 800 nmol, about 790 nmol, about 780 nmol, about 770 nmol, about 760 nmol, about 750 nmol, about 740 nmol, about 730 nmol, about 720 nmol, about 710 nmol, about 700 nmol, about 690 nmol, about 680 nmol, about 670 nmol, about 660 nmol, about 650 nmol, about 640 nmol, about 630 nmol, about 620 nmol, about 610 nmol, about 600 nmol, about 590 nmol, about 580 nmol, about 570 nmol, about 560 nmol, about 550 nmol, about 540 nmol, about 530 nmol, about 520 nmol, about 510 nmol, about 500 nmol, about 490 nmol, about 480 nmol, about 470 nmol, about 460 nmol, about 450 nmol, about 440 nmol, about 430 nmol, about 420 nmol, about 410 nmol, about 400 nmol, about 390 nmol, about 380 nmol, about 370 nmol, about 360 nmol, about 350 nmol, about 340 nmol, about 330 nmol, about 320 nmol, about 310 nmol, about 300 nmol, about 290 nmol, about 280 nmol, about 270 nmol, about 260 nmol, about 250 nmol, about 240 nmol, about 230 nmol, about 220 nmol, about 210 nmol, about 200 nmol, about 190 nmol, about 180 nmol, about 170 nmol, about 160 nmol, about 150 nmol, about 140 nmol, about 130 nmol, about 120 nmol, about 110 nmol, about 100 nmol, about 99 nmol, about 98 nmol, about 97 nmol, about 96 nmol, about 95 nmol, about 94 nmol, about 93 nmol, about 92 nmol, about -127- 165437951.15Docket No.: 146316.8006.WO00 91 nmol, about 90 nmol, about 89 nmol, about 88 nmol, about 87 nmol, about 86 nmol, about 85 nmol, about 84 nmol, about 83 nmol, about 82 nmol, about 81 nmol, about 80 nmol, about 79 nmol, about 78 nmol, about 77 nmol, about 76 nmol, about 75 nmol, about 74 nmol, about 73 nmol, about 72 nmol, about 71 nmol, about 70 nmol, about 69 nmol, about 68 nmol, about 67 nmol, about 66 nmol, about 65 nmol, about 64 nmol, about 63 nmol, about 62 nmol, about 61 nmol, about 60 nmol, about 59 nmol, about 58 nmol, about 57 nmol, about 56 nmol, about 95 nmol, about 54 nmol, about 53 nmol, about 52 nmol, about 51 nmol, about 50 nmol, about 49 nmol, about 48 nmol, about 47 nmol, about 46 nmol, about 45 nmol, about 44 nmol, about 43 nmol, about 42 nmol, about 41 nmol, about 40 nmol, about 39 nmol, about 38 nmol, about 37 nmol, about 36 nmol, about 35 nmol, about 34 nmol, about 33 nmol, about 32 nmol, about 31 nmol, about 30 nmol, about 29 nmol, about 28 nmol, about 27 nmol, about 26 nmol, about 25 nmol, about 24 nmol, about 23 nmol, about 22 nmol, about 21 nmol, about 20 nmol, about 19 nmol, about 18 nmol, about 17 nmol, about 16 nmol, about 15 nmol, about 94 nmol, about 13 nmol, about 12 nmol, about 11 nmol, about 10 nmol, about 9 nmol, about 8 nmol, about 7 nmol, about 6, about nmol, about 5 nmol, about 4 nmol, about 3 nmol, about 2 nmol, about 1 nmol, about 0.9 nmol, about 0.8 nmol, about 0.7 nmol, about 0.6 nmol, about 0.5 nmol, about 0.4 nmol, about 0.3 nmol, about 0.2 nmol, about 0.1 nmol, about 0.05 nmol, about 0.01 nmol, about 0.005 nmol, about 0.001 nmol, or less than about 0.001 nmol.

[0396] In some embodiments, at least one individual dose of the non-naturally occurring melanocortin analog is no more than at least 1000 nmol, at least 990 nmol, at least 980 nmol, at least 970 nmol, at least 960 nmol, at least 950 nmol, at least 940 nmol, at least 930 nmol, at least 920 nmol, at least 910 nmol, at least 900 nmol, at least 890 nmol, at least 880 nmol, at least 870 nmol, at least 860 nmol, at least 850 nmol, at least 840 nmol, at least 830 nmol, at least 820 nmol, at least 810 nmol, at least 800 nmol, at least 790 nmol, at least 780 nmol, at least 770 nmol, at least 760 nmol, at least 750 nmol, at least 740 nmol, at least 730 nmol, at least 720 nmol, at least 710 nmol, at least 700 nmol, at least 690 nmol, at least 680 nmol, at least 670 nmol, at least 660 nmol, at least 650 nmol, at least 640 nmol, at least 630 nmol, at least 620 nmol, at least 610 nmol, at least 600 nmol, at least 590 nmol, at least 580 nmol, at least 570 nmol, at least 560 nmol, at least 550 nmol, at least 540 nmol, at least 530 nmol, at least 520 nmol, at least 510 nmol, at least 500 nmol, at least 490 nmol, at least 480 nmol, at least 470 nmol, at least 460 nmol, at least 450 nmol, at least 440 nmol, at least -128- 165437951.15Docket No.: 146316.8006.WO00 430 nmol, at least 420 nmol, at least 410 nmol, at least 400 nmol, at least 390 nmol, at least 380 nmol, at least 370 nmol, at least 360 nmol, at least 350 nmol, at least 340 nmol, at least 330 nmol, at least 320 nmol, at least 310 nmol, at least 300 nmol, at least 290 nmol, at least 280 nmol, at least 270 nmol, at least 260 nmol, at least 250 nmol, at least 240 nmol, at least 230 nmol, at least 220 nmol, at least 210 nmol, at least 200 nmol, at least 190 nmol, at least 180 nmol, at least 170 nmol, at least 160 nmol, at least 150 nmol, at least 140 nmol, at least 130 nmol, at least 120 nmol, at least 110 nmol, at least 100 nmol, at least 99 nmol, at least 98 nmol, at least 97 nmol, at least 96 nmol, at least 95 nmol, at least 94 nmol, at least 93 nmol, at least 92 nmol, at least 91 nmol, at least 90 nmol, at least 89 nmol, at least 88 nmol, at least 87 nmol, at least 86 nmol, at least 85 nmol, at least 84 nmol, at least 83 nmol, at least 82 nmol, at least 81 nmol, at least 80 nmol, at least 79 nmol, at least 78 nmol, at least 77 nmol, at least 76 nmol, at least 75 nmol, at least 74 nmol, at least 73 nmol, at least 72 nmol, at least 71 nmol, at least 70 nmol, at least 69 nmol, at least 68 nmol, at least 67 nmol, at least 66 nmol, at least 65 nmol, at least 64 nmol, at least 63 nmol, at least 62 nmol, at least 61 nmol, at least 60 nmol, at least 59 nmol, at least 58 nmol, at least 57 nmol, at least 56 nmol, at least 95 nmol, at least 54 nmol, at least 53 nmol, at least 52 nmol, at least 51 nmol, at least 50 nmol, at least 49 nmol, at least 48 nmol, at least 47 nmol, at least 46 nmol, at least 45 nmol, at least 44 nmol, at least 43 nmol, at least 42 nmol, at least 41 nmol, at least 40 nmol, at least 39 nmol, at least 38 nmol, at least 37 nmol, at least 36 nmol, at least 35 nmol, at least 34 nmol, at least 33 nmol, at least 32 nmol, at least 31 nmol, at least 30 nmol, at least 29 nmol, at least 28 nmol, at least 27 nmol, at least 26 nmol, at least 25 nmol, at least 24 nmol, at least 23 nmol, at least 22 nmol, at least 21 nmol, at least 20 nmol, at least 19 nmol, at least 18 nmol, at least 17 nmol, at least 16 nmol, at least 15 nmol, at least 94 nmol, at least 13 nmol, at least 12 nmol, at least 11 nmol, at least 10 nmol, at least 9 nmol, at least 8 nmol, at least 7 nmol, at least 6, at least nmol, at least 5 nmol, at least 4 nmol, at least 3 nmol, at least 2 nmol, at least 1 nmol, at least 0.9 nmol, at least 0.8 nmol, at least 0.7 nmol, at least 0.6 nmol, at least 0.5 nmol, at least 0.4 nmol, at least 0.3 nmol, at least 0.2 nmol, at least 0.1 nmol, at least 0.05 nmol, at least 0.01 nmol, at least 0.005 nmol, at least 0.001 nmol, or less than at least 0.001 nmol.

