Orally deliverable non-naturally occurring melanocortin analogs and uses thereof for modulating weight loss

Abstract

Provided herein are methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction, such as obesity, in a subject in need thereof using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology.

Description

Docket No.: 146316.8032.WO00 ORALLY DELIVERABLE NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND USES THEREOF FOR MODULATING WEIGHT LOSS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 656,574, filed June 5, 2024; U.S. Provisional Patent Application No. 63 / 663,663, filed June 24, 2024; U.S. Provisional Patent Application No.63 / 675,181, filed July 24, 2024; U.S. Provisional Patent Application No. 63 / 681,082, filed August 8, 2024; and U.S. Provisional Patent Application No. 63 / 692,552, filed September 9, 2024, all of which are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and hereby incorporated by reference in its entirety. The .xml copy, created on February 14, 2025, is titled “1463168032WO00.xml” and is 490,834 bytes in size. BACKGROUND

[0003] The prevalence of obesity, diabetes, and metabolic syndrome has reached pandemic proportions, and is expected to continue to rise in the next two decades. These conditions place enormous stress on healthcare systems globally. Accordingly, various weight loss agents have been developed in an attempt to treat such conditions. Although some weight loss agents have been approved for ongoing use, many are not sufficiently effective in achieving desired amounts or types of weight loss. Further, commonly used weight loss agents are administered subcutaneously, requiring self-administered injections on a daily or weekly basis which may cause administration site irritation and discomfort.

[0004] Accordingly, despite recent advances treatment for obesity, diabetes, and metabolic syndrome, there is a demand for novel and effective weight loss agents that may be delivered via less invasive administration routes. -1- 180085204.4Docket No.: 146316.8032.WO00 SUMMARY

[0005] The present technology comprises methods of reducing body weight and / or fat mass in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog.

[0006] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, to produce an additive or synergistic effect on body weight and / or fat mass loss in the subject.

[0007] In some embodiments, the present technology comprises a method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non- naturally occurring melanocortin analog, to produce a synergistic or additive effect on glucose intolerance and / or diabetes mellitus in the subject.

[0008] In some embodiments, the present technology comprises a method of inducing a tanning effect in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0009] In some embodiments, the present technology comprises a method of inducing a tanning effect and weight loss in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0010] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with s use of a weight loss agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the weight loss agent.

[0011] In some embodiments, the present technology comprises a method of reducing obesity-related inflammation in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent -2- 180085204.4Docket No.: 146316.8032.WO00

[0012] In some embodiments, the present technology comprises a method of preserving or improving kidney function in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent.

[0013] In some embodiments, the non-naturally occurring melanocortin analog comprises a Formula according to Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; -3- 180085204.4Docket No.: 146316.8032.WO00 Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0014] In some embodiments, the present technology comprises a method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0015] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a -4- 180085204.4Docket No.: 146316.8032.WO00 non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0016] In some embodiments, the present technology comprises a method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0017] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0018] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0019] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0020] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0021] In some embodiments, the present technology comprises method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally -5- 180085204.4Docket No.: 146316.8032.WO00 occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0022] In some embodiments, the present technology comprises method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0023] In some embodiments, the present technology comprises method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0024] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0025] In some embodiments, the present technology comprises a method of treating, preventing, or reducing Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

[0026] In some embodiments, the present technology comprises a method of treating, preventing, or reducing weight gain after a weight loss or a weight loss plateau in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent. BRIEF DESCRIPTION OF THE DRAWINGS -6- 180085204.4Docket No.: 146316.8032.WO00

[0027] FIG. 1 illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14; C2) to Cynomolgus Monkeys at 30.0 mg / kg.

[0028] FIGS. 2A-2F illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43; O10)) to Cynomolgus Monkeys at 3 mg / kg, 10.0 mg / kg, 30.0 mg / kg, or 60 mg / kg.

[0029] FIGS. 3A-3C illustrates 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following SC administration of Compound E of FIGS.2A-2F to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0030] FIGS. 4A-4G illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs of the present technology. FIGS. 4A-4G illustrate 24-hour plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound E of FIGS.2A-2I to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg. FIGS.4H-4K illustrate 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following IP administration of Compound E (“O10”) at 10 mg / kg relative to setmelanotide. The shaded areas of 4D-4G represent the drug exposure at concentrations greater than the EC50. Area under the depicted lines represent the non-naturally occurring melanocortin analog exposure at concentrations greater than the EC50.

[0031] FIGS. 5A-5C illustrates 24-hour plasma and CSF concentrations of non- naturally occurring melanocortin analogs of the present technology following PO administration of Compound E of FIGS.2A-2I to Rats at 10.0 mg / kg and 30.0 mg / kg.

[0032] FIGS.6A and 6B show preliminary weight loss and daily food intake results in animals administered 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43). -7- 180085204.4Docket No.: 146316.8032.WO00

[0033] FIGS.7A-7D show food intake (g) at baseline in monkeys having diet-induced obesity (n=6) from 0.5 to 72 hours after saline administration at day 1 (D1). FIG.7A shows net weight of food intake among individual monkeys. FIG.7B shows net weight of food intake for each group average. FIG.7C shows cumulative food intake among individual monkeys. FIG.7D shows cumulative food intake for each group average.

[0034] FIGS. 8A-8H show food intake (g) in the same monkeys as FIGS. 7A-7D administered 1 mg / kg or 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 43) on day 8 (D8). FIG.8A shows net weight of food intake among individual monkeys at day 8 (D8). FIG.8B shows net weight of food intake for each group average of monkeys administered the same compound at D8. FIG. 8C shows cumulative food intake among individual monkeys of FIG. 8A at D8. FIG. 8D shows cumulative food intake for each group average of monkeys of FIG.8C administered the same compound at D8. FIG. 8E shows net weight of food intake among individual monkeys at day 12 (D12). FIG.8F shows net weight of food intake for each group average of monkeys administered the same compound at D12. FIG. 8G shows cumulative food intake among individual monkeys at D12. FIG.8H shows cumulative food intake for each group average of monkeys administered the same compound at D12.

[0035] FIGS. 9A and 9B show food intake patterns in diet-induced obese monkeys administered saline, compared to the same monkeys administered 1mg / kg or 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) in FIGS. 8A-8H.

[0036] FIGS. 10A-10C show changes in daily caloric intake (FIG. 10A), cumulative caloric intake (FIG.10B), percent change in caloric consumption from baseline through day 6 (FIG.10C) for diet-induced obese monkeys orally administered 10 mg / kg of or O10 (Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2).

[0037] FIGS.11A-11Q show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: -8- 180085204.4Docket No.: 146316.8032.WO00 43), saline, or semaglutide (sema) (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly).

[0038] FIG. 11R shows normalized cumulative food consumption in rats subcutaneously administered 1 mg.kg or 3 mg / kg of MC4R selective agonists (A07D (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 48), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 62)) (n=5 per group) or MC3R / MC4R co-agonists (O10) (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) (n=5) compared to saline controls (n=4).

[0039] FIG. 11S shows an average percent change in caloric consumption from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2) at a starting dose of 10 mg / kg and increased to 20 mg / kg.

[0040] FIGS.12A-12L show changes in body weight for diet included obese monkeys administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) orally and / or subcutaneously. Shown are changes in daily body weight and percent change in body weight from baseline (FIGS. 12A and 12B) for the diet-induced obese monkeys of FIGS. 11A-11Q through day 8. FIGS.12C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS.12A and 12B through day 15 compared to those administered semaglutide (sema) alone. FIG. 12D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered O10 at increasing dosages or with semaglutide. FIG. 12E shows body weight change in the monkeys of FIG.12D. FIG.12F shows body weight change as a percentage of initial weight in diet included obese monkeys administered O10 at changing doses and administration frequencies. FIG. 12G shows body weight changes as a percentage of initial in monkeys orally administered O10 (PO) with dose changes or semaglutide. FIG. 12H shows body weight change after removal of O10 administration for the monkeys of FIG. 12G. FIG. 12I shows percent change in body weight as a percentage of initial weight for diet induced obese monkeys orally administered O10 followed by subcutaneous administration. FIG.12J shows body weight percent change after removal of O10 treatment in monkeys. FIG.12K shows body weight percent change at an oral O10 dosing regimen in accordance with the -9- 180085204.4Docket No.: 146316.8032.WO00 embodiments of the present technology. FIG.12L shows body weight percent change from initial in monkeys orally administered O10 in combination with semaglutide compared to those administered semaglutide alone. (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly; sema: semglutide).

[0041] FIG. 12M shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2), O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2; SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 62)), or an equal dose of a melanocortin 3 receptor (MC3R) / MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43)).

[0042] FIG. 12N shows an average percent change in normalized body weight from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2; SEQ ID NO: 43) at a starting dose of 10 mg / kg and increased to 20 mg / kg and 30 mg / kg.

[0043] FIGS.13A-13N show changes in body composition for the diet-induced obese monkeys of FIGS.10A-10C.

[0044] FIGS. 14A-14D show blood chemistry levels in diet-induced obese monkeys orally administered 10 mg / kg O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43) once daily for week 1, 20mg / kg O10 once daily for week 2, and 15 mg / kg O10 twice daily weeks 3 and 4.

[0045] FIGS. 15A-15C show measurements of systolic blood pressure (FIG. 15A), diastolic blood pressure (FIG. 15B), and heart rate (FIG. 15C) in rats subcutaneously administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) at 0.5 mg / kg, 1 mg / kg, or 3 mg / kg.

[0046] FIGS.16A-16D show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg / kg, 1.0 mg / kg, 3.0 mg / kg, or 6.0 mg / kg, relative to control rats administered saline. -10- 180085204.4Docket No.: 146316.8032.WO00

[0047] FIGS.17A-17H show measurements of normalized heart rate (FIG.17A), QTc (FIG. 17B), systolic blood pressure (FIG. 17C), diastolic blood pressure (FIG. 17D), mean blood pressure (FIG.17E), QT interval (FIG.17F), QRS internal (FIG.17G), and RR internal (FIG.17H) in male cynomolgus monkeys orally (PO) administered O10 (Ac-Nle-c[Glu-His- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) at 3, 10, 30, or 60 mg / kg, relative to those subcutaneously (SC) administered setmelanotide at 3 mg / kg or orally administered saline. (N = 3 to 5 animals per group).

[0048] FIG. 18 shows results of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 43) screened for binding against a panel of 87 targets at 10µM. X- axis represents the percent inhibition of control at 10µM. (MC1R: melanocortin 1 receptor; MC4R: melanocortin 4 receptor).

[0049] FIG. 19 shows exemplary adipose tissue staining in diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43) at 10 mg / kg.

[0050] FIG. 20 shows plasma concentration of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) in monkeys orally (PO) administered 3mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg O10. DETAILED DESCRIPTION

[0051] The present technology comprises methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises promoting fat loss in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises reducing body weight and / or fat mass in a subject in need thereof using a non-naturally occurring melanocortin analog, or a pharmaceutical composition thereof, of the present technology. -11- 180085204.4Docket No.: 146316.8032.WO00

[0052] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology. 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.

[0053] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in any description, method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0054] 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.

[0055] 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.

[0056] 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. Typically, such variation may be as much 10% above and below a reference quantity, -12- 180085204.4Docket No.: 146316.8032.WO00 level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. 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.

[0057] The terms “administering” or “administer” include delivery of therapies (e.g., combination therapies, non-naturally occurring melanocortin analogs (also referred to herein as peptides and synthetic 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.

[0058] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.

[0059] 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.

[0060] As used herein, a “pharmaceutically acceptable carrier” of the first or 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” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the -13- 180085204.4Docket No.: 146316.8032.WO00 composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0061] The term “weight loss agent” refers to a therapeutic agent useful for the treatment or prevention of metabolic dysfunction or one or more symptoms associated with metabolic dysfunction in a subject. In some embodiments, such weight loss agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not metabolic dysfunction, or besides metabolic dysfunction. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.

[0062] The terms “treat,” “treatment,” and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease (e.g., metabolic dysfunction), the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1) a stabilization or reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the baseline of glucose levels before -14- 180085204.4Docket No.: 146316.8032.WO00 administration) of circulating glucose levels (2) inhibiting or reducing rate of fat mass gain, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by metabolic dysfunction, (4) an increase in disease-free, relapse-free, progression-free, and / or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) an increase in the oxidation of lipids or carbohydrates by at least by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial oxidation rate, (8) a stabilization or reduction (e.g. by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial loss rate) in the rate of lean muscle mass loss, (9) an increase in lean muscle mass, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond, (12) ) a stabilization or reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the baseline of lactate levels before administration) of circulating lactate levels, (13) a decrease in the need for surgery (e.g. gastric bypass, liposuction, sleeve gastrectomy, bariatric surgery), and (14) preventing or reducing organ burden induced by metabolic dysfunction. The terms “treat,” “treatment,” and “treating” include prophylactic and / or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length or frequency of the disease.

[0063] As used herein, the term “prevent,” “preventing,” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0064] 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 -15- 180085204.4Docket No.: 146316.8032.WO00 from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0065] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the weight loss agent has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to administration” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the weight loss agent has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0066] 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 / m2 to about 25 kg / m2.

[0067] 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 metabolic dysfunction.

[0068] 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. -16- 180085204.4Docket No.: 146316.8032.WO00

[0069] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro- opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule—i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the non- naturally occurring 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.

[0070] 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 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 -17- 180085204.4Docket No.: 146316.8032.WO00 appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0071] A “melanocortin receptor agonist” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0072] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating, and the like.

[0073] The “peptides” of the present technology 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.

[0074] 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.

[0075] 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- -18- 180085204.4Docket No.: 146316.8032.WO00 or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0076] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N— CHR—COOH, wherein R represents a side chain group. The various α-amino acids differ in the side-chain moiety that is attached to the α-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally 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.

[0077] 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. -19- 180085204.4Docket No.: 146316.8032.WO00

[0078] 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.

[0079] In the peptides of the present technology, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; Thr is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Val” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” 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 biphenylalanine; and so on.

[0080] 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.

[0081] 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 -20- 180085204.4Docket No.: 146316.8032.WO00 group are called β2amino acids. Further, β-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.

[0082] 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

[0083] 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; Nal(2′) is D-(2′-naphthyl)alanine.

[0084] 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; dPen is D-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; dBip is D- 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).

[0085] 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. -21- 180085204.4Docket No.: 146316.8032.WO00

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] The term “aliphatic” includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0091] 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.”

[0092] 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.

[0093] 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. -22- 180085204.4Docket No.: 146316.8032.WO00

[0094] 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.

[0095] 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.

[0096] An “amine” includes compounds that contain an amine group (—NH2).

[0097] 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.

[0098] An “imine” includes compounds that have a carbon-nitrogen double bond, with the nitrogen also attached to a hydrogen (NH═CH—R).

[0099] An “imide” includes compounds containing an imido group (—OC—NH—CO—).

[0100] A “nitrile” includes compounds that are carboxylic acid derivatives and contain a (—CN) group bound to an organic group.

[0101] The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine, and groups including one or more halogen atoms, such as —CF3 and the like.

[0102] 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, -23- 180085204.4Docket No.: 146316.8032.WO00 or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0103] 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.

[0104] “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 melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a 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 melanocortin analog that lacks a C-terminal extension.

[0105] As used herein, a “composition” refers to a mixture of the active ingredient with other chemical components.

[0106] 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

[0107] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and / or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Alternatively, some melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R. -24- 180085204.4Docket No.: 146316.8032.WO00

[0108] The non-naturally occurring melanocortin analogs of the present technology may be full agonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%.

[0109] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%.

[0110] If a non-naturally occurring melanocortin analog’s Emax agonist value is greater than it’s Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).

[0111] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist (ii) a full MC3R agonist; and (iii) a partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non-naturally occurring melanocortin is a full MC4R agonist. In some embodiments, the non-naturally occurring melanocortin agonist is a full MC3R agonist and a full MC3R agonist. In some embodiments, the non-naturally occurring melanocortin analog is a full MC4R agonist and partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non- naturally occurring melanocortin analogs of the present technology have an MC3R Emax agonist value of 50-84%. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology have a MC3R:MC4R half maximal effective concentration (EC50) selectivity ratio of less than or equal to 49. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise non-naturally occurring MC4R agonists or non-naturally occurring MC3R agonists.