[0397] In some embodiments, at least about one individual dose of the non-naturally occurring melanocortin analog is no more than at least about 1000 nmol, at least about 990 -129- 165437951.15Docket No.: 146316.8006.WO00 nmol, at least about 980 nmol, at least about 970 nmol, at least about 960 nmol, at least about 950 nmol, at least about 940 nmol, at least about 930 nmol, at least about 920 nmol, at least about 910 nmol, at least about 900 nmol, at least about 890 nmol, at least about 880 nmol, at least about 870 nmol, at least about 860 nmol, at least about 850 nmol, at least about 840 nmol, at least about 830 nmol, at least about 820 nmol, at least about 810 nmol, at least about 800 nmol, at least about 790 nmol, at least about 780 nmol, at least about 770 nmol, at least about 760 nmol, at least about 750 nmol, at least about 740 nmol, at least about 730 nmol, at least about 720 nmol, at least about 710 nmol, at least about 700 nmol, at least about 690 nmol, at least about 680 nmol, at least about 670 nmol, at least about 660 nmol, at least about 650 nmol, at least about 640 nmol, at least about 630 nmol, at least about 620 nmol, at least about 610 nmol, at least about 600 nmol, at least about 590 nmol, at least about 580 nmol, at least about 570 nmol, at least about 560 nmol, at least about 550 nmol, at least about 540 nmol, at least about 530 nmol, at least about 520 nmol, at least about 510 nmol, at least about 500 nmol, at least about 490 nmol, at least about 480 nmol, at least about 470 nmol, at least about 460 nmol, at least about 450 nmol, at least about 440 nmol, at least about 430 nmol, at least about 420 nmol, at least about 410 nmol, at least about 400 nmol, at least about 390 nmol, at least about 380 nmol, at least about 370 nmol, at least about 360 nmol, at least about 350 nmol, at least about 340 nmol, at least about 330 nmol, at least about 320 nmol, at least about 310 nmol, at least about 300 nmol, at least about 290 nmol, at least about 280 nmol, at least about 270 nmol, at least about 260 nmol, at least about 250 nmol, at least about 240 nmol, at least about 230 nmol, at least about 220 nmol, at least about 210 nmol, at least about 200 nmol, at least about 190 nmol, at least about 180 nmol, at least about 170 nmol, at least about 160 nmol, at least about 150 nmol, at least about 140 nmol, at least about 130 nmol, at least about 120 nmol, at least about 110 nmol, at least about 100 nmol, at least about 99 nmol, at least about 98 nmol, at least about 97 nmol, at least about 96 nmol, at least about 95 nmol, at least about 94 nmol, at least about 93 nmol, at least about 92 nmol, at least about 91 nmol, at least about 90 nmol, at least about 89 nmol, at least about 88 nmol, at least about 87 nmol, at least about 86 nmol, at least about 85 nmol, at least about 84 nmol, at least about 83 nmol, at least about 82 nmol, at least about 81 nmol, at least about 80 nmol, at least about 79 nmol, at least about 78 nmol, at least about 77 nmol, at least about 76 nmol, at least about 75 nmol, at least -130- 165437951.15Docket No.: 146316.8006.WO00 about 74 nmol, at least about 73 nmol, at least about 72 nmol, at least about 71 nmol, at least about 70 nmol, at least about 69 nmol, at least about 68 nmol, at least about 67 nmol, at least about 66 nmol, at least about 65 nmol, at least about 64 nmol, at least about 63 nmol, at least about 62 nmol, at least about 61 nmol, at least about 60 nmol, at least about 59 nmol, at least about 58 nmol, at least about 57 nmol, at least about 56 nmol, at least about 95 nmol, at least about 54 nmol, at least about 53 nmol, at least about 52 nmol, at least about 51 nmol, at least about 50 nmol, at least about 49 nmol, at least about 48 nmol, at least about 47 nmol, at least about 46 nmol, at least about 45 nmol, at least about 44 nmol, at least about 43 nmol, at least about 42 nmol, at least about 41 nmol, at least about 40 nmol, at least about 39 nmol, at least about 38 nmol, at least about 37 nmol, at least about 36 nmol, at least about 35 nmol, at least about 34 nmol, at least about 33 nmol, at least about 32 nmol, at least about 31 nmol, at least about 30 nmol, at least about 29 nmol, at least about 28 nmol, at least about 27 nmol, at least about 26 nmol, at least about 25 nmol, at least about 24 nmol, at least about 23 nmol, at least about 22 nmol, at least about 21 nmol, at least about 20 nmol, at least about 19 nmol, at least about 18 nmol, at least about 17 nmol, at least about 16 nmol, at least about 15 nmol, at least about 94 nmol, at least about 13 nmol, at least about 12 nmol, at least about 11 nmol, at least about 10 nmol, at least about 9 nmol, at least about 8 nmol, at least about 7 nmol, at least about 6, at least about nmol, at least about 5 nmol, at least about 4 nmol, at least about 3 nmol, at least about 2 nmol, at least about 1 nmol, at least about 0.9 nmol, at least about 0.8 nmol, at least about 0.7 nmol, at least about 0.6 nmol, at least about 0.5 nmol, at least about 0.4 nmol, at least about 0.3 nmol, at least about 0.2 nmol, at least about 0.1 nmol, at least about 0.05 nmol, at least about 0.01 nmol, at least about 0.005 nmol, at least about 0.001 nmol, or less than at least about 0.001 nmol.

[0398] In some embodiments, at least one individual dose of the non-naturally occurring melanocortin analog is no more than about 1000 mg, about 990 mg, about 980 mg, about 970 mg, about 960 mg, about 950 mg, about 940 mg, about 930 mg, about 920 mg, about 910 mg, about 900 mg, about 890 mg, about 880 mg, about 870 mg, about 860 mg, about 850 mg, about 840 mg, about 830 mg, about 820 mg, about 810 mg, about 800 mg, about 790 mg, about 780 mg, about 770 mg, about 760 mg, about 750 mg, about 740 mg, about 730 mg, about 720 mg, about 710 mg, about 700 mg, about 690 mg, about 680 -131- 165437951.15Docket No.: 146316.8006.WO00 mg, about 670 mg, about 660 mg, about 650 mg, about 640 mg, about 630 mg, about 620 mg, about 610 mg, about 600 mg, about 590 mg, about 580 mg, about 570 mg, about 560 mg, about 550 mg, about 540 mg, about 530 mg, about 520 mg, about 510 mg, about 500 mg, about 490 mg, about 480 mg, about 470 mg, about 460 mg, about 450 mg, about 440 mg, about 430 mg, about 420 mg, about 410 mg, about 400 mg, about 390 mg, about 380 mg, about 370 mg, about 360 mg, about 350 mg, about 340 mg, about 330 mg, about 320 mg, about 310 mg, about 300 mg, about 290 mg, about 280 mg, about 270 mg, about 260 mg, about 250 mg, about 240 mg, about 230 mg, about 220 mg, about 210 mg, about 200 mg, about 190 mg, about 180 mg, about 170 mg, about 160 mg, about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 92 mg, about 91 mg, about 90 mg, about 89 mg, about 88 mg, about 87 mg, about 86 mg, about 85 mg, about 84 mg, about 83 mg, about 82 mg, about 81 mg, about 80 mg, about 79 mg, about 78 mg, about 77 mg, about 76 mg, about 75 mg, about 74 mg, about 73 mg, about 72 mg, about 71 mg, about 70 mg, about 69 mg, about 68 mg, about 67 mg, about 66 mg, about 65 mg, about 64 mg, about 63 mg, about 62 mg, about 61 mg, about 60 mg, about 59 mg, about 58 mg, about 57 mg, about 56 mg, about 95 mg, about 54 mg, about 53 mg, about 52 mg, about 51 mg, about 50 mg, about 49 mg, about 48 mg, about 47 mg, about 46 mg, about 45 mg, about 44 mg, about 43 mg, about 42 mg, about 41 mg, about 40 mg, about 39 mg, about 38 mg, about 37 mg, about 36 mg, about 35 mg, about 34 mg, about 33 mg, about 32 mg, about 31 mg, about 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 94 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6, about mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, about 0.9 mg, about 0.8 mg, about 0.7 mg, about 0.6 mg, about 0.5 mg, about 0.4 mg, about 0.3 mg, about 0.2 mg, about 0.1 mg, about 0.05 mg, about 0.01 mg, about 0.005 mg, or about 0.001 mg.

[0399] In some embodiments, at least one individual dose of the non-naturally occurring melanocortin analog is no more than at least 1000 mg, at least 990 mg, at least 980 mg, at least 970 mg, at least 960 mg, at least 950 mg, at least 940 mg, at least 930 mg, at least 920 mg, at least 910 mg, at least 900 mg, at least 890 mg, at least 880 mg, at least -132- 165437951.15Docket No.: 146316.8006.WO00 870 mg, at least 860 mg, at least 850 mg, at least 840 mg, at least 830 mg, at least 820 mg, at least 810 mg, at least 800 mg, at least 790 mg, at least 780 mg, at least 770 mg, at least 760 mg, at least 750 mg, at least 740 mg, at least 730 mg, at least 720 mg, at least 710 mg, at least 700 mg, at least 690 mg, at least 680 mg, at least 670 mg, at least 660 mg, at least 650 mg, at least 640 mg, at least 630 mg, at least 620 mg, at least 610 mg, at least 600 mg, at least 590 mg, at least 580 mg, at least 570 mg, at least 560 mg, at least 550 mg, at least 540 mg, at least 530 mg, at least 520 mg, at least 510 mg, at least 500 mg, at least 490 mg, at least 480 mg, at least 470 mg, at least 460 mg, at least 450 mg, at least 440 mg, at least 430 mg, at least 420 mg, at least 410 mg, at least 400 mg, at least 390 mg, at least 380 mg, at least 370 mg, at least 360 mg, at least 350 mg, at least 340 mg, at least 330 mg, at least 320 mg, at least 310 mg, at least 300 mg, at least 290 mg, at least 280 mg, at least 270 mg, at least 260 mg, at least 250 mg, at least 240 mg, at least 230 mg, at least 220 mg, at least 210 mg, at least 200 mg, at least 190 mg, at least 180 mg, at least 170 mg, at least 160 mg, at least 150 mg, at least 140 mg, at least 130 mg, at least 120 mg, at least 110 mg, at least 100 mg, at least 99 mg, at least 98 mg, at least 97 mg, at least 96 mg, at least 95 mg, at least 94 mg, at least 93 mg, at least 92 mg, at least 91 mg, at least 90 mg, at least 89 mg, at least 88 mg, at least 87 mg, at least 86 mg, at least 85 mg, at least 84 mg, at least 83 mg, at least 82 mg, at least 81 mg, at least 80 mg, at least 79 mg, at least 78 mg, at least 77 mg, at least 76 mg, at least 75 mg, at least 74 mg, at least 73 mg, at least 72 mg, at least 71 mg, at least 70 mg, at least 69 mg, at least 68 mg, at least 67 mg, at least 66 mg, at least 65 mg, at least 64 mg, at least 63 mg, at least 62 mg, at least 61 mg, at least 60 mg, at least 59 mg, at least 58 mg, at least 57 mg, at least 56 mg, at least 95 mg, at least 54 mg, at least 53 mg, at least 52 mg, at least 51 mg, at least 50 mg, at least 49 mg, at least 48 mg, at least 47 mg, at least 46 mg, at least 45 mg, at least 44 mg, at least 43 mg, at least 42 mg, at least 41 mg, at least 40 mg, at least 39 mg, at least 38 mg, at least 37 mg, at least 36 mg, at least 35 mg, at least 34 mg, at least 33 mg, at least 32 mg, at least 31 mg, at least 30 mg, at least 29 mg, at least 28 mg, at least 27 mg, at least 26 mg, at least 25 mg, at least 24 mg, at least 23 mg, at least 22 mg, at least 21 mg, at least 20 mg, at least 19 mg, at least 18 mg, at least 17 mg, at least 16 mg, at least 15 mg, at least 94 mg, at least 13 mg, at least 12 mg, at least 11 mg, at least 10 mg, at least 9 mg, at least 8 mg, at least 7 mg, at least 6, at least mg, at least 5 mg, at least 4 mg, at least 3 mg, at least 2 mg, at least 1 mg, at least 0.9 mg, at least 0.8 -133- 165437951.15Docket No.: 146316.8006.WO00 mg, at least 0.7 mg, at least 0.6 mg, at least 0.5 mg, at least 0.4 mg, at least 0.3 mg, at least 0.2 mg, at least 0.1 mg, at least 0.05 mg, at least 0.01 mg, at least 0.005 mg, or at least 0.001 mg.

[0400] In some embodiments, at least about one individual dose of the non-naturally occurring melanocortin analog is no more than at least about 1000 mg, at least about 990 mg, at least about 980 mg, at least about 970 mg, at least about 960 mg, at least about 950 mg, at least about 940 mg, at least about 930 mg, at least about 920 mg, at least about 910 mg, at least about 900 mg, at least about 890 mg, at least about 880 mg, at least about 870 mg, at least about 860 mg, at least about 850 mg, at least about 840 mg, at least about 830 mg, at least about 820 mg, at least about 810 mg, at least about 800 mg, at least about 790 mg, at least about 780 mg, at least about 770 mg, at least about 760 mg, at least about 750 mg, at least about 740 mg, at least about 730 mg, at least about 720 mg, at least about 710 mg, at least about 700 mg, at least about 690 mg, at least about 680 mg, at least about 670 mg, at least about 660 mg, at least about 650 mg, at least about 640 mg, at least about 630 mg, at least about 620 mg, at least about 610 mg, at least about 600 mg, at least about 590 mg, at least about 580 mg, at least about 570 mg, at least about 560 mg, at least about 550 mg, at least about 540 mg, at least about 530 mg, at least about 520 mg, at least about 510 mg, at least about 500 mg, at least about 490 mg, at least about 480 mg, at least about 470 mg, at least about 460 mg, at least about 450 mg, at least about 440 mg, at least about 430 mg, at least about 420 mg, at least about 410 mg, at least about 400 mg, at least about 390 mg, at least about 380 mg, at least about 370 mg, at least about 360 mg, at least about 350 mg, at least about 340 mg, at least about 330 mg, at least about 320 mg, at least about 310 mg, at least about 300 mg, at least about 290 mg, at least about 280 mg, at least about 270 mg, at least about 260 mg, at least about 250 mg, at least about 240 mg, at least about 230 mg, at least about 220 mg, at least about 210 mg, at least about 200 mg, at least about 190 mg, at least about 180 mg, at least about 170 mg, at least about 160 mg, at least about 150 mg, at least about 140 mg, at least about 130 mg, at least about 120 mg, at least about 110 mg, at least about 100 mg, at least about 99 mg, at least about 98 mg, at least about 97 mg, at least about 96 mg, at least about 95 mg, at least about 94 mg, at least about 93 mg, at least about 92 mg, at least about 91 mg, at least about 90 mg, at least about 89 mg, at least about 88 mg, at least about 87 mg, at least about 86 mg, at least about 85 mg, at least about -134- 165437951.15Docket No.: 146316.8006.WO00 84 mg, at least about 83 mg, at least about 82 mg, at least about 81 mg, at least about 80 mg, at least about 79 mg, at least about 78 mg, at least about 77 mg, at least about 76 mg, at least about 75 mg, at least about 74 mg, at least about 73 mg, at least about 72 mg, at least about 71 mg, at least about 70 mg, at least about 69 mg, at least about 68 mg, at least about 67 mg, at least about 66 mg, at least about 65 mg, at least about 64 mg, at least about 63 mg, at least about 62 mg, at least about 61 mg, at least about 60 mg, at least about 59 mg, at least about 58 mg, at least about 57 mg, at least about 56 mg, at least about 95 mg, at least about 54 mg, at least about 53 mg, at least about 52 mg, at least about 51 mg, at least about 50 mg, at least about 49 mg, at least about 48 mg, at least about 47 mg, at least about 46 mg, at least about 45 mg, at least about 44 mg, at least about 43 mg, at least about 42 mg, at least about 41 mg, at least about 40 mg, at least about 39 mg, at least about 38 mg, at least about 37 mg, at least about 36 mg, at least about 35 mg, at least about 34 mg, at least about 33 mg, at least about 32 mg, at least about 31 mg, at least about 30 mg, at least about 29 mg, at least about 28 mg, at least about 27 mg, at least about 26 mg, at least about 25 mg, at least about 24 mg, at least about 23 mg, at least about 22 mg, at least about 21 mg, at least about 20 mg, at least about 19 mg, at least about 18 mg, at least about 17 mg, at least about 16 mg, at least about 15 mg, at least about 94 mg, at least about 13 mg, at least about 12 mg, at least about 11 mg, at least about 10 mg, at least about 9 mg, at least about 8 mg, at least about 7 mg, at least about 6, at least about mg, at least about 5 mg, at least about 4 mg, at least about 3 mg, at least about 2 mg, at least about 1 mg, at least about 0.9 mg, at least about 0.8 mg, at least about 0.7 mg, at least about 0.6 mg, at least about 0.5 mg, at least about 0.4 mg, at least about 0.3 mg, at least about 0.2 mg, at least about 0.1 mg, at least about 0.05 mg, at least about 0.01 mg, at least about 0.005 mg, or at least about 0.001 mg.

[0401] In some embodiments, a therapeutically effective dose of the non-naturally occurring melanocortin analog is at least about 0.001 mg / kg per body weight to about 10 mg / kg per body weight per day. In some embodiments, the therapeutically effective dose of the non-naturally occurring melanocortin analog is about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about -135- 165437951.15Docket No.: 146316.8006.WO00 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6.0 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 2.0 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8.0 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9.0 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, about 10.0 mg / kg per body weight per day, or more.