[0112] The non-naturally occurring melanocortin analogs in accordance with the present technology may have structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the MC4R and / or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) one or more pharmaceutical- like pharmacokinetic measurements (e.g., a pharmacokinetic measurement of a weight loss -25- 180085204.4Docket No.: 146316.8032.WO00 agent pharmaceutical composition or an oral non-naturally occurring melanocortin analog pharmaceutical), (iii) degradation resistance; (iv) equipotency on MC3R and MC4R activity, or (v) oral potency. In some embodiments, the oral potency is greater than a subcutaneous administration potency for an equivalent dose. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(v). In some embodiments, he non-naturally occurring melanocortin analogs comprise each of (i)-(v). Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs 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, Pro, dPro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and / or β-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include a D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0113] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at the R4position may be full agonists on MC4R. Further, inclusion of His at the R3position may result in full agonism on MC3R as well. By contrast, inclusion of His at the R3position may decrease activity on the melanocortin 3 receptor, resulting in only partial agonism on MC3R.

[0114] Non-naturally occurring melanocortin analogs in accordance with the present technology may induce or increase body weight and / or fat mass loss in a subject in need thereof while reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. Additionally, the non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stable heart rate, -26- 180085204.4Docket No.: 146316.8032.WO00 systolic blood pressure, and / or diastolic blood pressure following administration of a melanocortin analog of the present technology.

[0115] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; -27- 180085204.4Docket No.: 146316.8032.WO00 Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0116] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); -28- 180085204.4Docket No.: 146316.8032.WO00 R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); -29- 180085204.4Docket No.: 146316.8032.WO00 Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); -30- 180085204.4Docket No.: 146316.8032.WO00 Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); -31- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); -32- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); -33- 180085204.4Docket No.: 146316.8032.WO00 Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160).

[0117] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) wherein R4is dPhe or p(F)dPhe. When R4is dPhe or p(F)dPhe in the sequence of Formula (I), then R9is absent. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu -34- 180085204.4Docket No.: 146316.8032.WO00 R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

[0118] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu R3is selected from the group consisting of His, dHis, Pro, and Gln; -35- 180085204.4Docket No.: 146316.8032.WO00 R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0119] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu -36- 180085204.4Docket No.: 146316.8032.WO00 R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); -37- 180085204.4Docket No.: 146316.8032.WO00 Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); -38- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); -39- 180085204.4Docket No.: 146316.8032.WO00 Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160).

[0120] Further, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA) wherein R4is dPhe or p(F)dPhe, then R8may also be absent. Additionally, the sequence of Formula (I) or (I) may be cyclized through a lactam bond between R2and R7. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; -40- 180085204.4Docket No.: 146316.8032.WO00 R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

[0121] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; -41- 180085204.4Docket No.: 146316.8032.WO00 R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7, provided that when R3is Pro, then X1and Y3are present and R4is dPhe,

[0122] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); -42- 180085204.4Docket No.: 146316.8032.WO00 R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); -43- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); -44- 180085204.4Docket No.: 146316.8032.WO00 Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); -45- 180085204.4Docket No.: 146316.8032.WO00 Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); and Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125),

[0123] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IB) wherein R4is p(F)dPhe. In further embodiments, R3is His, R5is Arg, and R6is Trp. Accordingly, in some embodiments, the sequence of any one of Formulae (I)-(IB) is a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IC), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is His; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; -46- 180085204.4Docket No.: 146316.8032.WO00 Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

[0124] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IC), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is His; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and -47- 180085204.4Docket No.: 146316.8032.WO00 the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

[0125] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IB) wherein R4is dPhe. Accordingly, in some embodiments, the sequence of any one of Formulae (I)-(IB) is a sequence of Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3(ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: -48- 180085204.4Docket No.: 146316.8032.WO00 a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

[0126] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3(ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, -49- 180085204.4Docket No.: 146316.8032.WO00 provided that: when R3is Pro, then X1and Y3are present, when R2is Pro, then X1is present and R5is Arg.

[0127] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); -50- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); and Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125).

[0128] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA) wherein R4is dPhe or p(F)dPhe, then R8is present. In further embodiments, R4is dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IE): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IE), wherein: X1is absent or selected from the group consisting of Nle, Arg, and dArg; -51- 180085204.4Docket No.: 146316.8032.WO00 R1is Asp; R2is dAla or Ala; R3is His; R4is dPhe; R5is Arg; R6is Trp; R7is Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Lys at R7.

[0129] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IE), wherein: X1is absent or selected from the group consisting of Nle, Arg, and dArg; R1is Asp; R2is dAla or Ala; R3is His; R4is dPhe; R5is Arg; R6is Trp; R7is Lys; Y1is dVal; Y2is dPro; and -52- 180085204.4Docket No.: 146316.8032.WO00 the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Lys at R7.

[0130] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) that is cyclized between Asp or Glu at R2and Orn at R7. In further embodiments, R3is His and R4is p(F)dPhe or p(Cl)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0131] In some embodiments, the non-naturally occurring melanocortin analog compirses a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; -53- 180085204.4Docket No.: 146316.8032.WO00 R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0132] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IF) has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, the presence of Pro, dPro, transPro(guan), and / or 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.

[0133] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IF), have an N- terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C- terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (I)-(IF) may be at X1or R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IF) may be at any of R7, R8, R9, Y1, Y2, Y3, and Y4. -54- 180085204.4Docket No.: 146316.8032.WO00

[0134] 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 acyl group is acetyl group (e.g., ).

[0135] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0136] In the sequence of any one of Formulae (I)-(IF), Y1Y2Y3Y4or a fragment thereof represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1and Y2are present and Y3-Y4are absent. In some embodiments, Y3-Y4are absent, and Y1is D-valine and Y2is D-proline. In some embodiments, Y3-Y4are absent, and Y1is D-proline and Y2is D-valine. In some embodiments, Y3-Y4are absent, and Y1is D- tert-leucine and Y2is D-proline.

[0137] In some embodiments, Y1-Y3are present and Y4is absent. In some embodiments, Y4is absent and Y1is D-proline, Y2is D-valine, and Y3is D-proline. In some embodiments, Y4is absent, and Y1is D-tert-leucine, Y2is D-tert-leucine, and Y3is D-valine.

[0138] In some embodiments, Y1-Y4are present. In some embodiments, Y1-Y4are present and Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline.

[0139] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide grou In the sequence of any one of Formulae (I)-(IF), a non-naturally analog with a C- terminus modified by an amide may be represent

[0140] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (I)-(IF), a non- naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH. -55- 180085204.4Docket No.: 146316.8032.WO00

[0141] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IF) are cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

[0142] In some embodiments of the sequence of any one of Formulae (I)-(IF), R3is His. In further embodiments, R3is His and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between the Asp at R2and the Lys at R7. In still further embodiments, R4is p(F)dPhe or dPhe.

[0143] In some embodiments, X1, Y3, and Y4are all absent. In further embodiments, R1is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4is p(F)dPhe. In still further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2and R7via a lactam bond.

[0144] In other further embodiments, Y1is dTle, Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7); -56- 180085204.4Docket No.: 146316.8032.WO00 Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 8); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 24); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 27); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 28); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 29); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 30); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2and R7via a lactam bond.

[0145] In some embodiments, R1is Nle and R4is dPhe. In further embodiments, Y1is dVal or dPro, Y2is dPro or dVal. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 33); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2and R7via a lactam bond.

[0146] Alternatively, in some embodiments, at least one of X1, Y3and Y4is present. In further embodiments, R1is Nle, and R4is p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 6); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 25); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2and R7via a lactam bond -57- 180085204.4Docket No.: 146316.8032.WO00

[0147] In some embodiments, when R3is His, R4is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7, then R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is selected from His, transPro(guan), cisPro(guan). In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 46); and Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0148] In some embodiments, when R3is His, R4is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7, then R6is Trp. Alternatively, in some embodiments, R6is an amino acid other than Trp. In further embodiments, R6is dNal(2’). In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2and R7via a lactam bond.

[0149] In some embodiments of the sequence of any one of Formulae (I)-(IF), R3is His and the non-naturally occurring melanocortin analog is cyclized through a bond other than a lactam bond between Asp at R2and Lys at R7. In some embodiments, the non-naturally occurring melanocortin analog is cyclized through R2and R7via a bond other than a lactam bond between Asp at and Lys. For example, the non-naturally occurring melanocortin analog may be cyclized through R2and R7via a disulfide bond or a lactam formed between amino acids other than Asp and Lys.

[0150] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R2and Orn at R7. In further embodiments, R4is selected from dPhe, p(Cl)dPhe, and p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); -58- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

[0151] In other embodiments, the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dCys at R2and Cys at R7. In further embodiments, R4is p(Cl)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is Ac- Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization through R2and R7via a disulfide bond.

[0152] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog is cyclized through Asp at a residue position other than R2and / or Lys at a residue position other than R7. For example, the non-naturally occurring melanocortin analog may be cyclized through Asp at R1and Lys at R7or through Asp at R2and Lys at R8.

[0153] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R8. In further embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]- dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2and R8via a lactam bond.

[0154] In some embodiments, the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Asp at R1and Lys at R7. In further embodiments, R2is Ala or dAla and R4is dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 40); and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 41), -59- 180085204.4Docket No.: 146316.8032.WO00 wherein c represents cyclization through R1and R7via a lactam bond.

[0155] In other further embodiments, R2is Pro, and R4is Phe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1and R7via a lactam bond.

[0156] In some embodiments of the sequence of any one of Formula (I)-(ID), R3is an amino acid other than His. In some embodiments, R3is selected from dHis, Gln and Pro. In further embodiments, R2is Asp, R4is dPhe or p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37), wherein c represents cyclization through R2and R7via a lactam bond.

[0157] In some embodiments of the sequence of Formula (I), R3is an amino acid other than His and R9is absent. Alternatively, in some embodiments, R9is present. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Phe-Phe-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1and R9via a lactam bond.

[0158] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-10, 13-33, and 35-47.

[0159] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring -60- 180085204.4Docket No.: 146316.8032.WO00 melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-10, 14-33, 36, 37, and 42-47.

[0160] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-8, 14-31, 43, and 44.

[0161] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 10, 13, 33, 35- 37, 42, and 45-47.

[0162] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 38-41.

[0163] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 11, 12, and 43- 45. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 43-45.

[0164] Non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) may be an agonist of the melanocortin 4 receptor and an agonist of the melanocortin 3 receptor. In some embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) are full agonists of the melanocortin 4 receptor and full agonists of the melanocortin 3 receptor. In other embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) are full agonists of the melanocortin 4 receptor and partial agonists of the melanocortin 3 receptor. Non-Naturally Occurring Melanocortin Analog Synthesis

[0165] 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, -61- 180085204.4Docket No.: 146316.8032.WO00 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 of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology.

[0166] 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.

[0167] 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 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), the disclosure of which is incorporated herein by reference in its entirety.

[0168] 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. -62- 180085204.4Docket No.: 146316.8032.WO00

[0169] 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.

[0170] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tosyl), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.

[0171] 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 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.

[0172] 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.

[0173] 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 -63- 180085204.4Docket No.: 146316.8032.WO00 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.

[0174] 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- 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).

[0175] 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 C18 column. 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 Non-Naturally Occurring Melanocortin Analogs -64- 180085204.4Docket No.: 146316.8032.WO00

[0176] 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.

[0177] When the non-naturally occurring melanocortin analogs 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, 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. Conjugates -65- 180085204.4Docket No.: 146316.8032.WO00

[0178] The present technology further includes conjugates comprising a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally melanocortin analog is conjugated to a pharmaceutical agent. Non-limiting examples of suitable pharmaceutical agents include peptides, monoclonal antibodies, and small molecules. In some embodiments, the non-naturally occurring melanocortin analog is conjugated to semaglutide. In other embodiments, the non-naturally occurring melanocortin analog is conjugated to setmelanotide. In yet other embodiments, the non-naturally occurring melanocortin analog is conjugated to a small molecule MCR agonist.

[0179] Conjugates of the present technology further comprise a linker connecting the non-naturally occurring melanocortin analog to the pharmaceutical agent. In some embodiments, the linker is rigid. In some embodiments, the linker is flexible. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a glycine-serine (Gly / Ser) linker, a proline-threonine-glycine linker, an alanine linker, a lysine linker, a threonine linker, a valine-glycine-serine-threonine linker, an elastin-like peptide linker, a hexahistidine linker, a polyethylene glycol linker, a fatty acid linker, or a hydrocarbon linker.

[0180] In some embodiments, the linker is a peptide linker. The peptide linkers of the present technology may vary from 2 to 31 amino acids of any primary sequence in length and do not impose any constraints on the conformation or interactions of the linked partners. In some embodiments, the linkers vary from about 2-30, 2-29, 2-28, 2-27, 2-26, 2-25, 2-24, 2-23, 2-22, 2-21, 2-20, 2-19, 2-18, 2-17, 2-16, 2-15, 2- 14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-31, 3-30, 3-29, 3-28, 3-27, 3-26, 3-25, 3-24, 3-23, 3-22, 3-21, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-31, 4-30, 4-29, 4-28, 4-27, 4-26, 4-25, 4-24, 4-23, 4-22, 4-21, 4- 20, 4-19, 4-18, 4-17, 4-16, 4- 15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-31, 5- 30, 5-29, 5-28, 5-27, 5-26, 5-25, 5-24, 5-23, 5-22, 5-21, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5- 14, 5-13, 5-12, 5-11, 5- 10, 5-9, 5-8, 5-7, 5-6, 6-31, 6-30, 6-29, 6-28, 6-27, 6-26, 6-25, 6-24, 6-23, 6-22, 6-21, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 6- 7, 7-31, 7-30, 7-29, 7- 28, 7-27, 7-26, 7-25, 7-24, 7-23, 7-22, 7-21, 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-31, 8-30, 8-29, 8-28, 8-27, 8-26, 8-25, 8-24, 8-23, 8-22, 8-21, -66- 180085204.4Docket No.: 146316.8032.WO00 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 8-9, 9-31, 9-30, 9-29, 9-28, 9-27, 9-26, 9-25, 9-24, 9-23, 9-22, 9-21, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 9-10, 10-31, 10-30, 10-29, 10-28, 10-27, 10-26, 10-25, 10-24, 10-23, 10-22, 10-21, 10- 20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 10-11, 11-31, 11-30, 11-29, 11- 28, 11-27, 11-26, 11-25, 11-24, 11-23, 11-22, 11-21, 11-20, 11-19, 11-18, 11-17, 11-16, 11- 15, 11-14, 11-13, 11-12, 12-31, 12-30, 12-29, 12-28, 12-27, 12-26, 12-25,12-24, 12-23, 12- 22, 12-21, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 12-13, 13-31, 13-30, 13-29, 13- 28, 13-27, 13-26, 13-25, 13-24, 13-23, 13-22, 13-21, 13-20, 13-19, 13-18, 13-17, 13-16, 13- 15, 13-14, 14-31, 14-30, 14-29, 14-28, 14-27, 14-26, 14-25, 14-24, 14-23, 14-22, 14-21, 14- 20, 14-19, 14-18, 14-17, 14-16, 14-15, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15- 24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-31, 16-30, 16-29, 16-28, 16- 27, 16-26, 16-25, 16-24, 16-23, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-31, 17-30, 17- 29, 17-28, 17-27, 17-26, 17-25, 17-24, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-31, 18- 30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 18-19, 19-31, 19- 30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-31, 20-30, 20- 29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-31, 21-30, 21-29, 21-28, 21- 27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-31, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22- 24, 22-23, 23-31, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 24-31, 24-30, 24-29, 24- 28, 24-27, 24-26, 24-25, 25-31, 25-30, 25-29, 25-28, 25-27, 25-26, 26-31, 26-30, 26-29, 26- 28, 26-27, 27-31, 27-30, 27-29, 27-28, 28-31, 28-30, 28-29, 29-31, 29-30, or 30-31 amino acids of any primary sequence in length. The peptide linkers may be designed as appropriate for an intended use.