[0402] In some embodiments, the therapeutically effective dose of the non-naturally occurring melanocortin analog is at least 0.001 mg / kg, at least 0.005 mg / kg, at least 0.01 mg / kg, at least 0.02 mg / kg, at least 0.03 mg / kg, at least 0.04 mg / kg, at least 0.05 mg / kg, at least 0.06 mg / kg, at least 0.07 mg / kg, at least 0.08 mg / kg, at least 0.09 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 3.0 mg / kg, at least 3.1 mg / kg, at least 3.2 mg / kg, at least 3.3 mg / kg, at least 3.4 mg / kg, -136- 165437951.15Docket No.: 146316.8006.WO00 at least 3.5 mg / kg, at least 3.6 mg / kg, at least 3.7 mg / kg, at least 3.8 mg / kg, at least 3.9 mg / kg, at least 4.0 mg / kg, at least 4.1 mg / kg, at least 4.2 mg / kg, at least 4.3 mg / kg, at least 4.4 mg / kg, at least 4.5 mg / kg, at least 4.6 mg / kg, at least 4.7 mg / kg, at least 4.8 mg / kg, at least 4.9 mg / kg, at least 5.0 mg / kg, at least 5.1 mg / kg, at least 5.2 mg / kg, at least 5.3 mg / kg, at least 5.4 mg / kg, at least 5.5 mg / kg, at least 5.6 mg / kg, at least 5.7 mg / kg, at least 5.8 mg / kg, at least 5.9 mg / kg, at least 6.0 mg / kg, at least 6.1 mg / kg, at least 6.2 mg / kg, at least 6.3 mg / kg, at least 6.4 mg / kg, at least 6.5 mg / kg, at least 6.6 mg / kg, at least 6.7 mg / kg, at least 6.8 mg / kg, at least 6.9 mg / kg, at least 2.0 mg / kg, at least 7.1 mg / kg, at least 7.2 mg / kg, at least 7.3 mg / kg, at least 7.4 mg / kg, at least 7.5 mg / kg, at least 7.6 mg / kg, at least 7.7 mg / kg, at least 7.8 mg / kg, at least 7.9 mg / kg, at least 8.0 mg / kg, at least 8.1 mg / kg, at least 8.2 mg / kg, at least 8.3 mg / kg, at least 8.4 mg / kg, at least 8.5 mg / kg, at least 8.6 mg / kg, at least 8.7 mg / kg, at least 8.8 mg / kg, at least 8.9 mg / kg, at least 9.0 mg / kg, at least 9.1 mg / kg, at least 9.2 mg / kg, at least 9.3 mg / kg, at least 9.4 mg / kg, at least 9.5 mg / kg, at least 9.6 mg / kg, at least 9.7 mg / kg, at least 9.8 mg / kg, at least 9.9 mg / kg, at least 10.0 mg / kg per body weight per day, or more.

[0403] In some embodiments, the therapeutically effective dose of the non-naturally occurring melanocortin analog is at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.02 mg / kg, at least about 0.03 mg / kg, at least about 0.04 mg / kg, at least about 0.05 mg / kg, at least about 0.06 mg / kg, at least about 0.07 mg / kg, at least about 0.08 mg / kg, at least about 0.09 mg / kg, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 1.1 mg / kg, at least about 1.2 mg / kg, at least about 1.3 mg / kg, at least about 1.4 mg / kg, at least about 1.5 mg / kg, at least about 1.6 mg / kg, at least about 1.7 mg / kg, at least about 1.8 mg / kg, at least about 1.9 mg / kg, at least about 2.0 mg / kg, at least about 2.1 mg / kg, at least about 2.2 mg / kg, at least about 2.3 mg / kg, at least about 2.4 mg / kg, at least about 2.5 mg / kg, at least about 2.6 mg / kg, at least about 2.7 mg / kg, at least about 2.8 mg / kg, at least about 2.9 mg / kg, at least about 3.0 mg / kg, at least about 3.1 mg / kg, at least about 3.2 mg / kg, at least about 3.3 mg / kg, at least about 3.4 mg / kg, at least about 3.5 mg / kg, at least about 3.6 mg / kg, at least about 3.7 mg / kg, at least about 3.8 mg / kg, at least about 3.9 mg / kg, at least about 4.0 mg / kg, at least about 4.1 mg / kg, at -137- 165437951.15Docket No.: 146316.8006.WO00 least about 4.2 mg / kg, at least about 4.3 mg / kg, at least about 4.4 mg / kg, at least about 4.5 mg / kg, at least about 4.6 mg / kg, at least about 4.7 mg / kg, at least about 4.8 mg / kg, at least about 4.9 mg / kg, at least about 5.0 mg / kg, at least about 5.1 mg / kg, at least about 5.2 mg / kg, at least about 5.3 mg / kg, at least about 5.4 mg / kg, at least about 5.5 mg / kg, at least about 5.6 mg / kg, at least about 5.7 mg / kg, at least about 5.8 mg / kg, at least about 5.9 mg / kg, at least about 6.0 mg / kg, at least about 6.1 mg / kg, at least about 6.2 mg / kg, at least about 6.3 mg / kg, at least about 6.4 mg / kg, at least about 6.5 mg / kg, at least about 6.6 mg / kg, at least about 6.7 mg / kg, at least about 6.8 mg / kg, at least about 6.9 mg / kg, at least about 2.0 mg / kg, at least about 7.1 mg / kg, at least about 7.2 mg / kg, at least about 7.3 mg / kg, at least about 7.4 mg / kg, at least about 7.5 mg / kg, at least about 7.6 mg / kg, at least about 7.7 mg / kg, at least about 7.8 mg / kg, at least about 7.9 mg / kg, at least about 8.0 mg / kg, at least about 8.1 mg / kg, at least about 8.2 mg / kg, at least about 8.3 mg / kg, at least about 8.4 mg / kg, at least about 8.5 mg / kg, at least about 8.6 mg / kg, at least about 8.7 mg / kg, at least about 8.8 mg / kg, at least about 8.9 mg / kg, at least about 9.0 mg / kg, at least about 9.1 mg / kg, at least about 9.2 mg / kg, at least about 9.3 mg / kg, at least about 9.4 mg / kg, at least about 9.5 mg / kg, at least about 9.6 mg / kg, at least about 9.7 mg / kg, at least about 9.8 mg / kg, at least about 9.9 mg / kg, at least about 10.0 mg / kg per body weight per day, or more.

[0404] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.001 mg / kg to about 25 mg / kg per body weight of the subject. For example, the non-naturally occurring melanocortin analog is administered to the subject at least once daily in an amount ranging from about 0.001 mg / kg to about 25 mg / kg, from about 0.01 mg / kg to about 20 mg / kg, from about 0.1 mg / kg to about 15 mg / kg, from about 1 mg / kg to about 10 mg / kg, or from about 2 mg / kg to about 5 mg / kg, per body weight of the subject.

[0405] 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. For example, the non-naturally occurring melanocortin analog is administered to the subject at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 8 mg / kg, from about 2 mg / kg to about 6 mg / kg, or from about 4 mg / kg to about 5 mg / kg, per body weight of the subject. -138- 165437951.15Docket No.: 146316.8006.WO00

[0406] In some embodiments, the non-naturally occurring melanocortin analog comprises TCMCB07, and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.001 mg / kg to about 25 mg / kg per body weight of the subject. For example, the non-naturally occurring melanocortin analog comprising TCMCB07 is administered to the subject at least once daily in an amount ranging from about 0.001 mg / kg to about 25 mg / kg, from about 0.01 mg / kg to about 20 mg / kg, from about 0.1 mg / kg to about 15 mg / kg, from about 1 mg / kg to about 10 mg / kg, or from about 2 mg / kg to about 5 mg / kg, per body weight of the subject.

[0407] In some embodiments, the non-naturally occurring melanocortin analog comprises TCMCB07, and the non-naturally occurring melanocortin ana...

Claims

Docket No.: 146316.8006.WO00 CLAIMS I / We claim:

1. A method of stimulating appetite and / or increasing body weight of a subject having a kidney disease and / or a liver disease, the method comprising: administering to the subject a therapeutically effective amount of a non-naturally occurring melanocortin analog comprising 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), -266- 165437951.15Docket No.: 146316.8006.WO00 R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D- proline, L-proline, D-valine, and L-valine; -267- 165437951.15Docket No.: 146316.8006.WO00 Y4is absent or is D-aspartic acid or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; 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; 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 R3is Aba, Ata, or Aia, R6is Aia, then R4is not dNal(2’), or R4is dNal(2’) and R5is not Arg; when R4is p(Cl)dPhe, then R3is not Pro or His; when R4is p(I)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1and R7and at least one of R2and R3is Pro; when Y2-Y4are absent, then Y1is absent or is norleucine; -268- 165437951.15Docket No.: 146316.8006.WO00 when R2is Pro or Y2is Hyp, then R3is not Pro; when R3, R5, or R6is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1and R7or X1-X2are present and are Ac-dVal-dPro; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys or Cys-Pro-dNal(2’)-Arg-Trp-Cys, then R1is not Ac-Nle or Y1-Y2is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R8, then R3is not His or Y1is not dVal.

2. The method of claim 1, wherein the N-terminus, 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.

3. The method of claim 2, wherein the N-terminus, if present, is modified by an acyl group.

4. The method of claim 3, wherein the acyl group is acetyl group.

5. The method of claim 3, wherein the acyl group is formyl group.

6. The method of claim 2, wherein the N-terminus, if present, is modified by an imine group.

7. The method of claim 2, wherein the N-terminus, if present, is modified by an amide group.

8. The method of claim 7, wherein the amide group is a pyroglutamyl (pGlu) group. -269- 165437951.15Docket No.: 146316.8006.WO00 9. The method of claim 7, wherein the amide group is derived from a fatty acid.

10. The method of claim 1, wherein the N-terminus, if present, is not modified.

11. The method of claim 1, wherein the C-terminus is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

12. The method of claim 11, wherein the C-terminus is modified by an amide group.

13. The method of claim 12, wherein the amide group is an -NHalkyl amide group or an -NHaryl amide group.

14. The method of claim 13, wherein the -NHaryl amide group is p-nitroanilide group or 7-amino-4-methylcoumarin.

15. The method of claim 11, wherein the C-terminus is modified by an ester group.

16. The method of claim 1, wherein the C-terminus is not modified.

17. The method of claim 1, wherein R1is absent, and R2is D-aspartic acid.

18. The method of claim 17, wherein X1, X2, and X3are absent.

19. The method of claim 1, wherein R4is D-Nal(2′).

20. The method of claim 1, wherein Y3- Y8are absent.

21. The method of claim 20, wherein: -270- 165437951.15Docket No.: 146316.8006.WO00 Y1is D-valine and Y2is D-proline; or Y1is D-proline and Y2is D-valine.

22. The method of claim 1, wherein Y3is present and Y4-Y8are absent.

23. The method of claim 22, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; and / or Y3is D-valine or D-proline.

24. The method of claim 22, wherein: Y1is D-valine, Y2is D-valine, and Y3is D-proline; Y1is D-proline, Y2is D-valine, and Y3is D-valine; Y1is D-valine, Y2is D-proline, and Y3is D-valine; or Y1is D-proline, Y2is D-valine, and Y3is D-proline.

25. The method of claim 1, wherein Y3and Y4are present, and Y5-Y8are absent.

26. The method of claim 25, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; Y3is D-valine or D-proline; and / or Y4is D-valine or D-proline.

27. The method of claim 25, wherein: Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline; Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine; or Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-proline. -271- 165437951.15Docket No.: 146316.8006.WO00 28. The method of claim 1, wherein R1, R2, and R7are present and R8-R20are absent, and the sequence of Formula (I) is cyclized through R2and R7via a lactam bond.

29. The method of claim 1, wherein R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond.

30. The method of claim 29, wherein: R1is acetylated norleucine; R2is aspartic acid; R3is selected from the group consisting of proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine; R4is histidine or dNal(2′); R5is dNal(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.

31. The method of claim 29, wherein the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 10; D5), wherein c represents cyclization through R2and R8via a lactam bond.

32. The method of claim 1, wherein the sequence of Formula (I) is linear.

33. The method of claim 32, wherein the sequence of Formula (I) is Ac-Nle-Pro- dNal(2’)-Arg-Trp-dVal-dPro-NH2(SEQ ID NO: 14). -272- 165437951.15Docket No.: 146316.8006.WO00 34. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-transPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 33); Ac-cisPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 36); Dmt-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 39), wherein c represents cyclization through R2and R7via a lactam bond.

35. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c(Asp-dIle-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 86); Ac-Nle-c(Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 87); Ac-Nle-c(Asp-cisPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 88); Ac-Nle-c(Asp-Val-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c(Asp-Ile-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 90); Ac-Nle-c(Asp-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 91); Ac-Nle-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 92); -273- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c(Asp-dLeu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 95); and Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 96), wherein c represents cyclization through R2and R7via a lactam bond.

36. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-dHis-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2’)-dAla-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2’)-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2’)-dGlu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 111), wherein c represents cyclization through R2and R7via a lactam bond.

37. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(1’)-Lys)-dVal-dPro-NH2(SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(2’)-Lys)-dVal-dPro-NH2(SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTyr-Lys)-dVal-dPro-NH2(SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dAla-Lys)-dVal-dPro-NH2 (SEQ ID NO: 124), wherein c represents cyclization through R2and R7via a lactam bond.

38. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: -274- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dPro-NH2(SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-NH2 (SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dPro-NH2(SEQ ID 8O: 186); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dVal-NH2(SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dTle-NH2 (SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dTle-NH2 (SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

39. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Che-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 212); Ac-Nle-c(Asp-Oic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 213); Ac-Nle-c(Asp-Ioc-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 214); Ac-Nle-c(Asp-Tic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 217); Ac-Nle-c(Asp-His-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c(Asp-His-dNal(2’)-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 219); Ac-Nle-c(Asp-Pro-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 220); Ac-Nle-c(Asp-Pro-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 221); Ac-Nle-c(Asp-Pro-dNal(2’)-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 222); -275- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 224); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 225); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 226); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 228); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 229); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 230); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 231); Ac-Glu-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2(SEQ ID NO: 232); and Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 233), wherein c represents cyclization through R2and R7via a lactam bond.

40. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 234); Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 235); Ac-Nle-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 236); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 238); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-dArg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 240); Ac-Arg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 241); Ac-dArg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 242); -276- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Arg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 244); Ac-dArg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 245); Ac-Nle-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c(Asp-Pro-Trp-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 248); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Lys)-dVal-dPro-NH2(SEQ ID NO: 249); Ac-Nle-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH2 (SEQ ID NO: 251); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH2(SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (EQ ID NO: 254), wherein c represents cyclization through R2and any of R5-8via a lactam bond or a disulfide bond.

41. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-NH2(SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-Nle-NH2(SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2(SEQ ID NO: 260), wherein c represents cyclization through R2and any one of R7via a lactam bond.

42. The method of claim 1, wherein the sequence of Formula (I) is: -277- 165437951.15Docket No.: 146316.8006.WO00 Ac-dVal-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 262), wherein c represents cyclization through R2and R7via a lactam bond.

43. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 263); Ac-Glu-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R2and R7via a lactam bond. .

44. The method of claim 1, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 268); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 270); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 271); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 273); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 274); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 276); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 277); -278- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO: 280); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281); wherein c represents cyclization through R1or R2and R7via a lactam bond.

45. The method of claim 1, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 128, 182-189, 212-281, 394 and 399.

46. The method of claim 1, wherein the non-naturally occurring melanocortin analog comprises SEQ ID NO:

3.

47. The method of any one of claims 1-46, wherein the non-naturally occurring melanocortin analog is present in a composition.

48. The method of claim 47, wherein the composition further comprises a pharmaceutical salt.

49. The method of claim 47, wherein the composition further comprises a pharmaceutical carrier.

50. The method of claim 47, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition.

51. The method of claim 50, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO: 3), and wherein the non-naturally occurring -279- 165437951.15Docket No.: 146316.8006.WO00 melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition.

52. The method of claim 51, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

53. The method of any one of claims 1-52, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

54. The method of any one of claims 47-53, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

55. The method of any one of claims 47-54, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

56. The method of any one of claims 1-55, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

57. The method of any one of claims 1-56, 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.

58. The method of any one of claims 1-57, 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. -280- 165437951.15Docket No.: 146316.8006.WO00 59. The method of any one of claims 1-58, 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.

60. The method of any one of claims 1-59, 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.

61. The method of claim 59, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (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.

62. The method of claim 60, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (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.

63. The method of any one of claims 1-62, 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.

64. The method of any one of claims 1-62, 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.

65. The method of claim 49, wherein the pharmaceutical carrier comprises water.

66. The method of any one of claims 1-65, wherein the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further -281- 165437951.15Docket No.: 146316.8006.WO00 comprises fibrosis of at least a portion of the subject’s kidney, and optionally wherein the fibrotic liver disease further comprises fibrosis of at least a portion of the subject’s liver.

67. The method of any one of claims 1-65, wherein the kidney disease is chronic kidney disease (CKD), and / or renal failure.

68. The method of claim 67, wherein the subject has undergone or is undergoing dialysis.

69. The method of any one of claims 1-65, wherein the liver disease is nonalcoholic fatty liver disease (NAFLD).

70. The method of claim 69, wherein NAFLD is nonalcoholic steatohepatitis (NASH).

71. The method of any one of claims 1-70, 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.

72. The method of claim 71, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease and / or the liver disease.

73. The method of claim 71, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia.

74. The method of any one of claims 1-73, wherein the method (i) stimulates appetite of the subject; (ii) increases food consumption by 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 -282- 165437951.15Docket No.: 146316.8006.WO00 maintains muscle mass of the subject; (vii) prevents or reduces muscle mass 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.