[0181] The peptide linkers may comprise one or more of a Gly-rich linker (e.g., a flexible linker connecting various domains in a single protein without interfering with the function of each domain; a linker forming stable covalently linked dimers; a linker to connect two independent domains that create a ligand-binding site or recognition sequence), a Serine linker (e.g., a coiled structure linker); a coiled structure linker comprising a Gln, Arg, Glu, Ser, and / or Pro amino acids; a rigid space linker comprising one or more of a Pro, Arg, Phe, Thr, Glu, and / or Gln residues; a linker comprising a flexible Gly-rich regions that may may generate loops connecting domains; or a linker comprising a Thr, Ser, Gly, and / or Ala residue. -67- 180085204.4Docket No.: 146316.8032.WO00

[0182] In some embodiments, the linker comprises an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

[0183] In some embodiments, the linker comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0. In some embodiments, the linker comprises an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0. Table 0: Peptide Linker Amino Acid Sequences Name Amino Acid SEQ ID NO Linker A (GGS)1-5 173Docket No.: 146316.8032.WO00 Name Amino Acid SEQ ID NO

[0184] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology are present in a pharmaceutical composition.

[0185] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the pharmaceutical 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 pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0186] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF), and the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF) is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, 10 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 pharmaceutical composition. In some embodiments, the non- naturally occurring melanocortin analog comprising a sequence of Formula (IF) is present -69- 180085204.4Docket No.: 146316.8032.WO00 in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0187] In some embodiments, the composition 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 a sequence of Formula (IF).

[0188] The non-naturally occurring melanocortin analogs may be formulated with one or more pharmaceutically acceptable carriers and / or excipients. The carriers and / or excipients of the present technology facilitate delivery of the non-naturally occurring melanocortin analog to a subject. Other pharmaceutically acceptable carriers and / or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and / or stability of the non-naturally occurring melanocortin analog, and / or to reduce adverse injection site reactions.

[0189] In some embodiments, the pharmaceutical composition comprises 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the pharmaceutically acceptable carrier and / or excipient relative to a total weight of the pharmaceutical composition.

[0190] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is selected from the group consisting of water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer.

[0191] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is water. In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is a buffer. -70- 180085204.4Docket No.: 146316.8032.WO00

[0192] In some embodiments, the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to about 99.999 wt.%, about 5 to about 99.99 wt.%, about 10 to about 99.9 wt.%, about 15 to about 99 wt.%, about 20 to about 90 wt.%, about 30 to about 85 wt.%, about 40 to about 80 wt.%, about 50 to about 75 wt.%, or about 60 to about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0193] In some embodiments, the pharmaceutical composition contains at least 0.1 to at least 99.9999 wt.%, at least 1 to at least 99.999 wt.%, at least 5 to at least 99.99 wt.%, at least 10 to at least 99.9 wt.%, at least 15 to at least 99 wt.%, at least 20 to at least 90 wt.%, at least 30 to at least 85 wt.%, at least 40 to at least 80 wt.%, at least 50 to at least 75 wt.%, or at least 60 to at least 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0194] In some embodiments, the pharmaceutical composition contains at least about 0.1 to at least about 99.9999 wt.%, at least about 1 to at least about 99.999 wt.%, at least about 5 to at least about 99.99 wt.%, at least about 10 to at least about 99.9 wt.%, at least about 15 to at least about 99 wt.%, at least about 20 to at least about 90 wt.%, at least about 30 to at least about 85 wt.%, at least about 40 to at least about 80 wt.%, at least about 50 to at least about 75 wt.%, or at least about 60 to at least about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0195] Any pharmaceutically acceptable carriers and / or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable carriers and / or excipients include buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, preservatives, lipids, and antioxidants. The pharmaceutical composition may comprise any combination of the one or more pharmaceutically acceptable carriers and / or excipients previously described in relation to the first and pharmaceutical compositions. In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients comprise water.

[0196] 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 -71- 180085204.4Docket No.: 146316.8032.WO00 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.

[0197] In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients are isotonic. In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0198] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt. Any pharmaceutical salt known in the art may be included in the pharmaceutical composition. For examples, to achieve a desirable tonicity, the pharmaceutical composition may include a salt selected from the group consisting of sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.

[0199] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 25 mg / mL, or about 5 mg / mL to about 10 mg / mL, relative to a total volume of the composition.

[0200] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least 0.1 mg / mL to at least 50 mg / mL, at least 1 mg / mL to at least 25 mg / mL, or at least 5 mg / mL to at least 10 mg / mL, relative to a total volume of the composition.

[0201] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least about 0.1 mg / mL to at least about 50 mg / mL, at least about 1 mg / mL to at least about 25 mg / mL, or at least about 5 mg / mL to at least about 10 mg / mL, relative to a total volume of the composition.

[0202] Pharmaceutically acceptable carriers and / or excipients that may be included in the pharmaceutical composition generally include a pH buffered aqueous solution comprising one or more of the following components: (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally -72- 180085204.4Docket No.: 146316.8032.WO00 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.

[0203] In the pH buffered solution of the pharmaceutical composition, the water 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.

[0204] In some embodiments, the pharmaceutical 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.

[0205] In some embodiments, the pharmaceutical composition includes water in an amount of at least 1 wt% to at least 90 wt%, at least 10 wt% to at least 75 wt%, or at least 25 wt% to at least 50 wt%, relative to a total weight of the composition.

[0206] In some embodiments, the pharmaceutical composition includes water in an amount of at least about 1 wt% to at least about 90 wt%, at least about 10 wt% to at least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition.

[0207] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0208] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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. -73- 180085204.4Docket No.: 146316.8032.WO00

[0209] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical 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.

[0210] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0211] The term “Tris” refers to tris(hydroxymethyl)aminomethane, which is 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 pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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.

[0212] In some embodiments, Tris is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0213] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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. -74- 180085204.4Docket No.: 146316.8032.WO00

[0214] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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.

[0215] In some embodiments, the pH buffered aqueous solution provides the pharmaceutical composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0216] In some embodiments, a weight ratio of sodium acetate to Tris is about 1:4 to about 4:1, about 2:7 to about 7:2, about 1:3 to about 3:1, about 2:5 to about 5:2, about 1:2 to about 2:1, about 2:3 to about 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1.

[0217] In some embodiments, a weight ratio of sodium acetate to Tris is at least 1:4 to at least 4:1, at least 2:7 to at least 7:2, at least 1:3 to at least 3:1, at least 2:5 to at least 5:2, at least 1:2 to at least 2:1, at least 2:3 to at least 3:2, or at least 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least 1:1.

[0218] In some embodiments, a weight ratio of sodium acetate to Tris is at least about 1:4 to at least about 4:1, at least about 2:7 to at least about 7:2, at least about 1:3 to at least about 3:1, at least about 2:5 to at least about 5:2, at least about 1:2 to at least about 2:1, at least about 2:3 to at least about 3:2, or at least about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least about 1:1.

[0219] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 1:1 to about 20:1, about 3:2 to about 15:1, about 2:1 to about 12:1, about 3:1 to about 10:1, about 4:1 to about 9:1, about 5:1 to about 8:1, or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1. -75- 180085204.4Docket No.: 146316.8032.WO00

[0220] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 7:1.

[0221] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 7:1.

[0222] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is about 1:1 to about 20:1, about 3:2 to about 15:1, about 2:1 to about 12:1, about 3:1 to about 10:1, about 4:1 to about 9:1, about 5:1 to about 8:1, or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0223] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 7:1.

[0224] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non- naturally occurring melanocortin analog to Tris is at least about 7:1.

[0225] In addition to sodium acetate and Tris, the pharmaceutical composition may include other buffering agents. Non-limiting examples of additional buffering agents include -76- 180085204.4Docket No.: 146316.8032.WO00 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 pharmaceutical composition comprises acetic acid as an additional buffering agent.

[0226] The pharmaceutical composition may further comprise one or more chelating agents. Suitable chelating agents include, but are not limited to edetate disodium dihydrate, calcium disodium edetate, sodium edetate, calcium versetamide sodium, calteridol, and diethylenetriaminepentaacetic acid. In some embodiments, the pharmaceutical composition further comprises edetate disodium dihydrate.

[0227] The pharmaceutical composition may further 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. In some embodiments, when the pharmaceutical composition comprises a preservative agent, the preservative agent is phenol, benzyl alcohol, or a combination thereof.

[0228] If present in the pharmaceutical composition, 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.

[0229] The pharmaceutical composition may further comprise an emulsifier. Non- limiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose. -77- 180085204.4Docket No.: 146316.8032.WO00

[0230] The pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and / or improve permeability of the non-naturally occurring melanocortin analog. In some embodiments, the lipid is a phospholipid. Non-limiting examples of phospholipids that may be included in the pharmaceutical composition include egg phosphatidylcholine, hydrogenated soybean phoshphaditylcholine, glycerophosphocholine, lecithin, and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3- phosphoethanolamine sodium salt. In some embodiments, when the pharmaceutical composition comprises a lipid, the lipid is N-(carbonyl-methoxypolyethylene glycol 2000)- 1,2-distearoyl-glycero-3-phosphoethanolamine sodium salt

[0231] The pharmaceutical composition may further comprise a bulking agent. Inclusion of a bulking agent may increase the stability of the pharmaceutical composition. Non-limiting examples of bulking agents that may be included in the pharmaceutical composition include sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, glycine, histidine, and polyvinyl pyrrolidone. In some embodiments, when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.

[0232] In some embodiments, the pharmaceutical composition is in the form of an aqueous solution or a suspension. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0233] In some embodiments, the pharmaceutical composition has a pH ranging from about 6.5 to about 8.5. In some embodiments, the pharmaceutical 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.

[0234] In some embodiments, the pharmaceutical composition has a pH ranging from at least 6.5 to at least 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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. -78- 180085204.4Docket No.: 146316.8032.WO00

[0235] In some embodiments, the pharmaceutical composition has a pH ranging from at least about 6.5 to at least about 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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.

[0236] In some embodiments, the pharmaceutical 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 pharmaceutical composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0237] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 pharmaceutical composition has a pH ranging from at least 7.3 to at least 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0238] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 pharmaceutical composition has a pH ranging from at least about 7.3 to at least about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0239] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 pharmaceutical 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 pharmaceutical composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg. -79- 180085204.4Docket No.: 146316.8032.WO00

[0240] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 at least 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least 250 mOsm / kg, at least 260 mOsm / kg, at least 270 mOsm / kg, at least 280 mOsm / kg, at least 290 mOsm / kg, at least 300 mOsm / kg, at least 310 mOsm / kg, at least 320 mOsm / kg, at least 330 mOsm / kg, at least 340 mOsm / kg, at least 350 mOsm / kg, or at least 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least 275 mOsm / kg to at least 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least 279 mOsm / kg, at least 314 mOsm / kg, or at least 329 mOsm / kg.

[0241] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 at least about 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least about 250 mOsm / kg, at least about 260 mOsm / kg, at least about 270 mOsm / kg, at least about 280 mOsm / kg, at least about 290 mOsm / kg, at least about 300 mOsm / kg, at least about 310 mOsm / kg, at least about 320 mOsm / kg, at least about 330 mOsm / kg, at least about 340 mOsm / kg, at least about 350 mOsm / kg, or at least about 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least about 275 mOsm / kg to at least about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 279 mOsm / kg, at least about 314 mOsm / kg, or at least about 329 mOsm / kg.

[0242] In some embodiments, the pharmaceutical composition has a viscosity ranging from about 0.5 cP to about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from about 0.5 cP to about 5 cP, about 0.75 cP to about 4.5 cP, about 1.0 cP to about 4 cP, about 1.2 cP to about 3.5 cP, about 1.3 cP to about 3 cP, about 1.4 cP to about 2.5 cP, about 1.5 cP to about 2 cP, or about 1.6 cP to about 1.8 cP. In some -80- 180085204.4Docket No.: 146316.8032.WO00 embodiments, the pharmaceutical 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 pharmaceutical composition has a viscosity of about 1.4 cP or about 1.6 cP.

[0243] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least 0.5 cP to at least 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least 0.5 cP to at least 5 cP, at least 0.75 cP to at least 4.5 cP, at least 1.0 cP to at least 4 cP, at least 1.2 cP to at least 3.5 cP, at least 1.3 cP to at least 3 cP, at least 1.4 cP to at least 2.5 cP, at least 1.5 cP to at least 2 cP, or at least 1.6 cP to at least 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 pharmaceutical composition has a viscosity of at least 1.4 cP or at least 1.6 cP.

[0244] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least about 0.5 cP to at least about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least about 0.5 cP to at least about 5 cP, at least about 0.75 cP to at least about 4.5 cP, at least about 1.0 cP to at least about 4 cP, at least about 1.2 cP to at least about 3.5 cP, at least about 1.3 cP to at least about 3 cP, at least about 1.4 cP to at least about 2.5 cP, at least about 1.5 cP to at least about 2 cP, or at least about 1.6 cP to at least about 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 pharmaceutical composition has a viscosity of at least about 1.4 cP or at least about 1.6 cP.

[0245] In some embodiments, the pharmaceutical composition disclosed is 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. -81- 180085204.4Docket No.: 146316.8032.WO00

[0246] When the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration), 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.

[0247] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises a non-naturally occurring melanocortin analog in a concentration of 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 even 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.

[0248] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises sodium acetate in a concentration of 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.

[0249] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of 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.

[0250] In some embodiments, the pharmaceutical composition comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, -82- 180085204.4Docket No.: 146316.8032.WO00 cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0251] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0252] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0253] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. The solvent or vehicle may be purified water, ethyl alcohol, and / or propylene glycol. In some embodiments, the pharmaceutical composition comprises between 0.03 wt% and 1 wt% melanocortin analog solubilized or suspended in a solvent or vehicle. For example, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of about 0.03 wt%, about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%.

[0254] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least 0.03 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.15 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.3 wt%, at least 0.35 wt%, at least 0.4 wt%, at least 0.45 wt%, at least 0.5 wt%, at least 0.55 wt%, at least 0.6 wt%, at least 0.65 wt%, at least 0.7 wt%, at least 0.75 wt%, at least 0.8 wt%, at least 0.85 wt%, at least 0.9 wt%, at least 0.95 wt%, or at least 1 wt%.

[0255] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least about 0.03 wt%, at least about 0.05 wt%, at least about 0.1 wt%, at least about 0.15 wt%, at least about 0.2 wt%, at least about 0.25 wt%, at least about 0.3 wt%, at least about 0.35 wt%, at least about 0.4 wt%, at least about 0.45 wt%, at least about 0.5 wt%, at least about 0.55 wt%, at least about 0.6 wt%, at least about 0.65 wt%, at least about 0.7 wt%, at least about 0.75 wt%, at least -83- 180085204.4Docket No.: 146316.8032.WO00 about 0.8 wt%, at least about 0.85 wt%, at least about 0.9 wt%, at least about 0.95 wt%, or at least about 1 wt%.

[0256] The non-naturally occurring melanocortin analogs of the present technology may be formulated for administration using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the peptide injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. The non-naturally occurring melanocortin analog of the combination therapy may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, pessaries, ocular drops, skin patches, orally soluble formulations, enteric formulations, solutions sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, anti-oxidants and other agents known in the art. In general, any route of administration by which the peptides are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. Administration includes delivery across the blood brain barrier. Administration includes delivery through mucous membranes, buccal administration, ophthalmic administration, oral administration, dermal administration, inhalation administration, nasal administration, urethral administration, vaginal administration, rectal administration, and the like.

[0257] In some embodiments, the pharmaceutical 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.

[0258] In some embodiments, the pharmaceutical composition is formulated for oral administration. For example, the pharmaceutical composition may be in the form of a tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art. -84- 180085204.4Docket No.: 146316.8032.WO00

[0259] The composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, or nebulizer. In some embodiments, the pharmaceutical composition includes a propellant, such as hydrofluoroalkane.

[0260] In some embodiments, the pharmaceutical 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. Dosing

[0261] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered hourly (such as every hour, every 2 hours, every 4 hours, every 8 hours, etc.), once a day, or twice a day. In some embodiments, the non-naturally occurring melanocortin analog is administered every morning, every evening, or every afternoon. In some embodiments, the non-naturally occurring melanocortin analog is administered before a meal, after a meal, or with a meal.

[0262] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof may be administered as a dosing regimen comprising once, twice, or three times daily administration on a (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; or (viii) monthly schedule. The (i)-(viii) schedules may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more. In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered at various dosages during the dosing regimen (e.g., a first dose with an effective amount of 10 mg / kg and a second dose with an effective amount of 5 mg / kg). -85- 180085204.4Docket No.: 146316.8032.WO00

[0263] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered once every other day, once every 2 or 3 days, once every third day, once per week, once every other week, once every third week, once every month, once every six weeks, once every other month, once every three months, once every six months, or once per year.

[0264] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of about 2 dosages, about 3 dosages, about 4 dosages, about 5 dosages, about 10 dosages, about 15 dosages, about 20 dosages, about 30 dosages, about 40 dosages, about 50 dosages or more.

[0265] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least 2 dosages, at least 3 dosages, at least 4 dosages, at least 5 dosages, at least 10 dosages, at least 15 dosages, at least 20 dosages, at least 30 dosages, at least 40 dosages, at least 50 dosages or more.

[0266] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least about 2 dosages, at least about 3 dosages, at least about 4 dosages, at least about 5 dosages, at least about 10 dosages, at least about 15 dosages, at least about 20 dosages, at least about 30 dosages, at least about 40 dosages, at least about 50 dosages or more.

[0267] In some embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is the same during a treatment regimen. In other embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is different during a treatment regimen. The non-naturally occurring melanocortin analog or the pharmaceutical composition thereof may be administered even less frequently. Alternatively, the dosage regimen may be decreased or increased from an initial dosing regimen for days, weeks, months, or years. In some embodiments, the dosing regimen is repeated at other intervals. -86- 180085204.4Docket No.: 146316.8032.WO00

[0268] 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, 0.01 mg / kg to 20 mg / kg, 0.05 mg / kg to 15 mg / kg, 0.075 mg / kg to 10 mg / kg, 0.1 mg / kg to 8 mg / kg, 0.2 mg / kg to 6 mg / kg, 0.3 mg / kg to 4 mg / kg, 0.4 mg / kg to 2 mg / kg, or 0.5 mg / kg to 1 mg / kg per body weight of the subject. 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, about 1 mg / kg to about 7.5 mg / kg, or about 2.5 mg / kg to about 5 mg / kg per body weight of the subject.

[0269] The methods of the present technology may be performed on the subject for about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for about 1 day, about 2 days, about 5 days, about 6 days, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years.

[0270] The methods of the present technology may be performed on the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for at least 1 day, at least 2 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0271] The methods of the present technology may be performed on the subject for at least about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for at least about 1 day, at least about 2 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. -87- 180085204.4Docket No.: 146316.8032.WO00

[0272] In some embodiments, a method of the present technology is performed on the subject for 1 day, 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.

[0273] In some embodiments, at least one active ingredient of the combination therapy is administered to a subject in a continuous doing schedule. As used herein, a “continuous dosing schedule” is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 21-day or 28-day treatment cycles without dose interruptions is an exemplary continuous dosing schedule.

[0274] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0275] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0276] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg to about 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg to about 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg to about 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily. -88- 180085204.4Docket No.: 146316.8032.WO00

[0277] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg to at least 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg / kg to at least 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg / kg to at least 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg / kg to at least 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0278] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg to at least about 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg / kg to at least about 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg / kg to at least about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg / kg to at least about 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0279] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, or about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about -89- 180085204.4Docket No.: 146316.8032.WO00 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg per body weight of the subject once daily.

[0280] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 50 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, at least 100 mg / kg, at least 125 mg / kg, at least 150 mg / kg, at least 175 mg / kg, at least 200 mg / kg, at least 250 mg / kg, at least 300 mg / kg, at least 350 mg / kg, at least 400 mg / kg, at least 450 mg / kg, or at least 500 mg / kg, at least 550 mg / kg, at least 600 mg / kg, at least 650 mg / kg, at least 700 mg / kg, at least 750 mg / kg, at least 800 mg / kg, at least 850 mg / kg, at least 900 mg / kg, at least 950 mg / kg, or at least 1000 mg / kg per body weight of the subject once daily.

[0281] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at least about 450 mg / kg, or at least about 500 mg / kg, at least about 550 mg / kg, at least about 600 mg / kg, at least about 650 mg / kg, at least about 700 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 850 mg / kg, at least about 900 mg / kg, at least about 950 mg / kg, or at least about 1000 mg / kg per body weight of the subject once daily.

[0282] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg per body weight of the subject once daily.

[0283] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg per body weight of the subject once daily. -90- 180085204.4Docket No.: 146316.8032.WO00

[0284] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg per body weight of the subject once daily.

[0285] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg per body weight of the subject once daily.

[0286] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg / kg per body weight of the subject once daily.

[0287] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg per body weight of the subject once daily.

[0288] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg / kg per body weight of the subject once daily.

[0289] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg / kg per body weight of the subject once daily.

[0290] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg / kg per body weight of the subject once daily.

[0291] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg per body weight of the subject once daily.

[0292] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg / kg per body weight of the subject once daily.

[0293] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg / kg per body weight of the subject once daily.

[0294] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg / kg per body weight of the subject once daily.

[0295] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 25 mg / kg per body weight of the subject once daily.

[0296] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg / kg per body weight of the subject once daily. -91- 180085204.4Docket No.: 146316.8032.WO00

[0297] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 35 mg / kg per body weight of the subject once daily.

[0298] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 40 mg / kg per body weight of the subject once daily.

[0299] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg / kg per body weight of the subject once daily.

[0300] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg per body weight of the subject once daily.

[0301] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg / kg per body weight of the subject once daily.

[0302] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg / kg per body weight of the subject once daily.

[0303] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg / kg per body weight of the subject once daily.

[0304] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 25 mg / kg per body weight of the subject once daily.

[0305] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg / kg per body weight of the subject once daily.

[0306] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 35 mg / kg per body weight of the subject once daily.

[0307] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 40 mg / kg per body weight of the subject once daily.

[0308] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg / kg per body weight of the subject once daily.

[0309] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about -92- 180085204.4Docket No.: 146316.8032.WO00 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg per body weight of the subject twice daily.

[0310] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg per body weight of the subject twice daily.

[0311] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg per body weight of the subject twice daily.

[0312] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg per body weight of the subject twice daily.

[0313] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg per body weight of the subject twice daily.

[0314] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg / kg per body weight of the subject twice daily.

[0315] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg per body weight of the subject twice daily.

[0316] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg / kg per body weight of the subject twice daily.

[0317] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg / kg per body weight of the subject twice daily.

[0318] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg / kg per body weight of the subject twice daily.

[0319] In some embodiments, the non-naturally occurring melanocortin analog is administered at one or more doses. In some embodiments, the non-naturally occurring melanocortin analog is administered at two or more doses. -93- 180085204.4Docket No.: 146316.8032.WO00

[0320] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily or twice daily. In some embodiments, the non- naturally occurring melanocortin analog is administered at a second dose once daily or twice daily.

[0321] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose that is a projected human equivalent dose (HED) based on a nonhuman primate dose. In some embodiments, the HED based on a 10 mg / kg nonhuman primate dose ranges from about 300 mg to about 550 mg.

[0322] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily for about 5 days to about 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for about 5 days to about 10 days, after administration of the first dose. In some embodiments, the non-naturally occurring melanocortin analog is administered at a third dose twice daily for about 7 days to about 21 days, after administration of the second dose. In some embodiments, the second dose is greater than the first dose. In some embodiments, the third dose comprises a cumulative dose that is greater than the second dose.

[0323] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a second dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose.

[0324] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a third dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and / or the second dose. -94- 180085204.4Docket No.: 146316.8032.WO00

[0325] In some embodiments, the dosage of the second dose is greater than the dosage of the first dose. In some embodiments, the first dose is administered about once a day and the second dose is administered about twice a day.

[0326] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and / or the second dose. In some embodiments, the first dose and / or the second dose is administered about once a day, and the third dose is administered about twice a day.

[0327] In some embodiments, the non-naturally occurring melanocortin analog is administered using two or more different administration routes. The two or more different administration routes may comprise an oral administration and a subcutaneous administration. The oral administration may occur before, during, or after the subcutaneous administration.

[0328] In some embodiments, the first dose and the second dose comprise different routes of administration. In some embodiments, the first dose comprises an oral dose and the second dose comprises a subcutaneous dose. In some embodiments, the first dose and / or second dose and the third dose comprise different routes of administration. In some embodiments, the first dose and / or the second dose comprises an oral dose and the third dose comprises a subcutaneous dose.

[0329] In some embodiments, the second dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose.

[0330] In some embodiments, the third dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose and / or the second dose.

[0331] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at two or more dosage amounts, each dosage amount differing from the other. The first -95- 180085204.4Docket No.: 146316.8032.WO00 dosage amount, the second dosage amount, and the third dosage amount may each be greater than, less than, equal to, or substantially equivalent to another dosage amount. For example, the first dosage amount is less than a second dosage amount which is greater than a third dosage amount also greater than the first dosage amount. The dosage amounts refer to doses administered more than once over a period of time, such as a first dosage amount administered daily, BID, TID, or weekly, a second dosage amount administered daily, BID, TID, or weekly, and a third dosage amount administered daily, BID, TID, or weekly. In some embodiments, the first dosage amount, the second dosage amount, or the third dosage amount may be administered every other day, every second day, every third day, twice per week, or twice per month. For example, the first dosage amount of 10 mg / kg may be administered once a day for 7 days, followed by the second dosage amount of 20 mg / kg once a day for 7 days, followed by the third dosage amount of 15 mg / kg twice a day for at least about 7 days. In some embodiments, the third dosage amount is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0332] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) may be administered using more than one route of administration. For example, the first dosage amount and the second dosage amount may be administered by two different routes of administration. In addition, the first dosage amount and the second dosage amount administered via different routes of administration may be the same or different dosage amounts. In some embodiments, the first dosage amount is administered orally and the second dosage amount is administered subcutaneously. The dosage frequency and / or duration of the dosage amounts may be the same or may be different. For example, the frequency of each dosage amount may be more than once per day, once per day, once every other day, once per week, or once every other week, or once per month. As another example, the duration of each dosage amount may be one day, two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month. For example, a dosing regimen may comprise a first dosage amount administered once a day or twice a day for about 5 weeks, and a second dosage amount administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dosage amount is administered the day after the duration of the -96- 180085204.4Docket No.: 146316.8032.WO00 first dosage amount is complete, or two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month after the first dosage amount is complete. In some embodiments, the second dosage amount is administered at least about 1 week after administration of the first dosage is complete.

[0333] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a dose of (i) 10 mg / kg once a day for 7 days, followed by (ii) 20 mg / kg once a day for 7 days, followed by (iii) 15 mg / kg twice a day for at least about 7 days. In some embodiments, (iii) is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0334] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) comprises a (i) first dose administered orally once a day or twice a day for about 5 weeks, and (ii) second dose administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dose is administered at least about 1 week after administration of the first dose is complete.

[0335] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg to about 20 mg / kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg / kg to about 40 mg / kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg / kg to about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days or more.

[0336] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg administered once a day for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (ii) at a second dose of about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, or about 40 mg / kg administered once a day after administration of the first dose about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (iii) at a third dose of about 5 -97- 180085204.4Docket No.: 146316.8032.WO00 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, or about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days, about, 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days or more.

[0337] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg / kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0338] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg / kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0339] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg / kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0340] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg to about 75 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg to about 60 mg once daily. In some -98- 180085204.4Docket No.: 146316.8032.WO00 embodiments, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0341] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise about 2.5 mg / mL to about 100 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 2.5 mg / mL to about 10 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 6 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as about 5 dosage units to about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units.

[0342] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non- naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0343] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 5 mg to about 1000 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In -99- 180085204.4Docket No.: 146316.8032.WO00 some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day. Combination Therapies

[0344] The present technology comprises combination therapies including a non- naturally occurring melanocortin analog and a weight loss agent of the present technology. The non-naturally occurring melanocortin analog may be present in a single composition or as distinct compositions. For example, the weight loss agent may be present in a first pharmaceutical composition and the non-naturally occurring analog may be present in a second pharmaceutical composition. As will be described in more detail below, the first and second pharmaceutical compositions may be administered concurrently, sequentially, or cyclically. Alternatively, pharmaceutical combinations of the present technology may be formulated as a single pharmaceutical composition comprising a non-naturally occurring melanocortin analog and a weight loss agent.

[0345] In some embodiments of the combination therapy, the weight loss agent is present in a first pharmaceutical composition and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition. The weight loss agent may be formulated with one or more pharmaceutically acceptable carriers and / or excipients to form the first pharmaceutical composition. Similarly, the non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and / or excipients to form the second pharmaceutical composition. In some embodiments, the first and the second pharmaceutical compositions are different.

[0346] In some embodiments, the first pharmaceutical composition comprising the weight loss agent and the second pharmaceutical composition comprising the non-naturally occurring melanocortin analog are administered concurrently.

[0347] In other embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially. In sequential administration, the first pharmaceutical composition may be administered before the second pharmaceutical -100- 180085204.4Docket No.: 146316.8032.WO00 composition, after the second pharmaceutical composition, or both. Likewise, the second pharmaceutical composition may be administered before the first pharmaceutical composition, after the first pharmaceutical composition, or both.

[0348] In still other embodiments, the first pharmaceutical composition and the second pharmaceutical composition may be administered cyclically.

[0349] In some embodiments, the weight loss agent is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the weight loss agent is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 750 mg / mL, 0.01 mg / mL to 500 mg / mL, 0.05 mg / mL to 250 mg / mL, 0.1 mg / mL to 100 mg / mL, 0.2 mg / mL to 80 mg / mL, 0.3 mg / mL to 60 mg / mL, 0.4 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 0.5 mg / mL to 30 mg / mL, or 1 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0350] In some embodiments, the weight loss agent is a GLP-1 receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the GLP-1 receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 750 mg / mL, 0.01 mg / mL to 500 mg / mL, 0.05 mg / mL to 250 mg / mL, 0.08 mg / mL to 50 mg / mL, 0.1 mg / mL to 50 mg / mL, 0.2 mg / mL to 10 mg / mL, 0.3 mg / mL to 8 mg / mL 0.5 mg / mL to 5 mg / mL, or 1 mg / mL to 3.5 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0351] In some embodiments, the weight loss agent is semaglutide and is present in the first pharmaceutical composition in a concentration of 0.5 mg / mL to 5.0 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, semaglutide is present in the first pharmaceutical composition in a concentration of 0.5 mg / mL to 5.0 mg / mL, 0.5 mg / mL to 4.0 mg / mL, 0.6 mg / mL to 3.5 mg / mL, 0.65 mg / mL to 3.2 mg / mL, 0.65 mg / mL to 3.0 mg / mL, 0.8 mg / mL to 2.8 mg / mL, 1.0 mg / mL to 3.0 mg / mL, 1.0 mg / mL to 2.8 mg / mL, 1.2 mg / mL to 3.0 mg / mL, 1.2 mg / mL to 2.8 mg / mL, 0.6 mg / mL to 2.3 mg / mL, 0.6 mg / mL to 2.0 mg / mL, 0.6 mg / mL to 1.8 mg / mL, 0.6 mg / mL to 1.5 mg / mL, or 1.3 mg / mL to 2.8 mg / mL, relative to a total volume of the first pharmaceutical composition. In some -101- 180085204.4Docket No.: 146316.8032.WO00 embodiments, semaglutide is present in the first pharmaceutical composition in a concentration of about 0.68 mg / mL, 1 mg / mL, 1.34 mg / mL, 2.0 mg / mL, 2.26 mg / mL, 2.68 mg / mL, or 3.2 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0352] In some embodiments, the weight loss agent is Ozempic®. In some embodiments, the weight loss agent is Wegovy®.

[0353] In some embodiments, the weight loss agent is semaglutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 40 mg. In some embodiments, semgalutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, semaglutide is present in the first pharmaceutical composition in an amount of about 3 mg or less, 7 mg or less, or 14 mg or less.

[0354] In some embodiments, the weight loss agent is Rybelsus®.

[0355] In some embodiments, the weight loss agent is exenatide and is present in the first pharmaceutical composition in a concentration of 5 µg / mL to 1000 µg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of 5 µg / mL to 1000 µg / mL, 10 µg / mL to 900 µg / mL, 20 µg / mL to 800 µg / mL, 50 µg / mL to 700 µg / mL, 70 µg / mL to 600 µg / mL, 90 µg / mL to 550 µg / mL, 100 µg / mL to 500 µg / mL, 110 µg / mL to 450 µg / mL, 120 µg / mL to 400 µg / mL, 130 µg / mL to 350 µg / mL, 140 µg / mL to 350 µg / mL, 150 µg / mL to 300 µg / mL, 200 µg / mL to 300 µg / mL, or 200 µg / mL to 250 µg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of about 250 µg / mL, relative to a total volume of the first pharmaceutical composition.