75. The method of any one of claims 1-74, wherein the method increases body weight of and / or increases food consumption by the subject.

76. The method of claim 74, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

77. The method of claim 74, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

78. The method of claim 75 or 76, 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 of the non-naturally occurring melanocortin analog.

79. The method of claim 76 or 77, 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 of the non- naturally occurring melanocortin analog.

80. The method of any one of claims 76-79, 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 of the non- naturally occurring melanocortin analog is stopped.

81. The method of any one of claims 74 and 89-93, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety. -283- 165437951.15Docket No.: 146316.8006.WO00 82. The method of claim 34, wherein the appetite is assessed between meals.

83. The method of any one of claims 74 and 89-95, wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.

84. The method of claim 74 or 75, wherein food consumption of the subject is increased by at least 25% to 2,000% after the administration of the non-naturally occurring melanocortin analog.

85. The method of claim 74 or 75, wherein food consumption of the subject is increased by at least 50% to 500% after the administration of the non-naturally occurring melanocortin analog.

86. The method of claim 84 or 85, wherein 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 of the non-naturally occurring melanocortin analog.

87. The method of claim 84 or 85, wherein food consumption 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 of the non-naturally occurring melanocortin analog.

88. The method of any one of claims 84-87, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

89. The method of any one of claims 74-75 and 97-101, wherein the food consumption is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day. -284- 165437951.15Docket No.: 146316.8006.WO00 90. The method of claim 74, wherein anorexia is determined by food consumption.

91. The method of claim 74 or 75, wherein body weight of the subject is increased by at least 5% to 200% after the administration of the non-naturally occurring melanocortin analog.

92. The method of claim 74 or 75, wherein body weight of the subject is increased by at least 5% to 25% after the administration of the non-naturally occurring melanocortin analog.

93. The method of claim 74 or 75, wherein body weight of the subject is increased by at least 20% to 100% after the administration of the non-naturally occurring melanocortin analog.

94. The method of any one of claims 91-93, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

95. The method of claim 74, wherein muscle mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog.

96. The method of claim 74, wherein muscle mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog.

97. The method of claim 74, wherein muscle mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog. -285- 165437951.15Docket No.: 146316.8006.WO00 98. The method of any one of claims 95-97, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

99. The method of any one of claims 74 and 108-111, wherein the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

100. The method of claim 74, wherein fat mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog.

101. The method of claim 74, wherein fat mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog.

102. The method of claim 74, wherein fat mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog.

103. The method of any one of claims 100-102, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

104. The method of any one of claims 1-73, wherein the method stimulates appetite in the subject compared to a control subject having the kidney disease or the liver disease, wherein the control subject is not administered the non-naturally occurring melanocortin analog.

105. The method of claim 104, wherein the control subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss. -286- 165437951.15Docket No.: 146316.8006.WO00 106. The method of claim 105, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease or the liver disease.

107. The method of claim 105, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia.

108. The method of any one of claims 104-107, wherein appetite of the subject is increased after the administration by at least 10% to 200%, relative to appetite of the control subject.

109. The method of any one of claims 104-107, wherein appetite of the subject is increased after the administration by at least 25% to 100%, relative to appetite of the control subject.

110. The method of claim 108 or 109, 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 of the non-naturally occurring melanocortin analog.

111. The method of claim 108 or 109, 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 of the non-naturally occurring melanocortin analog.

112. The method of any one of claims 108-111, 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 of the non- naturally occurring melanocortin analog is stopped.

113. The method of any one of claims 105-112, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety. -287- 165437951.15Docket No.: 146316.8006.WO00 114. The method of claim 113, wherein the appetite is assessed between meals.

115. The method of any one of claims 104-114, wherein the subject comprises two or more subjects, and wherein the appetite of the subject is an average appetite of the two or more subjects.

116. The method of any one of claims 104-115, wherein the control subject comprises two or more control subjects, and wherein the appetite of the control subject is an average appetite of the two or more control subjects.

117. The method of any one of claims 104-107, wherein food consumption of the subject is increased after the administration by at least 25% to 2,000%, relative to food consumption of the control subject.

118. The method of any one of claims 104-107, wherein food consumption of the subject is increased after the administration by at least 50% to 500%, relative to food consumption of the control subject.

119. The method of claim 117 or 118, wherein 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.

120. The method of claim 117 or 118, wherein food consumption 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 of the non-naturally occurring melanocortin analog.

121. The method of any one of claims 117-120, wherein 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 of the non-naturally occurring melanocortin analog is stopped. -288- 165437951.15Docket No.: 146316.8006.WO00 122. The method of any one of claims 117-121, wherein the food consumption is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

123. The method of any one of claims 104-107, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 5% to 200% greater than that of the control subject.

124. The method of any one of claims 104-107, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 5% to 25% greater than that of the control subject.

125. The method of any one of claims 104-107, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 20% to 100% greater than that of the control subject.

126. The method of any one of claims 123-125, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

127. The method of any one of claims 104-107, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein muscle mass gain of the subject after the administration is at least 1% to 100% greater than that of the control subject.

128. The method of any one of claims 104-107, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and -289- 165437951.15Docket No.: 146316.8006.WO00 wherein muscle mass gain of the subject after the administration is at least 5% to 15% greater than that of the control subject.

129. The method of any one of claims 104-107, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein muscle mass gain of the subject after the administration is at least 25% to 50% greater than that of the control subject.

130. The method of any one of claims 127-129, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

131. The method of any one of claims 104-107, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein fat mass gain of the subject after the administration is at least 1% to 100% greater than that of the control subject.

132. The method of any one of claims 104-107, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein fat mass gain of the subject after the administration is at least 5% to 15% greater than that of the control subject.

133. The method of any one of claims 104-107, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein fat mass gain of the subject after the administration is at least 25% to 50% greater than that of the control subject.

134. The method of any one of claims 131-133, wherein the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or -290- 165437951.15Docket No.: 146316.8006.WO00 5 years, after the administration of the non-naturally occurring melanocortin analog is stopped.

135. The method of any one of claims 1-134, wherein the subject is a human.

136. The method of any one of claims 1-135, wherein the subject is an animal.

137. The method of claim 135, wherein the subject has a body mass index (BMI) of 18.5 kg / m2 to 35 kg / m2.

138. The method of claim 135, wherein the subject has a BMI of less than 20 kg / m2.

139. The method of claim 135, wherein the subject has a BMI of less than 18.5 kg / m2.

140. The method of any one of claims 1-139, further comprising administering an appetite-regulating agent to the subject.

141. The method of any one of claims 1-140, wherein the subject does not experience an adverse event following administration of the non-naturally occurring melanocortin analog.

142. The method of any one of claims 1-141, wherein the subject does not experience an adverse event attributable to the non-naturally occurring melanocortin analog following the administration.

143. The method of any one of claims 76-83, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject experiences the increase in appetite. -291- 165437951.15Docket No.: 146316.8006.WO00 144. The method of any one of claims 84-90, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject experiences the increase in food consumption.

145. The method of any one of claims 91-94, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject experiences the increase in body weight.

146. The method of any one of claims 1-74, wherein the subject is cachectic before the non-naturally occurring melanocortin analog is administered.

147. The method of claim 146, wherein the subject is cachectic if they meet the Fearon criteria of weight loss.

148. The method of claim 147, wherein the Fearon criteria of weight loss comprises (1) a weight loss greater than 5% within 6 months before the administration, or (2) a weight loss greater than 2% wherein the subject has a BMI less than 20 kg / m2or the subject has sarcopenia.

149. The method of any one of claims 146-148, wherein the subject is no longer cachectic after the non-naturally occurring melanocortin analog is administered.

150. The method of any one of claims 146-149, wherein the subject no longer meets the Fearon criteria of weight loss after the non-naturally occurring melanocortin analog is administered.

151. The method of claim 149, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject is no longer cachectic. -292- 165437951.15Docket No.: 146316.8006.WO00 152. The method of claim 150, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject no longer meets the Fearon criteria of weight loss.

153. The method of any one of claims 1-70 or 74, wherein the subject is pretreated with the non-naturally occurring melanocortin analog before the subject becomes cachectic.

154. The method of any one of claims 1-70, 74 or 153, wherein the subject does not meet the Fearon criteria of weight loss.