[0356] In some embodiments, the weight loss agent is Byetta®.

[0357] In some embodiments, the weight loss agent is exenatide and is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 5.0 mg / mL, 0.25 mg / mL to 4.5 mg / mL, 0.5 mg / mL to 4.5 mg / mL, 0.75 mg / mL to 4.0 mg / mL, 1.0 mg / mL to 3.75 -102- 180085204.4Docket No.: 146316.8032.WO00 mg / mL, 1.25 mg / mL to 3.5 mg / mL, 1.5 mg / mL to 3.25 mg / mL, 1.75 mg / mL to 3.0 mg / mL, 2.0 mg / mL to 2.75 mg / mL, or 2.25 mg / mL to 2.5 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of about 2.35 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0358] In some embodiments, the weight loss agent is Bydureon®.

[0359] In some embodiments, the weight loss agent is dulaglutide and is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 100 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, dulaglutide is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 100 mg / mL, 0.05 mg / mL to 90 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.2 mg / mL to 70 mg / mL, 0.3 mg / mL to 60 mg / mL, 0.5 mg / mL to 50 mg / mL,0.6 mg / mL to 45 mg / mL, 0.7 mg / mL to 40 mg / mL, 0.8 mg / mL to 35 mg / mL, 0.9 mg / mL to 30 mg / mL, 1.0 mg / mL to 25 mg / mL, 1.1 mg / mL to 20 mg / mL, 1.2 mg / mL to 15 mg / mL, or 1.5 mg / mL to 10 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, dulagultide is present in the first pharmaceutical composition in a concentration of about 1.5 mg / mL, 3.0 mg / mL, 6.0 mg / mL, or 9.0 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0360] In some embodiments, the weight loss agent is Trulicity®.

[0361] In some embodiments, the weight loss agent is orforglipron and is present in the first pharmaceutical composition in an amount of about 0.01 mg to about 100 mg. In some embodiments, orforglipron is present in the first pharmaceutical composition in an amount of 0.01 mg to 100 mg, 0.05 mg to 90 mg, 0.1 mg to 80 mg, 0.2 mg to 70 mg, 0.3 mg to 60 mg, 0.4 mg to 50 mg, 0.5 mg to 45 mg, 0.6 mg to 40 mg, 0.7 mg to 35 mg, 0.8 mg to 30 mg, 0.9 mg to 25 mg, 1.0 mg to 20 mg, 1.1 mg to 18 mg, 1.2 mg to 16 mg, 1.3 mg to 14 mg, 1.4 mg to 12 mg, or 1.5 mg to 10 mg. In some embodiments, orforglipron is present in the first pharmaceutical composition in an amount of about 2 mg or less, 4 mg or less, 5 mg or less, 6 mg or less, 8 mg or less, 12 mg or less, 16 mg or less, or 24 mg or less. -103- 180085204.4Docket No.: 146316.8032.WO00

[0362] In some embodiments, the weight loss agent is a long-acting GIP receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the long-acting GIP receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0363] In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the dual GLP-1 / GIP receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4.0 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0364] In some embodiments, the weight loss agent is tirzepatide and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, tirzepatide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4.0 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, tirzepatide is present in the first pharmaceutical composition in a concentration of about 5 mg / mL, 10 mg / mL, 15 mg / mL, -104- 180085204.4Docket No.: 146316.8032.WO00 20 mg / mL, 25 mg / mL, or 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0365] In some embodiments, the weight loss agent is Mounjaro™. In some embodiments, the weight loss agent is Zepbound™.

[0366] In some embodiments, the weight loss agent is a GLP-1 / glucagon receptor coagonist and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, the GLP-1 / glucagon receptor coagonist is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg.

[0367] In some embodiments, the weight loss agent is mazdutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, mazdutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, mazdutide is present in the first pharmaceutical composition in an amount of about 5 mg or less, 6 mg or less, 7 mg or less, 8 mg or less, 9 mg or less, or 10 mg or less.

[0368] In some embodiments, the weight loss agent is a GLP-1 / GIP / glucagon receptor trifunctional agonist and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, the GLP-1 / GIP / glucagon receptor trifunctional agonist is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. -105- 180085204.4Docket No.: 146316.8032.WO00

[0369] In some embodiments, the weight loss agent is retatrutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, retatrutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, retatrutide is present in the first pharmaceutical composition in an amount of about 0.5 mg or less, 1.5 mg or less, 3 mg or less, 6 mg or less, 9 mg or less, or 12 mg or less.

[0370] In some embodiments, the weight loss agent is an MC4 receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the MC4 receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 900 mg / mL, 0.05 mg / mL to 800 mg / mL, 0.1 mg / mL to 700 mg / mL, 0.5 mg / mL to 600 mg / mL, 1 mg / mL to 500 mg / mL, 2.5 mg / mL to 400 mg / mL, 5 mg / mL to 300 mg / mL, 7.5 mg / mL to 200 mg / mL, 10 mg / mL to 100 mg / mL, 25 mg / mL to 90 mg / mL, or 50 mg / mL to 75 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0371] In some embodiments, the weight loss agent is setmelanotide, and setmelanotide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, setmelanotide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 500 mg / mL, 0.01 mg / mL to 250 mg / mL, 0.05 mg / mL to 100 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.5 mg / mL to 60 mg / mL, 1 mg / mL to 50 mg / mL, 2 mg / mL to 40 mg / mL, 2.5 mg / mL to 35 mg / mL, 3 mg / mL to 30 mg / mL, 3.5 mg / mL to 25 mg / mL, 4 mg / mL to 20 mg / mL, 4.5 mg / mL to 20 mg / mL, or 5 mg / mL to 15 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, setmelanotide is present in the first pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the first pharmaceutical composition. -106- 180085204.4Docket No.: 146316.8032.WO00 Methods

[0372] The present technology also provides methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction comprising administering a non-naturally occurring melanocortin analog to a subject in need thereof. The methods of the present technology may promote fat loss, prevent muscle loss, decrease body weight, accelerate weight loss, decrease fat mass to lean mass ratio, improve body composition and / or BMI, reduce waist circumference, or any combination thereof.

[0373] The present technology comprises methods of reducing body weight and / or fat mass in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog of the present technology to the subject.

[0374] In some embodiments, the present technology comprises methods of reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass.

[0375] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.

[0376] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in an obese subject (e.g., an obese subject without diabetes mellitus or an obese subject having diabetes mellitus), comprising administering a non- naturally occurring melanocortin analog to the subject.

[0377] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0378] In some embodiments, the methods of the present technology (i) reduce a lipid droplets size (e.g., an average lipid droplet size); (ii) increase an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increase an adipose tissue vascularization level; (iv) increase, maintain, or prevent reduction of a beige or brown adipocyte level; (v) increase a metabolic rate; (vi) increase a calorie burn level; -107- 180085204.4Docket No.: 146316.8032.WO00 and / or (vii) increase, maintain, or prevent reduction of an insulin sensitivity level, relative to a control.

[0379] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0380] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0381] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0382] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0383] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0384] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a -108- 180085204.4Docket No.: 146316.8032.WO00 metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0385] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hypothalamic obesity (e.g., congenital hypothalamic damage and / or or damage from tumors or trauma) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0386] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0387] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0388] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. Nonlimiting examples of syndromic obesity include Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet- Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome.

[0389] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating non-alcoholic steatohepatitis (NASH) (i.e., metabolic dysfunction-associated steatohepatitis (MASH)), in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -109- 180085204.4Docket No.: 146316.8032.WO00

[0390] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0391] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0392] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject.

[0393] In some embodiments, method further comprises preserving or improving kidney function in the subject.

[0394] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0395] The present technology further provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0396] In some embodiments, the method comprises orally administering a non- naturally occurring melanocortin analog comprising a sequence of Formula (I) to the subject. Any of the sequences of Formula (I) listed above may be used in the methods of the present technology. In some embodiments, the method comprises orally administering a non- naturally occurring melanocortin analog comprising a sequence of Formula (IA) to the subject. Any of the sequences of Formula (IA) listed above may be used in the methods of the present technology.

[0397] The present technology also provides methods of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). -110- 180085204.4Docket No.: 146316.8032.WO00

[0398] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA).

[0399] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).

[0400] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).

[0401] The present technology also provides methods of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject.

[0402] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass.

[0403] In some embodiments, wherein the method further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

[0404] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, -111- 180085204.4Docket No.: 146316.8032.WO00 comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject.

[0405] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass. In some embodiments, the method further comprises reducing body weight and / or fat mass in the subject.

[0406] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject. In some embodiments, the method further comprises preserving or improving kidney function in the subject.

[0407] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0408] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0409] In some embodiments of the methods, after administration of the non-naturally occurring melanocortin analog, the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0410] In some embodiments of the methods after administration of the non-naturally occurring melanocortin analog, the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0411] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in body weight about 10 days, -112- 180085204.4Docket No.: 146316.8032.WO00 about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0412] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in body weight at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0413] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in body weight at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0414] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, or about a 30% reduction in fat mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0415] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 12.5%, at least a 15%, at least a 17.5%, at least a 20%, at least a 25%, or at least a 30% reduction in fat mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0416] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 12.5%, at least about a 15%, at least -113- 180085204.4Docket No.: 146316.8032.WO00 about a 17.5%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in fat mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0417] In some embodiments of the methods of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in lean mass loss about 10 days, about 20 days, or about 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology.

[0418] In some embodiments of the methods of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in lean mass loss at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0419] In some embodiments of the methods of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in lean mass loss at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0420] In some embodiments of the method of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% increase in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0421] In some embodiments of the method of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% increase in lean -114- 180085204.4Docket No.: 146316.8032.WO00 mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0422] In some embodiments of the method of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% increase in lean mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0423] In some embodiments, the subject exhibits about a 5%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 60%, or about a 70% reduction in food intake per day about 10 days, about 20 days, or about 30 days after administration of a first dose of the combination therapy. In some embodiments, the reduction in food intake occurs about 0.5 hours, about 1 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 6 weeks after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0424] Food intake may reflect cumulative food intake, net food intake, or both. Cumulative food intake may represent total food intake. Net food intake may represent the difference between total food intake and energy expenditure. Cumulative and net food intake may represent a food intake measurement from start to end of dosing, from start to an intermediate time point of dosing (i.e., a time point after the start of dosing but prior to the end of dosing), from an intermediate time point to end of dosing, or between two or more intermediate time points.

[0425] The methods of the present technology alter a subject’s preference for food having high-fat content or low-fat content or is otherwise calorically dense or less calorically dense. In some embodiments, the methods of the present technology increase a subject’s preference for one or more of a lower-fat food or a less calorically dense food relative to the -115- 180085204.4Docket No.: 146316.8032.WO00 food preference of the subject at baseline or of a control. In some embodiments, the methods of the present technology decrease the subject’s preference for one or more of a higher-fat food or a more calorically dense food relative to the food preference of the subject at baseline or of a control.

[0426] In some embodiments of the methods of the present technology, the blood glucose level of the subject is decreased following administration of the combination therapy. In some embodiments, the blood glucose level of the subject is decreased following administration of a first dose of the combination therapy.

[0427] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a blood glucose level about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0428] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a blood glucose level at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0429] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a blood glucose level at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0430] In some embodiments, the subject of the methods of the present technology may experience no change in or a reduction in one or more of an alkaline phosphatase level, -116- 180085204.4Docket No.: 146316.8032.WO00 a total protein level, an albumin level, a globulin level, a gamma-glutamyl transferase (GGT), a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in a biological sample from the subject. Nonlimiting examples of biological samples include a circulatory fluid sample (e.g., blood, serum, lymphatic fluid), a urine sample, or a tissue sample.

[0431] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0432] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0433] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after -117- 180085204.4Docket No.: 146316.8032.WO00 administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0434] In some embodiments, the subject of the methods of the present technology experiences no change or a reduction in one or more of a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.

[0435] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0436] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology, relative to a control.

[0437] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, -118- 180085204.4Docket No.: 146316.8032.WO00 a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0438] In some embodiments, the subject of the methods of the present technology experiences no change or an increase in one or more of a red blood cell count, a hemoglobin level, a hematocrit level, a mean corpuscular volume level, a mean corpuscular hemoglobin level, or a mean corpuscular hemoglobin concentration level in a biological sample from the subject, relative to a control. In some embodiments, the red blood cell count, a hemoglobin level, the hematocrit level, the mean corpuscular volume level, the mean corpuscular hemoglobin level, or the mean corpuscular hemoglobin concentration level is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non- naturally occurring melanocortin analog, relative to a control.

[0439] In some embodiments, the subject of the methods of the present technology may experience no change in or an increase in an albumin to globulin ratio in a biological sample from the subject, relative to a control. In some embodiments, the albumin to globulin ratio is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0440] In some embodiments, the subject administered a non-naturally occurring melanocortin analog of the present technology exhibits one or more of: (a) a reduction in fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; -119- 180085204.4Docket No.: 146316.8032.WO00 (b) a reduction in epididymal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (c) a reduction in perirenal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (d) a reduction in body weight at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (e) a reduction in body mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (f) an increase in lean mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (g) an increase in muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (h) an increase in glucose tolerance by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (i) a reduction in a fat mass to lean mass ratio at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (j) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (k) a reduction in waist circumference at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; -120- 180085204.4Docket No.: 146316.8032.WO00 (l) a reduction in an adverse cardiovascular event by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (m) a reduction in brain mass loss by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (n) a reduction in a hemoglobin A1c level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (o) a reduction in nausea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (p) a reduction in vomiting by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (q) a reduction in diarrhea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (r) a reduction in inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (s) a reduction in obesity-related inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (t) an increase in kidney function by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; -121- 180085204.4Docket No.: 146316.8032.WO00 (u) a reduction in hyperplasia by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (v) a reduction in alcohol use by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (w) a reduction in metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (x) a reduction in a symptom associated with metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (y) a reduction in blood sugar by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (z) a reduction in weight gain after treatment with a weight loss agent or a non-naturally occurring melanocortin analog is terminated by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (aa) a reduction in body weight measured in kg by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (bb) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (cc) a reduction in trunk fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; -122- 180085204.4Docket No.: 146316.8032.WO00 (dd) an increase in a bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ee) an increase in a whole-body bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ff) an increase in a trunk bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (gg) an increase in a bone density level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (hh) an increase in a trunk muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ii) a reduction in food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (jj) a reduction in caloric intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (kk) a reduction in a high-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (ll) a reduction in a calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; -123- 180085204.4Docket No.: 146316.8032.WO00 (mm) an increase in a low-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; or (nn) an increase in a less calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control.

[0441] In some embodiments, any one of (a)-(nn) is maintained for at about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0442] In some embodiments, any one of (a)-(nn) is maintained for at least 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0443] In some embodiments, any one of (a)-(nn) is maintained for at least about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0444] In some embodiments, any one of (a)-(nn) occurs during or after administration of a first, a second, and / or a third dose of the non-naturally occurring melanocortin analog. In some embodiments, any one of (a)-(nn) is greater during or after administration the second dose relative to during or after administration of the first dose. In some embodiments, any one of (a)-(nn) is greater during or after administration the third dose relative to during or after administration of the first dose or the second dose.

[0445] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some -124- 180085204.4Docket No.: 146316.8032.WO00 embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and / or or nuclear magnetic resonance (NMR). Weight Loss Agents

[0446] Administration of the non-naturally occurring melanocortin analogs of the present technology may comprise rebound-resistant weight loss (i.e., prevention of weight gain after treatment completion) and / or increased muscle retention, relative to a control. The control may comprise administration of a conventional weight loss agent alone. The rebound resistant weight loss may comprise a prevention or a reduction in fat mass gain and / or BMI increase, relative to the control. In some embodiments, the non-naturally occurring melanocortin analog is administered as a combination therapy with a weight loss agent, where the combination therapy achieves the same or greater weight loss as administration of the weight loss agent alone, but at a reduced dose or dosing frequency relative to the weight loss agent.

[0447] In some embodiments, the rebound-resistant weight loss is maintained for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0448] In some embodiments, the rebound-resistant weight loss is maintained for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0449] In some embodiments, the rebound-resistant weight loss is maintained for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0450] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1%. -125- 180085204.4Docket No.: 146316.8032.WO00

[0451] In some embodiments, the present technology comprises a method of suppressing appetite in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the weight loss agent. Administration of the non-naturally occurring melanocortin analog prior to, during, and / or after administration of the weight loss agent may produce an additive or synergistic effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a GLP-1 receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces an additive effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces a synergistic effect on suppressing the subject’s appetite.

[0452] In some embodiments, the method reduces food intake of the subject. Administration of the non-naturally occurring melanocortin analog prior to, during, and / or after administration of the weight loss agent may produce an additive or synergistic effect on reducing the subject’s food intake. In some embodiments, the method reduces fat body mass and / or body weight of the subject. In some embodiments, the reduction in food intake is a reduction in caloric intake.

[0453] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0454] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating body weight gain a during or after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0455] In some embodiments, the present technology comprises a method of maintaining body weight after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -126- 180085204.4Docket No.: 146316.8032.WO00

[0456] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0457] The methods of the present technology may decrease the risk and / or incidence of adverse cardiovascular events associated with the use of a weight loss agent including, but not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof.

[0458] The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.

[0459] The weight loss agents of the present technology may include any conventional weight loss agents known in the art. Non-limiting examples of conventional weight loss agents include antihyperglycemic agents such as metformin, sulfonylureas (e.g., glimepiride, glipizide, and glyburide), meglitinides (e.g., repaglinide and nateglinide), thiazolidinediones (e.g., pioglitazone, rosiglitazone), dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, and linagliptin), sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., empagliflozin, ertugliflozin, dapagliflozin, and canagliflozin), alpha- glucosidase inhibitors (e.g., acarbose and miglitol), bromocriptine, and colesevelam; glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (Ozempic®, Wegovy® and Rybelsus®), danuglipron, lotiglipron, orforglipron, exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia® and Adlyxin®); glucose-dependent insulinotropic polypeptide (GIP) receptor agonists such as synthetic incretin hormone and long-acting GIP receptor agonists such as LY3537021; dual GLP-1 / GIP receptor agonists such as tirzepatide (Mounjaro™ and Zepbound™); GLP-1 / glucagon receptor coagonists such as efinopegdutide (MK-6024) and mazdutide; GLP-1 / GIP / glucagon receptor trifunctional agonists such as retatrutide; amylin agonists such as amylin hormone analogue; -127- 180085204.4Docket No.: 146316.8032.WO00 neuregulin 4 (NRG4) agonists; peptide YY analog agonists; patatin-like phospholipase domain-containing protein 3 (PNPLA3) siRNA; lipase inhibitors such as orlistat (Xenical or Alli); norepinephrine and dopamine reuptake inhibitors such as bupropion-naltrexone (Contrave®); antiepileptics such as phentermine-topiramate (Qsymia®); and melanocortin 4 (MC4) receptor agonists such as setmelanotide (Imcivree®).

[0460] In some embodiments, the weight loss agent is in a free base form. In other embodiments, the weight loss agent is in a salt form. Any salt form of the weight loss agent known in the art may be used in the methods described herein. For example, when the weight loss agent is a salt form of setmelanotide, it may be setmelanotide acetate.

[0461] In some embodiments, the pharmaceutical combination comprises one weight loss agent. In other embodiments, the pharmaceutical combination comprises two or more weight loss agents. In some embodiments in which the pharmaceutical combination comprises two or more weight loss agents, the two or more weight loss agents are from the same class of weight loss agents, e.g., the two or more weight loss agents are GLP-1 agonists. Alternatively, in some embodiments in which the pharmaceutical combination comprises two or more weight loss agents, each of the two or more weight loss agents are from a different class of weight loss agents, e.g., one weight loss agent is a GLP-1 agonist, another is a GIP agonist, and so on.

[0462] In some embodiments, the weight loss agent is selected from GLP-1 receptor agonists, GIP receptor agonists including long-acting GIP receptor agonists, a dual GLP- 1 / GIP receptor agonists, GLP-1 / glucagon receptor coagonists, GLP-1 / GIP / glucagon receptor trifunctional agonists, and melanocortin 4 (MC4) receptor agonists. In some embodiments, the weight loss agent is selected from GLP-1 receptor agonists, GIP receptor agonists, a dual GLP-1 / GIP receptor agonists, GLP-1 / glucagon receptor coagonists, and GLP-1 / GIP / glucagon receptor trifunctional agonists.

[0463] In some embodiments, the weight loss agent is a GLP-1 receptor agonist. In some embodiments, the weight loss agent is a peptide GLP-1 receptor agonist. In other embodiments, the weight loss agent is a small molecule GLP-1 receptor agonist. In some embodiments, the weight loss agent is a GLP-1 receptor agonist and is one or more of semaglutide (Ozempic® and Wegovy®), danuglipron, lotiglipron, orforglipron, exenatide -128- 180085204.4Docket No.: 146316.8032.WO00 (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia®). In some embodiments, the GLP-1 receptor agonist is one or more of semaglutide (Ozempic®, Wegovy® and Rybelsus®), exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), and lixisenatide (Lyxumia® and Adlyxin®). In some embodiments, the GLP-1 receptor agonist is danuglipron. In some embodiments, the GLP-1 receptor agonist is lotiglipron. In some embodiments, the GLP-1 receptor agonist is orfoglipron. In some embodiments, the GLP-1 receptor agonist is taspoglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide (e.g., Ozempic® or Wegovy®). In some embodiments, the GLP-1 receptor agonist is exenatide (Byetta® an Bydureon®). In some embodiments, the GPL-1 receptor agonist is liraglutide (Victoza® and Saxenda®). In some embodiments, the GLP-1 receptor agonist is dulaglutide (Trulicity®). In some embodiments, the GLP-1 receptor agonist is albiglutide (Tanzeum®). In some embodiments, the GLP-1 receptor agonist is lixisenatide (Lyxumia® and Adlyxin®).

[0464] In some embodiments, the GLP-1 receptor agonist is a compound of Formula (IV): V), or a pharmaceutically a X is N or CH;Y is N or CR4; n is 0 or 1; R is hydrogen; -129- 180085204.4Docket No.: 146316.8032.WO00 R1is —C1-C6 alkylene-R5; R2is hydrogen, oxo, or C1-C6 alkyl; R3is hydrogen, oxo, or C1-C6 alkyl and R4is hydrogen, OH, or C1-C6 alkyl; or R3and R4are taken together with the carbon atoms to which they are attached to form C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl; R5is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R5is S, and further wherein R5is optionally substituted by halo, —O—C1- 6 alkyl, C1-6 alkyl, C1-6 alkenyl, or C1-C6 haloalkyl; Ring A is 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, —O—, C1-C6 alkylene, *—O—C1-C6 alkylene-**, *—C1-C6 alkylene-O— **, or *—NR6—C1-C6 alkylene-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B; when L is *—O—C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally substituted by RL, wherein each RLis independently C1-C6 alkyl or halo, or two RLare taken together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl; and when L is C1-C6 alkylene, the C1-C6 alkylene is optionally substituted by RL1, wherein each RL1is independently halo, OH, oxo, or C1-C6 alkyl, or two RL1are taken together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl; R6is hydrogen or C1-C6 alkyl; and Ring B is C3-C10 cycloalkyl, C6-C14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12- membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1- C6 alkyl, C1-C6 haloalkyl, —COCH3, —CONH2, —S(O)2CH3, and phenyl. -130- 180085204.4Docket No.: 146316.8032.WO00

[0465] In further embodiments, the GLP-1 receptor agonist is a compound of Formula (IVa): a),R7is hydrogen, chloro, bromo, fluoro, methyl, or vinyl; and R8is: mpound of-131- 180085204.4Docket No.: 146316.8032.WO00 ). [ceptor agonist is a compound of any one of Formulae (IV), (IVa), and (IVb), in the form of a salt. In some embodiments, the salt is a meglumine salt.

[0468] Various other GLP-1 receptor agonists which may be employed as a weight loss agent in the present technology include, but are not limited to, peptides and small molecules disclosed in WO2006 / 134340, WO2007 / 100535, WO2008 / 10101, WO2008 / 152403, WO2009 / 155257, WO2009 / 155258, WO2010 / 070252, WO2010 / 070253, WO2010 / 070255, WO2010 / 070251, WO2011 / 006497, WO2011 / 160630, WO2011 / 160633, WO2013 / 092703, WO2014 / 041195, WO2015 / 055802, WO2015149627, WO2015 / 155139, WO2015 / 155140, WO2015 / 155141, WO2015 / 155151, WO2015 / 193378, WO2015 / 193381, WO2016 / 0154014, WO2016 / 046753, US2022 / 0089578, and US2023 / 0150998, which are incorporated herein by reference in their entireties.

[0469] In some embodiments, the weight loss agent is a GIP receptor agonist, such as a long-acting GIP receptor agonist. In some embodiments, the weight loss agent is LY3537021.

[0470] In other embodiments, the pharmaceutical combination comprises a first weight loss agent which is a long-acting GIP receptor agonist and a second weight loss agent which is a GLP-1 receptor agonist. The long-acting GIP receptor agonist may be LY3537021 and the GLP-1 receptor agonist may be any one of semaglutide (Ozempic® and Wegovy®), danuglipron, lotiglipron, orforglipron, exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia®). In some embodiments, the GLP-1 receptor agonist is one or -132- 180085204.4Docket No.: 146316.8032.WO00 more of semaglutide (Ozempic®, Wegovy® and Rybelsus®), exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), and lixisenatide (Lyxumia® and Adlyxin®). In some embodiments, the first weight loss agent is LY3537021, and the second weight loss agent is liraglutide.

[0471] In some embodiments, the weight loss agent is a bifunctional or trifunctional GLP-1 agonist, e.g., a GLP-1 agonist that also has agonist activity at one or two other receptors. In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist. In some embodiments, the weight loss agent is tirzepatide (Mounjaro™ and Zepbound™). In some embodiments, the weight loss agent is a dual GIP / GLP-1 receptor agonist of a Formula (II) Specific dual GLP-1 / GIP receptor agonists according to Formula (II) that may be used in the presently described combination therapy and methods are disclosed in US 2023 / 0293638, which is incorporated herein by reference in its entirety.

[0472] In some embodiments, the weight loss agent is a GLP-1 / glucagon receptor coagonist. In some embodiments, the weight loss agent is efinopegdutide or mazdutide. In some embodiments, the weight loss agent is a GLP-1 / GIP / glucagon receptor trifunctional agonist. In some embodiments, the weight loss agent is retatrutide.

[0473] In some embodiments, the weight loss agent is an MC4 receptor agonist. In some embodiments, the weight loss agent is setmelanotide (e.g., Imcivree®). Anti-Cancer Agents

[0474] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more conditions and / or side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms or conditions associated with cancer via administration of a non-naturally occurring melanocortin analog to a subject in need thereof. The methods may promote appetite and food consumption, and increase or maintain body weight, muscle mass, and / or fat mass of the subject. The methods are also effective in treating anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, nausea, emesis, and symptoms associated with hypermetabolic immunoinflammatory syndrome. In some embodiments, the methods are effective in improving quality of life and / or increasing life expectancy. The methods of the present -133- 180085204.4Docket No.: 146316.8032.WO00 technology include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to onset, during, and / or after onset of such conditions and / or side effects. These methods also include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to, during, and / or after administration of an anti-cancer agent to the subject who may have cancer or may have another condition which is not cancer, but administration of the anti-cancer agent provides therapeutic benefit to the non-cancer condition. Additional Benefits Over GLP-1 Receptor Agonist Monotherapies

[0475] The non-naturally occurring melanocortin 4 receptor agonists of the present technology may solve or improve shortcomings observed with administration of GLP-1 receptor agonist monotherapies. In some embodiments, the GLP-1 receptor agonist is semaglutide or tirzepatide. For example, the non-naturally occurring melanocortin 4 receptor agonists of the present technology may serve as a GLP-1 receptor agonist alternative or may counteract unwanted outcomes resulting from administration of a GLP-1 receptor agonist when the non-naturally occurring melanocortin 4 receptor agonist is administered alone (e.g., as a monotherapy or before or after administration of a GLP-1 receptor agonist) or in combination with a GLP-1 receptor agonist (e.g., before administration of the GLP-1 receptor agonist, after administration of the GLP-1 receptor agonist, or concurrently with administration of the GLP-1 receptor agonist). For example, the non-naturally occurring melanocortin 4 receptor agonists may improve one or more of tolerance (e.g., a reduction in nausea), muscle retention, patient preference and / or compliance relative to administration of a GLP-1 receptor agonist alone or otherwise without the non-naturally occurring melanocortin 4 receptor agonist. Administration of the GLP-1 receptor agonist alone *i.e., GLP-1 receptor agonist monotherapy) refers to administration without the non-naturally occurring melanocortin 4 receptor agonist of the present technology. Administration of the GLP-1 receptor agonist alone may comprise administration with one or more compounds that are not the non-naturally occurring melanocortin 4 receptor agonists of the present technology.

[0476] Without intending to be limiting, the improved tolerance may be attributed to lower dosages of the GLP-1 receptor agonists when administered in combination with the -134- 180085204.4Docket No.: 146316.8032.WO00 non-naturally occurring melanocortin 4 receptor agonists compared to higher dosages of the GLP-1 receptor agonists administered alone without the non-naturally occurring melanocortin 4 receptor agonists. Non-limiting examples of improved tolerance include reduced nausea, improved muscle retention, and improved patient compliance. In some embodiments, the GLP-1 receptor agonist administered in combination with the non- naturally occurring melanocortin analog is administered at a dose that is about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 30% or less, about 35% or less, about 40% or less, about 45% or less, about 50% or less, about 55% or less, 60% or less, about 65% or less, about 70% or less, or about 75% or less of the dose of the GLP-1 receptor agonist administered alone without the non-naturally occurring melanocortin analogs.

[0477] In some embodiments, the non-naturally occurring melanocortin 4 receptor agonists may improve tolerance of a GLP-1 receptor agonist, relative to administration of a GLP-1 receptor agonist alone or otherwise without the non-naturally occurring melanocortin 4 receptor agonist. The improved tolerance may comprise a reduction in nausea compared to administration of a GLP-1 receptor agonist alone.

[0478] In some embodiments, the non-naturally occurring melanocortin 4 receptor agonists may improve a muscle retention level relative to administration of a GLP-1 receptor agonist alone or otherwise without the non-naturally occurring melanocortin 4 receptor agonist The improved muscle retention may comprise a reduced muscle mass loss, an increase in muscle mass gain, or an increase in muscle mass maintenance, relative to administration of a GLP-1 receptor agonist alone. The muscle mass may comprise lean muscle mass.

[0479] In some embodiments, non-naturally occurring melanocortin 4 receptor agonists may improve a patient preference and / or compliance with relative to administration of a GLP- 1 receptor agonist alone or otherwise without the non-naturally occurring melanocortin 4 receptor agonist. The improved patient preference and / or compliance may comprise a preference for the administration route of the non-naturally occurring melanocortin 4 receptor agonists relative to the administration route of the GLP-1 receptor agonists. The administration route of the non-naturally occurring melanocortin 4 receptor agonist may -135- 180085204.4Docket No.: 146316.8032.WO00 comprise a long-lasting injection, wherein the injection effects are maintained for a longer period of time relative to the effects from the GLP-1 receptor agonist. In some embodiments, the preference and / or compliance is attributed to a preference for an oral administration of the non-naturally occurring melanocortin 4 receptor agonist compared to the GLP-1 receptor agonist administered via injection.

[0480] The non-naturally occurring melanocortin 4 receptor agonists may serve as a GLP-1 receptor agonist (e.g., semaglutide or tirzepatide) alternative and / or a follow-on treatment to sustain or enhance weight loss, or otherwise prevent weight gain following administration of a GLP-1 receptor agonist For example, the non-naturally occurring melanocortin 4 receptor agonists may serve as a substitute to GLP-1 receptor agonists by weight loss in subjects that were non-responsive to GLP-1 receptor agonists, reducing or preventing one or more side effects that are experienced from a GLP-1 receptor agonist, or reducing or preventing weight loss plateau that is experienced during or after administration of a GLP-1 receptor agonist. Such outcomes may be attributed to (1) lower doses of GLP- 1 receptor agonists, (2) reduced frequency of administration of GLP-1 receptor agonists, (3) a reduced total duration of time of GLP-1 receptor agonist administration, or (4) a rescue effect of the non-naturally occurring melanocortin 4 receptor agonists, when the GLP-1 receptor agonists are administered in combination with the non-naturally occurring melanocortin 4 receptor agonists of the present technology, that is, when the non-naturally occurring melanocortin 4 receptor agonists are administered before, during, or after administration of the GLP-1 receptor agonist. In some embodiments, after administration includes after completion of the GLP-1 receptor agonist treatment.