155. Use of a non-naturally occurring melanocortin analog for stimulating appetite and / or increasing body weight of a subject having a kidney disease and / or a liver disease, the non-naturally occurring melanocortin analog comprising 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), trans-4-guanidinyl-proline (transPro(guan)), cis-4- guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac- transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2is absent or is selected from the group consisting of proline, histidine, D- hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D- -293- 165437951.15Docket No.: 146316.8006.WO00 leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4- amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc), R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D- phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- phenylalanine, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8is absent or is lysine; R9-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, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2is absent or is D-proline; X3is absent; -294- 165437951.15Docket No.: 146316.8006.WO00 Y1is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; 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 or aspartic acid; Y5-Y8are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1is cysteine and R7is cysteine; 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 or aspartic acid, and R7is lysine or Dap; a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; 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; 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; -295- 165437951.15Docket No.: 146316.8006.WO00 when R3is Aba, Ata, or Aia, R6is Aia, then R4is not dNal(2’), or R4is dNal(2’) and R5is not Arg; when R4is p(Cl)dPhe, then R3is not Pro or His; when R4is p(I)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1and R7and at least one of R2and R3is Pro; when Y2-Y4are absent, then Y1is absent or is norleucine; when R2is Pro or Y2is Hyp, then R3is not Pro; when R3, R5, or R6is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1and R7or X1-X2are present and are Ac-dVal-dPro; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys or Cys-Pro-dNal(2’)-Arg-Trp-Cys, then R1is not Ac-Nle or Y1-Y2is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R8, then R3is not His or Y1is not dVal.

156. The use of claim 155, wherein the N-terminus, 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.

157. The use of claim 156, wherein the N-terminus, if present, is modified by an acyl group.

158. The use of claim 157, wherein the acyl group is acetyl group.

159. The use of claim 157, wherein the acyl group is formyl group. -296- 165437951.15Docket No.: 146316.8006.WO00 160. The use of claim 156, wherein the N-terminus, if present, is modified by an imine group.

161. The use of claim 156, wherein the N-terminus, if present, is modified by an amide group.

162. The use of claim 161, wherein the amide group is a pyroglutamyl (pGlu) group.

163. The use of claim 161, wherein the amide group is derived from a fatty acid.

164. The use of claim 155, wherein the N-terminus, if present, is not modified.

165. The use of claim 155, wherein the C-terminus is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

166. The use of claim 165, wherein the C-terminus is modified by an amide group.

167. The use of claim 166, wherein the amide group is an -NHalkyl amide group or an -NHaryl amide group.

168. The use of claim 167, wherein the -NHaryl amide group is p-nitroanilide group or 7-amino-4-methylcoumarin.

169. The use of claim 165, wherein the C-terminus is modified by an ester group.

170. The use of claim 155, wherein the C-terminus is not modified.

171. The use of claim 155, wherein R1is absent, and R2is D-aspartic acid. -297- 165437951.15Docket No.: 146316.8006.WO00 172. The use of claim 171, wherein X1, X2, and X3are absent.

173. The use of claim 155, wherein R4is D-Nal(2′).

174. The use of claim 155, wherein Y3- Y8are absent.

175. The use of claim 174, wherein: Y1is D-valine and Y2is D-proline; or Y1is D-proline and Y2is D-valine.

176. The use of claim 155, wherein Y3is present and Y4-Y8are absent.

177. The use of claim 176, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; and / or Y3is D-valine or D-proline.

178. The use of claim 176, wherein: Y1is D-valine, Y2is D-valine, and Y3is D-proline; Y1is D-proline, Y2is D-valine, and Y3is D-valine; Y1is D-valine, Y2is D-proline, and Y3is D-valine; or Y1is D-proline, Y2is D-valine, and Y3is D-proline.

179. The use of claim 155, wherein Y3and Y4are present, and Y5-Y8are absent.

180. The use of claim 179, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; Y3is D-valine or D-proline; and / or Y4is D-valine or D-proline. -298- 165437951.15Docket No.: 146316.8006.WO00 181. The use of claim 179, wherein: Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline; Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine; or Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-proline.

182. The use of claim 155, wherein R1, R2, and R7are present and R8-R20are absent, and the sequence of Formula (I) is cyclized through R2and R7via a lactam bond.

183. The use of claim 155, wherein R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond.

184. The use of claim 183, wherein: R1is acetylated norleucine; R2is aspartic acid; R3is selected from the group consisting of proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine; R4is histidine or dNal(2′); R5is dNal(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.

185. The use of claim 183, wherein the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5), wherein c represents cyclization through R2and R8via a lactam bond. -299- 165437951.15Docket No.: 146316.8006.WO00 186. The use of claim 155, wherein the sequence of Formula (I) is linear.

187. The use of claim 186, wherein the sequence of Formula (I) is Ac-Nle-Pro- dNal(2’)-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14).

188. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-transPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-cisPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 36); Dmt-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 39), wherein c represents cyclization through R2and R7via a lactam bond.

189. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c(Asp-dIle-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c(Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 87); Ac-Nle-c(Asp-cisPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 88); -300- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-Val-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c(Asp-Ile-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c(Asp-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 91); Ac-Nle-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 92); Ac-Nle-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c(Asp-dLeu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 94); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 95); and Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 96), wherein c represents cyclization through R2and R7via a lactam bond.

190. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-dHis-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2’)-dAla-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2’)-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2’)-dGlu-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 111), wherein c represents cyclization through R2and R7via a lactam bond.

191. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(2’)-Lys)-dVal-dPro-NH2(SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dAla-Lys)-dVal-dPro-NH2(SEQ ID NO: 124), -301- 165437951.15Docket No.: 146316.8006.WO00 wherein c represents cyclization through R2and R7via a lactam bond.

192. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-dPro-NH2(SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-NH2(SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID NO: 186); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dVal-NH2 (SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dTle-NH2(SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dTle-NH2 (SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

193. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Che-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 212); Ac-Nle-c(Asp-Oic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 213); Ac-Nle-c(Asp-Ioc-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 214); Ac-Nle-c(Asp-Tic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle-c(Asp-His-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 218); -302- 165437951.15Docket No.: 146316.8006.WO00 Ac-Nle-c(Asp-His-dNal(2’)-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 219); Ac-Nle-c(Asp-Pro-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c(Asp-Pro-dNal(2’)-transPro(guan)-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 221); Ac-Nle-c(Asp-Pro-dNal(2’)-cisPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 222); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ata-Lys)-dVal-dPro-NH2(SEQ ID NO: 224); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 225); Ac-Nle-c(Asp-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 226); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-Glu-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2(SEQ ID NO: 228); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 229); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 230); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2(SEQ ID NO: 231); Ac-Glu-c(Asp-Pro-dNal(2′)-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 232); and Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2(SEQ ID NO: 233), wherein c represents cyclization through R2and R7via a lactam bond.

194. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c(Asp-Glu-His-dNal(2′)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 235); Ac-Nle-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 236); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 238); -303- 165437951.15Docket No.: 146316.8006.WO00 Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-dArg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 240); Ac-Arg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 241); Ac-dArg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 242); Ac-Nle-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Arg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 244); Ac-dArg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 245); Ac-Nle-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c(Asp-Pro-Trp-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 248); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 249); Ac-Nle-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH2(SEQ ID NO: 251); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(EQ ID NO: 254), wherein c represents cyclization through R2and any of R5-8via a lactam bond or a disulfide bond.

195. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-NH2(SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-Nle-NH2 (SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258); -304- 165437951.15Docket No.: 146316.8006.WO00 Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 260), wherein c represents cyclization through R2and any one of R7via a lactam bond.

196. The use of claim 155, wherein the sequence of Formula (I) is: Ac-dVal-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 262), wherein c represents cyclization through R2and R7via a lactam bond.

197. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 263); Ac-Glu-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R2and R7via a lactam bond.

198. The use of claim 155, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 270); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 273); -305- 165437951.15Docket No.: 146316.8006.WO00 Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 276); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 277); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO: 279); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2(SEQ ID NO: 280); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281); wherein c represents cyclization through R1or R2and R7via a lactam bond.

199. The use of claim 155, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 128, 182-189, 212-281, 394 and 399.

200. The use of claim 155, wherein the non-naturally occurring melanocortin analog comprises SEQ ID NO:

3.

201. The use of any one of claims 155-200, wherein the non-naturally occurring melanocortin analog is present in a composition.

202. The use of claim 201, wherein the composition further comprises a pharmaceutical salt.

203. The use of claim 201, wherein the composition further comprises a pharmaceutical carrier.

204. The use of claim 201, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a -306- 165437951.15Docket No.: 146316.8006.WO00 total volume of the composition.

205. The use of claim 204, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition.

206. The use of claim 205, wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

207. The use of any one of claims 155-206, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

208. The use of any one of claims 201-207, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

209. The use of any one of claims 201-208, wherein the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

210. The use of any one of claims 155-209, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

211. The use of any one of claims 155-210, 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. -307- 165437951.15Docket No.: 146316.8006.WO00 212. The use of any one of claims 155-211, 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.

213. The use of any one of claims 155-212, 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.

214. The use of any one of claims 155-213, 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.

215. The use of claim 213, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (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.

216. The use of claim 214, wherein the non-naturally occurring melanocortin analog comprises TCMCB07 (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.

217. The use of any one of claims 155-216, 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.

218. The use of any one of claims 155-217, 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. -308- 165437951.15Docket No.: 146316.8006.WO00 219. The use of claim 203, wherein the pharmaceutical carrier comprises water.

220. The use of any one of claims 155-219, wherein the kidney disease and / or the liver disease is a fibrotic disease, optionally wherein the fibrotic kidney disease further comprises fibrosis of at least a portion of the subject’s kidney, and optionally wherein the fibrotic liver disease further comprises fibrosis of at least a portion of the subject’s liver.

221. The use of any one of claims 155-219, wherein the kidney disease is chronic kidney disease (CKD), and / or renal failure.

222. The use of claim 221, wherein the subject has undergone or is undergoing dialysis.

223. The use of any one of claims 155-219, wherein the liver disease is nonalcoholic fatty liver disease (NAFLD).

224. The use of claim 223, wherein NAFLD is nonalcoholic steatohepatitis (NASH).

225. The use of any one of claims 155-224, 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.

226. The use of claim 225, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease and / or the liver disease.

227. The use of claim 225, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia. -309- 165437951.15Docket No.: 146316.8006.WO00 228. The use of any one of claims 155-227, wherein the use (i) stimulates appetite of the subject; (ii) increases food consumption by 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 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.

229. The use of any one of claims 155-228, wherein the use increases body weight of and / or increases food consumption by the subject.

230. The use of claim 228, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

231. The use of claim 228, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

232. The use of claim 229 or 230, 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 of the non-naturally occurring melanocortin analog.

233. The use of claim 230 or 231, 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 of the non- naturally occurring melanocortin analog.

234. The use of any one of claims 230-233, 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 of the non- naturally occurring melanocortin analog is stopped. -310- 165437951.15Docket No.: 146316.8006.WO00 235. The use of any one of claims 225-232, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

236. The use of claim 235, wherein the appetite is assessed between meals.

237. The use of any one of claims 225-232 wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.

238. The use of claim 228 or 229, wherein food consumption of the subject is increased by at least 25% to 2,000% after the administration of the non-naturally occurring melanocortin analog.

239. The use of claim 228 or 229, wherein food consumption of the subject is increased by at least 50% to 500% after the administration of the non-naturally occurring melanocortin analog.

240. The use of claim 238 or 239, wherein 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 of the non-naturally occurring melanocortin analog.

241. The use of claim 238 or 239, wherein food consumption 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 of the non-naturally occurring melanocortin analog.

242. The use of any one of claims 238-241, wherein 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 of the non-naturally occurring melanocortin analog is stopped. -311- 165437951.15Docket No.: 146316.8006.WO00 243. The use of any one of claims 238-242, wherein the food consumption is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

244. The use of claim 228, wherein anorexia is determined by food consumption.

245. The use of claim 228 or 229, wherein body weight of the subject is increased by at least 5% to 200% after the administration of the non-naturally occurring melanocortin analog.

246. The use of claim 228 or 229, wherein body weight of the subject is increased by at least 5% to 25% after the administration of the non-naturally occurring melanocortin analog.

247. The use of claim 228 or 229, wherein body weight of the subject is increased by at least 20% to 100% after the administration of the non-naturally occurring melanocortin analog.

248. The use of any one of claims 245-247, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

249. The use of claim 228, wherein muscle mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog.

250. The use of claim 228, wherein muscle mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog. -312- 165437951.15Docket No.: 146316.8006.WO00 251. The use of claim 228, wherein muscle mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog.

252. The use of any one of claims 249-251, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

253. The use of any one of claims 228 and 262-265, wherein the muscle mass is cardiac muscle mass, skeletal muscle mass, or both.

254. The use of claim 228, wherein fat mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog.

255. The use of claim 228, wherein fat mass of the subject is increased by at least 5% to 15% after the administration of the non-naturally occurring melanocortin analog.

256. The use of claim 228, wherein fat mass of the subject is increased by at least 25% to 50% after the administration of the non-naturally occurring melanocortin analog.

257. The use of any one of claims 254-256, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

258. The use of any one of claims 155-227, wherein the use stimulates appetite in the subject compared to a control subject having the kidney disease or the liver disease, wherein the control subject is not administered the non-naturally occurring melanocortin analog. -313- 165437951.15Docket No.: 146316.8006.WO00 259. The use of claim 258, wherein the control subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss.

260. The use of claim 259, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the kidney disease or the liver disease.

261. The use of claim 259, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia.

262. The use of any one of claims 258-261, wherein appetite of the subject is increased after the administration by at least 10% to 200%, relative to appetite of the control subject.

263. The use of any one of claims 258-261, wherein appetite of the subject is increased after the administration by at least 25% to 100%, relative to appetite of the control subject.

264. The use of claim 262 or 263, 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 of the non-naturally occurring melanocortin analog.

265. The use of claim 262 or 263, 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 of the non- naturally occurring melanocortin analog.

266. The use of any one of claims 262-265, 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 of the non- naturally occurring melanocortin analog is stopped. -314- 165437951.15Docket No.: 146316.8006.WO00 267. The use of any one of claims 259-266, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

268. The use of claim 267, wherein the appetite is assessed between meals.

269. The use of any one of claims 258-268, wherein the subject comprises two or more subjects, and wherein the appetite of the subject is an average appetite of the two or more subjects.

270. The use of any one of claims 258-269, wherein the control subject comprises two or more control subjects, and wherein the appetite of the control subject is an average appetite of the two or more control subjects.

271. The use of any one of claims 258-261, wherein food consumption of the subject is increased after the administration by at least 25% to 2,000%, relative to food consumption of the control subject.

272. The use of any one of claims 258-261, wherein food consumption of the subject is increased after the administration by at least 50% to 500%, relative to food consumption of the control subject.

273. The use of claim 271 or 272, wherein 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.

274. The use of claim 271 or 272, wherein food consumption 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 of the non-naturally occurring melanocortin analog. -315- 165437951.15Docket No.: 146316.8006.WO00 275. The use of any one of claims 271-274, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

276. The use of any one of claims 271-275, wherein the food consumption is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

277. The use of any one of claims 258-261, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 5% to 200% greater than that of the control subject.

278. The use of any one of claims 258-261, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 5% to 25% greater than that of the control subject.

279. The use of any one of claims 258-261, wherein body weight of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein weight gain of the subject after the administration is at least 20% to 100% greater than that of the control subject.

280. The use of any one of claims 277-279, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

281. The use of any one of claims 258-261, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and -316- 165437951.15Docket No.: 146316.8006.WO00 wherein muscle mass gain of the subject after the administration is at least 1% to 100% greater than that of the control subject.

282. The use of any one of claims 258-261, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein muscle mass gain of the subject after the administration is at least 5% to 15% greater than that of the control subject.

283. The use of any one of claims 258-261, wherein muscle mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein muscle mass gain of the subject after the administration is at least 25% to 50% greater than that of the control subject.

284. The use of any one of claims 281-283, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

285. The use of any one of claims 258-261, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein fat mass gain of the subject after the administration is at least 1% to 100% greater than that of the control subject.

286. The use of any one of claims 258-261, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and wherein fat mass gain of the subject after the administration is at least 5% to 15% greater than that of the control subject.

287. The use of any one of claims 258-261, wherein fat mass of the subject is increased after the administration of the non-naturally occurring melanocortin analog, and -317- 165437951.15Docket No.: 146316.8006.WO00 wherein fat mass gain of the subject after the administration is at least 25% to 50% greater than that of the control subject.

288. The use of any one of claims 184-287, wherein 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 of the non-naturally occurring melanocortin analog is stopped.

289. The use of any one of claims 155-288, wherein the subject is a human.

290. The use of any one of claims 155-288, wherein the subject is an animal.

291. The use of claim 289, wherein the subject has a body mass index (BMI) of 18.5 kg / m2 to 35 kg / m2.

292. The use of claim 289, wherein the subject has a BMI of less than 20 kg / m2.

293. The use of claim 289, wherein the subject has a BMI of less than 18.5 kg / m2.

294. The use of any one of claims 155-293, further comprising administering an appetite-regulating agent to the subject.

295. The use of any one of claims 155-294, wherein the subject does not experience an adverse event following administration of the non-naturally occurring melanocortin analog.

296. The use of any one of claims 155-295, wherein the subject does not experience an adverse event attributable to the non-naturally occurring melanocortin analog following the administration. -318- 165437951.15Docket No.: 146316.8006.WO00 297. The use of any one of claims 155-294, wherein the subject continues to be administered with the non-naturally occurring melanocortin analog after the subject experiences the increase in food consumption. -319- 165437951.15

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