[0481] Additionally, the non-naturally occurring melanocortin 4 receptor agonists may promote one or more of a healthier weight loss (e.g., a weight loss with no or reduced unwanted side effects, less rapid weight loss) relative to weight loss experienced from administration of a GLP-1 receptor agonist and plateau-resistant dosing when administered as a monotherapy. In some embodiments, the non-naturally occurring melanocortin 4 receptor agonist monotherapy comprises administration of a non-naturally occurring melanocortin 4 receptor agonist to a subject that has not received a GLP-1 receptor agonist. In some embodiments, the monotherapy comprises administration of a non-naturally -136- 180085204.4Docket No.: 146316.8032.WO00 occurring receptor agonist to a subject that has, but is not currently receiving, a GLP-1 receptor agonist. In some embodiments, the non-naturally occurring melanocortin 4 receptor agonist matches GLP-1 receptor agonist weight loss while maintaining food intake or while reducing a decrease in food intake that is observed with GLP-1 receptor agonist administration.

[0482] Administration of the non-naturally occurring melanocortin 4 receptor agonists of the present technology may comprise rebound-resistant weight loss (i.e., prevention of weight gain after treatment completion) and / or increased muscle retention when administered alone or as a combination therapy with a GLP-1 receptor agonist, relative to a GLP-1 receptor agonist monotherapy. The rebound resistant weight loss may comprise a prevention or reduction in fat mass gain and / or BMI increase, relative to the GLP-1 receptor agonist monotherapy. In some embodiments, the combination therapy achieves the same weight loss as administration of the GLP-1 receptor agonist alone, but at a reduced dose or dosing frequency relative to the GLP-1 receptor agonist. In some embodiments, the rebound-resistant weight loss is maintained for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin 4 receptor agonists is complete and / or discontinued. In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin 4 receptor agonists is complete and / or discontinued.

[0483] In some embodiments, the combination therapy comprises co-administration of the non-naturally occurring melanocortin 4 receptor agonist and the GLP-1 receptor agonist. In some embodiments, the combination therapy comprises administering a non-naturally occurring melanocortin 4 receptor agonist before or after a GLP-1 receptor agonist to a subject receiving a GLP-1 receptor agonist treatment.

[0484] The non-naturally occurring melanocortin agonist may be administered at any amount, frequency, duration, or combination with the GLP-1 receptor agonists as described herein. Similarly, the GLP-1 receptor agonist may be administered at any amount, -137- 180085204.4Docket No.: 146316.8032.WO00 frequency, duration, or combination with the non-naturally occurring melanocortin agonist as described herein. In some embodiments, the non-naturally occurring melanocortin agonist is administered at a dose of about 10 to about 250 mg. The non-naturally occurring melanocortin agonist may be administered at a low dose to maintain weight (e.g., about 20 mg) or to prevent weight rebound (e.g., less than about 100 mg), relative to GLP-1 monotherapies. The non-naturally occurring melanocortin agonist may be administered at a high dose (e.g., about 200 mg) promote rapid weight loss. In some embodiments, the non- naturally occurring melanocortin 4 receptor agonist is administered in combination with a GLP-1 receptor agonist to promote rapid weight loss without decreasing food intake as much as administration for the GLP-1 receptor agonist alone, wherein the dose of the GLP-1 agonist in combination with the non-naturally occurring melanocortin 4 receptor agonist is reduced relative to the GLP-1 agonist administered as a monotherapy, to achieve the same or greater weight loss effect. O10 and Semaglutide or Tirzepatide

[0485] In some embodiments, the non-naturally occurring melanocortin receptor analog is O10 (SEQ ID NO: 43) and the GLP-1 receptor agonist is semaglutide or tirzepatide.

[0486] In some embodiments, administration of O10 comprises increased tolerance in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. The increased tolerance may comprise reduced or prevented nausea relative to the semaglutide or tirzepatide monotherapies.

[0487] In some embodiments, administration of O10 comprises increased muscle retention in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. The increased muscle retention may comprise reduced or prevented muscle mass loss or increased muscle mass (e.g., lean muscle mass) relative to the semaglutide or tirzepatide monotherapies.

[0488] In some embodiments, administration of O10 comprises increased muscle retention in a subject relative to administration of semaglutide monotherapy or tirzepatide -138- 180085204.4Docket No.: 146316.8032.WO00 monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. The increased muscle retention may comprise reduced or prevented muscle mass loss or increased muscle mass (e.g., lean muscle mass) relative to the semaglutide or tirzepatide monotherapies.

[0489] In some embodiments, administration of O10 comprises increased preference and / or compliance with O10 administration in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. The increased compliance / preference may comprise a long- lasting weight loss effect relative to the semaglutide or tirzepatide monotherapies. In some embodiments, the preference and / or compliance is attributed to a preference for the oral administration of the non-naturally occurring melanocortin 4 receptor agonist compared to the GLP-1 receptor agonist administered via injection.

[0490] In some embodiments, administration of O10 comprises reduced unwanted side effects, reduced weight loss plateau, and reduced weight loss rebound in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. The increased muscle retention may comprise reduced or prevented muscle mass loss or increased muscle mass (e.g., lean muscle mass) relative to the semaglutide or tirzepatide monotherapies.

[0491] In some embodiments, administration of O10 comprises an improved weight loss (e.g., a healthier weight loss characterized by minimal muscle mass loss or maintained or increased muscle mass) in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide.

[0492] In some embodiments, administration of O10 comprises a rebound-resistant weight loss in a subject relative to administration of semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide. In some embodiments, the rebound-resistant weight loss comprises an increased or maintained -139- 180085204.4Docket No.: 146316.8032.WO00 muscle mass relative to the semaglutide monotherapy or tirzepatide monotherapy. In some embodiments, the rebound-resistant weight loss comprises a reduction in muscle mass loss relative to the semaglutide monotherapy or tirzepatide monotherapy.

[0493] In some embodiments, administration of O10 comprises a reduced dose or reducing dosing frequency relative to the dose or dosing frequency of semaglutide monotherapy or tirzepatide monotherapy to achieve the same or improved weight loss effect. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide.

[0494] In some embodiments, administration of O10 comprises a reduced maintenance dose or maintenance dosing frequency the dose or dosing frequency of semaglutide monotherapy or tirzepatide monotherapy to achieve the same or improved weight maintenance and / or appetite suppression. In some embodiments, the administration of O10 comprises O10 monotherapy or O10 combination therapy with semaglutide or tirzepatide.

[0495] In some embodiments, the semaglutide monotherapy comprises a dose of about 0.10 mg to about 5.0 mg administered once weekly. In some embodiments the semaglutide monotherapy comprises a dose of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, or 2.4 mg administered once weekly. In some embodiments, the semaglutide monotherapy comprises administering a 0.25 mg dose once weekly for 4 weeks, followed by a 0.5 mg dose administered once weekly for 4 weeks, followed by a 1.0 mg dose administered once weekly for 4 weeks, followed by a 1.7 mg dose administered once weekly for 4 weeks, followed by a 2.4 mg dose administered once weekly for 4 weeks. In some embodiments, the semaglutide monotherapy is administered subcutaneously.

[0496] In some embodiments, the tirzepatide monotherapy comprises a dose of about 0.5 mg to about 25 mg administered once weekly. In some embodiments the tirzepatide monotherapy comprises a dose of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg administered once weekly. In some embodiments, the tirzepatide monotherapy comprises administering a 2.5 mg dose once weekly for 4 weeks, followed by a 5.0 mg dose administered once weekly for 4 weeks, followed by a 7.5 mg dose administered once weekly for 4 weeks, followed by a 10.0 mg dose administered once weekly for 4 weeks, followed by -140- 180085204.4Docket No.: 146316.8032.WO00 a 12.5 mg dose administered once weekly for 4 weeks, followed by a 15.0 mg dose administered once weekly for 4 weeks. In some embodiments, the tirzepatide monotherapy is administered subcutaneously.

[0497] In some embodiments, the semglutide monotherapy comprises a dose of about 0.25 to about 2 mg administered once daily. In some embodiments, the semglutide monotherapy comprises administering a 0.25 mg dose administered once weekly for about 4 weeks, optionally increasing the dose to 0.5 mg administered weekly for at least 4 weeks, optionally increasing the dose to 1.0 mg administered once weekly for at least 4 weeks, optionally increasing the dose to 2 mg administered once weekly dose about 4 weeks. In some embodiments, the 3 mg dose is administered once daily. In some embodiments, the semglutide monotherapy is administered subcutaneously.

[0498] In some embodiments, the semglutide monotherapy comprises a dose of about 1.5 mg to about 25 mg administered once daily. In some embodiments, the semglutide monotherapy comprises administering a 3.0 mg dose administered once daily for about 30 days, increasing the dose to 7.0 mg administered once daily for about 30 days, and optionally increasing the dose to 14 mg administered once daily for about 30 days. In some embodiments, the semglutide monotherapy is administered orally. GLP-1 Receptor Agonist Monotherapies

[0499] In some embodiments, the GLP-1 receptor agonist monotherapy comprises a dose of about 0.10 mg to about 5.0 mg administered once weekly. In some embodiments the GLP-1 receptor agonist monotherapy comprises a dose of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, or 2.4 mg administered once weekly. In some embodiments, the GLP-1 receptor agonist monotherapy comprises administering a 0.25 mg dose once weekly for 4 weeks, followed by a 0.5 mg dose administered once weekly for 4 weeks, followed by a 1.0 mg dose administered once weekly for 4 weeks, followed by a 1.7 mg dose administered once weekly for 4 weeks, followed by a 2.4 mg dose administered once weekly for 4 weeks. In some embodiments, the GLP-1 receptor agonist monotherapy is administered subcutaneously. In some embodiments, the GLP-1 receptor agonist in the GLP-1 receptor agonist monotherapy is semaglutide. -141- 180085204.4Docket No.: 146316.8032.WO00

[0500] In some embodiments, the GLP-1 receptor agonist monotherapy comprises a dose of about 0.5 mg to about 25 mg administered once weekly. In some embodiments the GLP-1 receptor agonist monotherapy comprises a dose of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg administered once weekly. In some embodiments, the GLP-1 receptor agonist monotherapy comprises administering a 2.5 mg dose once weekly for 4 weeks, followed by a 5.0 mg dose administered once weekly for 4 weeks, followed by a 7.5 mg dose administered once weekly for 4 weeks, followed by a 10.0 mg dose administered once weekly for 4 weeks, followed by a 12.5 mg dose administered once weekly for 4 weeks, followed by a 15.0 mg dose administered once weekly for 4 weeks. In some embodiments, the GLP-1 receptor agonist monotherapy is administered subcutaneously. In some embodiments, the GLP-1...

Claims

Docket No.: 146316.8032.WO00 CLAIMS I / We claim:

1. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, to produce an additive or synergistic effect on body weight and / or fat mass loss in the subject.

2. Use of (a) a weight loss agent and (b) a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, producing an additive or synergistic effect on body weight and / or fat mass loss in the subject 3. The method or the use of claim 1 or 2, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

4. The method or the use of claim 3, wherein the lean mass is lean muscle mass.

5. The method or the use of any one of claims 1 to 4, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

6. A method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, to produce a synergistic or additive effect on glucose intolerance and / or diabetes mellitus in the subject.

7. Use of (a) a weight loss agent and (b) a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a -339- 180085204.4Docket No.: 146316.8032.WO00 subject in need thereof, producing a synergistic or additive effect on glucose intolerance and / or diabetes mellitus in the subject.

8. The method or the use of claim 6 or 7, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

9. The method or the use of claim 8, wherein the lean mass is lean muscle mass.

10. The method or the use of any one of claims 6 to 9, wherein the method or the use further comprises reducing body weight and / or fat mass in the subject.

11. A method of inducing a tanning effect in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject.

12. Use of a non-naturally occurring melanocortin analog for inducing a tanning effect in a subject.

13. A method of inducing a tanning effect and weight loss in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject.

14. Use of a non-naturally occurring melanocortin analog for inducing a tanning effect and weight loss in a subject.

15. The method or the use of claim 13 or 14, further comprising administering a weight loss agent to the subject.

16. The method or the use of any one of claims 1-15, wherein a muscle mass is maintained in the subject, relative to baseline. -340- 180085204.4Docket No.: 146316.8032.WO00 17. The method or the use of claim 16, wherein the muscle mass comprises lean muscle mass.

18. The method or the use of any one of claims 13-17, wherein the subject experiences at least about 1%, 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%, relative to a control.

19. The method or the use of any one of claims 11-18, wherein the subject is administered a dose of about 100 mg / kg or greater of the non-naturally occurring melanocortin analog.

20. The method or the use of any one of claims 11-18, wherein the subject is administered a dose of at least about 200 mg / kg or greater of the non-naturally occurring melanocortin analog.

21. The method or the use of any one of claims 1-10 or 15-20, wherein the method or the use increases tolerance for the weight loss agent relative to a treatment comprising administration of a weight loss agent without a non-naturally occurring melanocortin analog.

22. The method or the use of claim 21, wherein the increased tolerance comprises reduced nausea.

23. The method or the use of any one of claims 1-10 or 15-22, wherein the method or the use maintains or increases a muscle mass level relative to a treatment comprising administration of a weight loss agent without a non-naturally occurring melanocortin analog.

24. The method or the use of claim 23, wherein the muscle mass comprises lean muscle mass.

25. The method or the use of any one of claims 1-10 or 15-24, wherein the method or the use increases a preference level or a compliance level for the weight loss agent -341- 180085204.4Docket No.: 146316.8032.WO00 relative to a treatment comprising administration of a weight loss agent without a non- naturally occurring melanocortin analog.

26. The method or the use of any one of claims 1-10 or 15-25, wherein the method or the use comprises increasing a weight loss level for the weight loss agent relative to a treatment comprising administration of a weight loss agent without a non-naturally occurring melanocortin analog.

27. The method or the use of any one of claims 1-10 or 15-26, wherein the method or the use comprises a reduction in one or more side effects associated with the weight loss agent relative to a treatment comprising administration of a weight loss agent without a non- naturally occurring melanocortin analog.

28. The method or the use of any one of claims 1-10 or 15-27, wherein the method or the use comprises reducing a weight loss plateau for the weight loss agent relative to a treatment comprising administration of a weight loss agent without a non-naturally occurring melanocortin analog.

29. The method or the use of any one of claims 1-10 or 15-28, wherein the method or the use reduces an appetite level or a weight gain level relative to a treatment comprising administration of a weight loss agent without a non-naturally occurring melanocortin analog.

30. The method or the use of any one of claims 1-10 or 15-29, wherein the weight loss agent is administered at a dose that is less than a dose required to elicit a response in the subject without the non-naturally occurring melanocortin analog.

31. The method or the use of any one of claims 1-10 or 15-29, wherein the non- naturally occurring melanocortin analog is administered at a dose that is less than a dose required to elicit a response in the subject without the weight loss agent.

32. The method of the use of any one of claims 1-31, wherein the weight loss -342- 180085204.4Docket No.: 146316.8032.WO00 agent is a GLP-1 receptor agonist.

33. The method or the use of any one of claims 1-32, wherein the weight loss agent is semaglutide and is administered at a dose of about 0.01 mg to about 10 mg once per week.

34. The method or the use of claim 33, wherein semaglutide is administered subcutaneously at a dose of less than 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2 mg, or 2.4 mg once per week.

35. The method or the use of any one of claims 1-10 or 15-31, wherein the weight loss agent is semaglutide and is administered at a dose of about 0.5 mg to about 40 mg once daily.

36. The method or the use of claim 35, wherein semaglutide is administered orally at a dose of less than 3 mg, 7 mg or 14 mg once daily.

37. The method or the use of any one of claims 1-10 or 15-31, wherein the weight loss agent is semaglutide and is administered at a dose of about 12.5 nmol / kg or 25 nmol / kg per body weight of the subject once every three days.

38. The method or the use of any one of claims 1-10 or 15-31, wherein the weight loss agent is exenatide and is administered at a dose of about 0.5 mg to about 100 mg twice daily.

39. The method or the use of claim 38, wherein exenatide is administered subcutaneously at a dose of less than 5 mg or 10 mg twice daily.

40. The method or the use of any one of claims 1-10 or 15-27, wherein the weight loss agent is exenatide and is administered at a dose of about 0.5 mg to about 50 mg once per week. -343- 180085204.4Docket No.: 146316.8032.WO00 41. The method or the use of claim 40, wherein exenatide is administered subcutaneously at a dose of less 2 mg once per week.

42. The method or the use of any one of 1-10 or 15-27, wherein the weight loss agent is dulaglutide and is administered at a dose of about 0.05 mg to about 50 mg once per week.

43. The method or the use of claim 42, wherein dulaglutide is administered subcutaneously at a dose of less than 0.75 mg, 1.5 mg, 3.0 mg or 4.5 mg once per week.

44. The method or the use of any one of claims 1-10 or 15-27, wherein the weight loss agent is orforglipron and is administered at a dose of about 0.01 mg to about 100 mg once daily.

45. The method or the use of claim 44, wherein orforglipron is administered orally at a dose of less than 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg, or 24 mg once daily.

46. The method or the use of any one of claims 1-10 or 15-27, wherein the weight loss agent is a dual GLP-1 / GIP receptor agonist.

47. The method or the use of claim 46, wherein the dual GIP / GLP-1 receptor agonist is tirzepatide and is administered at a dose of about 0.5 mg to about 50 mg once per week.

48. The method or the use of claim 47, wherein tirzepatide is administered subcutaneously at a dose of less than 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg once per week.

49. The method or the use of claim 46, wherein the dual GLP-1 / GIP receptor agonist is tirzepatide and is administered at a dose of about 12.5 nmol / kg or 25 nmol / kg per -344- 180085204.4Docket No.: 146316.8032.WO00 body weight of the subject once every three days.

50. The method or the use of any one of claims 1-49, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg / kg to about 10 mg / kg per body weight of the subject once daily.

51. The method or the use of claim 50, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg / kg or 3 mg / kg per body weight of the subject once daily.

52. The method or the use of any one of claims 1-51, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

53. The method or the use of any one of claims 1-51, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

54. The method or the use of any one of claims 1-53, wherein the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.

55. The method or the use of claim 54, wherein the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.

56. The method or the use of claim 54, wherein the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.

57. The method or the use of any one of claims 1-55, wherein the non-naturally occurring melanocortin analog is an agonist of the melanocortin 4 receptor. -345- 180085204.4Docket No.: 146316.8032.WO00 58. The method or the use of claim 57, wherein the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 4 receptor.

59. The method or the use of any one of claims 1-58, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).

60. The method or the use of any one of claims 1-58, wherein the non-naturally occurring melanocortin analog is selected from the group consisting of SEQ ID NOs: 43-45.

61. The method or the use of any one of claims 1-53, wherein the non-naturally occurring melanocortin analog is an antagonist of the melanocortin 3 receptor.

62. The method or the use of claim 61, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor.

63. The method or the use of claim 61, wherein t the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.

64. The method or the use of any one of claims 1-63, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to administration of the weight loss agent, and wherein administration of the non-naturally occurring melanocortin analog makes the subject more responsive to the weight loss agent, compared to a subject who has not been administered the non-naturally occurring melanocortin agonist.

65. The method or the use of any one of claims 1-63, wherein the non-naturally occurring melanocortin analog is administered to the subject after administration of the weight loss agent, and wherein the subject failed to lose sufficient body weight and / or fat mass following administration with the weight loss agent without the non-naturally occurring melanocortin analog.

66. The method or the use of claim 65, wherein the non-naturally occurring -346- 180085204.4Docket No.: 146316.8032.WO00 melanocortin analog is administered to the subject after administration of the weight loss agent for one dose, one week, or one cycle.

67. The method or the use of claim 65, wherein the non-naturally occurring melanocortin analog is administered to the subject after treatment with the weight loss agent is complete.

68. The method or the use of any one of claims 1-63, wherein the weight loss agent is administered to the subject for a period of time before administration of the non- naturally occurring melanocortin analog, and wherein, while the non-naturally occurring melanocortin analog is administered to the subject, administration of the weight loss agent is paused, and wherein, when administration of the non-naturally occurring melanocortin analog is completed, administration of the weight loss agent is resumed.

69. The method or the use of any one of claims 1-10 or 15-63, wherein the non- naturally occurring melanocortin analog is administered to the subject for a period of time before administration of the weight loss agent, and wherein, while weight loss agent is administered to the subject, administration of the non-naturally occurring melanocortin analog is paused, and wherein, when administration of the weight loss agent is completed, administration of the non-naturally occurring melanocortin analog is resumed.

70. The method or the use of any one of claims 1-69, wherein the method or the use further comprises preventing or reducing one or more side effects associated with the weight loss agent.

71. The method or the use of claim 70, wherein the one or more side effects associated with the weight loss agent is a gastrointestinal effect.

72. The method or the use of claim 71, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea. -347- 180085204.4Docket No.: 146316.8032.WO00 73. The method or the use of claim 70, wherein the one or more side effects associated with the weight loss agent is an adverse cardiovascular event.

74. The method or the use of claim 73, wherein the adverse cardiovascular event is one or more of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, and peripheral vascular disease.

75. The method or the use of any one of claims 1-74, wherein the method or the use further comprises preventing or reducing one or more side effects associated with a conventional non-naturally occurring melanocortin analog.

76. The method or the use of any one of claims 75, wherein the one or more side effects associated with the conventional non-naturally occurring melanocortin analog is an adverse cardiovascular event.

77. The method or the use of claim 76, wherein the adverse cardiovascular event is sinus tachycardia.

78. The method or the use of any one of claims 1-77, wherein the method or the use further comprises reducing obesity-related inflammation in the subject.

79. The method or the use of any one of claims 1-78, wherein the method or the use further comprises preserving or improving kidney function in the subject.

80. A method of treating, preventing, or reducing one or more side effects associated with use of a weight loss agent in a subject, comprising administering a non- naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the weight loss agent. -348- 180085204.4Docket No.: 146316.8032.WO00 81. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with the use of a weight loss agent in a subject, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the weight loss agent.

82. The method or the use of claim 80, wherein the GLP-1 receptor is administered at a dose sufficient to elicit weight loss in the subject, and wherein the dose sufficient to elicit weight loss in the subject is lower than a dose of the weight loss agent required to elicit weight loss in the subject without the non-naturally occurring melanocortin analog.

83. The method or the use of any one of claims 80-82, wherein the one or more side effects associated with the use of a weight loss agent is an adverse cardiovascular event.

84. The method or use of claim 83, wherein the adverse cardiovascular event is one or more of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, and peripheral vascular disease.

85. The method of the use of any one of claims 80-82, wherein the one or more side effects associated with the use of the weight loss agent is a gastrointestinal effect.

86. The method or the use of claim 85, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea.

87. A method of reducing obesity-related inflammation in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and -349- 180085204.4Docket No.: 146316.8032.WO00 (b) a non-naturally occurring melanocortin analog, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent 88. Use of (a) a weight loss agent and (b) a non-naturally occurring melanocortin analog for reducing obesity-related inflammation in a subject in need thereof, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent.

89. A method of preserving or improving kidney function in a subject in need thereof, comprising administering to the subject: (a) a weight loss agent; and (b) a non-naturally occurring melanocortin analog, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent.

90. Use of (a) a weight loss agent and (b) a non-naturally occurring melanocortin analog for preserving or improving kidney function in a subject in need thereof, wherein the non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the weight loss agent.

91. The method or the use of any one of claims 1-90, wherein the subject has a metabolic dysfunction selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies.

92. The method or the use of any one of claims 1-91, wherein the method or the use does not reduce efficacy of the weight loss agent relative to a control. -350- 180085204.4Docket No.: 146316.8032.WO00 93. The method or the use of any one of claims 1-91, wherein the method or the use increases efficacy of the weight loss agent relative to a control.

94. The method or the use of any one of claims 1-91, wherein the method or the use does not plateau body weight loss in the subject.

95. The method or the use of any one of claims 1-91, wherein the method or the use does not plateau fat mass loss in the subject.

96. The method or the use of any one of claims 1-95, wherein the method or the use prevents fat mass gain after administration of the weight loss agent relative to a control.

97. The method or the use of any one of claims 1-96, wherein the method or the use prevents body weight gain after administration of the weight loss agent relative to a control.

98. The method or the use of any one of claims 1-96, wherein the method or the use reduces body weight gain after administration of the weight loss agent relative to a control.

99. The method or the use of any one of claims 1-96, wherein the method or the use reduces fat mass gain after administration of the weight loss agent relative to a control.

100. The method or the use of any one of claims 1-99, wherein the method or the use reduces a blood sugar level in the subject relative to a control.

101. The method or the use of any one of claims 1-100, wherein the method or the use prevents a blood sugar elevation in the subject after administration of the weight loss agent relative to a control. -351- 180085204.4Docket No.: 146316.8032.WO00 102. The method or the use of any one of claims 1-100, wherein the method or the use reduces a blood sugar elevation in the subject after administration of the weight loss agent relative to a control.

103. The method or the use of any one of claims 1-102, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the weight loss agent relative to a control.

104. The method or the use of any one of claims 1-102, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the weight loss agent relative to a control.

105. The method or the use of any one of claims 1-104, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg to about 20 mg / kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg / kg to about 40 mg / kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg / kg to about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.

106. The method or the use of any one of claims 1-104, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

107. The method or the use of any one of claims 1-104, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third -352- 180085204.4Docket No.: 146316.8032.WO00 dose of about 15 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

108. The method or the use of any one of claims 1-104, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

109. The method or the use of any one of claims 1-108, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

110. The method or the use of any one of claims 1-109 wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: -353- 180085204.4Docket No.: 146316.8032.WO00 Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

111. The method or the use of any one of claim 109 or 110, wherein the non- naturally occurring melanocortin analog is cyclized between Glu at R2and and Orn at R7.

112. The method or the use of claim 111, comprising a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

113. The method or the use of claim 109 or 110, wherein R4is p(F)dPhe or dPhe.

114. The method or the use of claim 113, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); and Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45), wherein c represents cyclization through R2and R7via a lactam bond. -354- 180085204.4Docket No.: 146316.8032.WO00 115. The method or the use of claim 113, wherein the non-naturally occurring melanocortin analog comprises a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); or Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44), wherein c represents cyclization through R2and R7via a lactam bond.

116. The method or the use of claim 113, wherein the non-naturally occurring melanocortin analog comprises a sequence of: Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal- dPro-NH2 (SEQ ID NO: 45), wherein c represents cyclization through R2and R7via a lactam bond.

117. The method or the use of claim 109 or 110, wherein R4is p(F)dPhe or p(Cl)dPhe.

118. The method or the use of claim 117, wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

119. The method or the use of claim 109 or 110, wherein R4is para-fluoro-D- phenylalanine (p(F)dPhe).

120. The method or the use of any one of claims 109-119, wherein the non-naturally occurring melanocortin analog comprises a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg- -355- 180085204.4Docket No.: 146316.8032.WO00 Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), wherein c represents cyclization through R2and R7via a lactam bond.

121. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising administering to the subject (i) a weight loss agent and (ii) orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; -356- 180085204.4Docket No.: 146316.8032.WO00 Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

122. The method or the use of any one of claims 1-121, wherein the weight loss agent is present in a first pharmaceutical composition.

123. The method or the use of claim 122, wherein the first pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and / or carriers. -357- 180085204.4Docket No.: 146316.8032.WO00 124. The method or the use of claim 123, wherein the one or more pharmaceutically acceptable excipients and / or carriers of the first pharmaceutical composition comprise water.

125. The method or the use of any one of claims 122-124, wherein the weight loss agent is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

126. The method or the use of claim 125, wherein the weight loss agent is semaglutide and is present in the first pharmaceutical composition in a concentration of 0.5 mg / mL to 5.0 mg / mL, 0.5 mg / mL to 4.0 mg / mL, 0.6 mg / mL to 3.5 mg / mL, 0.65 mg / mL to 3.2 mg / mL, 0.65 mg / mL to 3.0 mg / mL, 0.8 mg / mL to 2.8 mg / mL, 1.0 mg / mL to 3.0 mg / mL, 1.0 mg / mL to 2.8 mg / mL, 1.2 mg / mL to 3.0 mg / mL, 1.2 mg / mL to 2.8 mg / mL, 0.6 mg / mL to 2.3 mg / mL, 0.6 mg / mL to 2.0 mg / mL, 0.6 mg / mL to 1.8 mg / mL, 0.6 mg / mL to 1.5 mg / mL, or 1.3 mg / mL to 2.8 mg / mL, relative to a total volume of the first pharmaceutical composition.

127. The method or the use of claim 125, wherein the weight loss agent is semaglutide and is present in the first pharmaceutical composition in an amount of 0.5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg.

128. The method or the use of claim 125, wherein the weight loss agent is exenatide, and is present in the first pharmaceutical composition in a concentration of 5 µg / mL to 1000 µg / mL, 10 µg / mL to 900 µg / mL, 20 µg / mL to 800 µg / mL, 50 µg / mL to 700 µg / mL, 70 µg / mL to 600 µg / mL, 90 µg / mL to 550 µg / mL, 100 µg / mL to 500 µg / mL, 110 µg / mL to 450 µg / mL, 120 µg / mL to 400 µg / mL, 130 µg / mL to 350 µg / mL, 140 µg / mL to 350 µg / mL, 150 µg / mL to 300 µg / mL, 200 µg / mL to 300 µg / mL, or 200 µg / mL to 250 µg / mL, relative to a total volume of the first pharmaceutical composition.

129. The method or the use of claim 125, wherein the weight loss agent is -358- 180085204.4Docket No.: 146316.8032.WO00 exenatide, and is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 5.0 mg / mL, 0.25 mg / mL to 4.5 mg / mL, 0.5 mg / mL to 4.5 mg / mL, 0.75 mg / mL to 4.0 mg / mL, 1.0 mg / mL to 3.75 mg / mL, 1.25 mg / mL to 3.5 mg / mL, 1.5 mg / mL to 3.25 mg / mL, 1.75 mg / mL to 3.0 mg / mL, 2.0 mg / mL to 2.75 mg / mL, or 2.25 mg / mL to 2.5 mg / mL, relative to a total volume of the first pharmaceutical composition.

130. The method or the use of claim 125, wherein the weight loss agent is dulaglutide and is present in the first pharmaceutical composition in a concentration 0.01 mg / mL to 100 mg / mL, 0.05 mg / mL to 90 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.2 mg / mL to 70 mg / mL, 0.3 mg / mL to 60 mg / mL, 0.5 mg / mL to 50 mg / mL,0.6 mg / mL to 45 mg / mL, 0.7 mg / mL to 40 mg / mL, 0.8 mg / mL to 35 mg / mL, 0.9 mg / mL to 30 mg / mL, 1.0 mg / mL to 25 mg / mL, 1.1 mg / mL to 20 mg / mL, 1.2 mg / mL to 15 mg / mL, or 1.5 mg / mL to 10 mg / mL, relative to a total volume of the first pharmaceutical composition.

131. The method or the use of claim 125, wherein the weight loss agent is orforglipron and is present in the first pharmaceutical composition in an amount of 0.01 mg to 100 mg, 0.05 mg to 90 mg, 0.1 mg to 80 mg, 0.2 mg to 70 mg, 0.3 mg to 60 mg, 0.4 mg to 50 mg, 0.5 mg to 45 mg, 0.6 mg to 40 mg, 0.7 mg to 35 mg, 0.8 mg to 30 mg, 0.9 mg to 25 mg, 1.0 mg to 20 mg, 1.1 mg to 18 mg, 1.2 mg to 16 mg, 1.3 mg to 14 mg, 1.4 mg to 12 mg, or 1.5 mg to 10 mg.

132. The method or the use of any one of claims 122-124, wherein the weight loss agent is a dual GLP-1 / GIP receptor agonist and is present in the first pharmaceutical composition in a concentration of 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

133. The method or the use of claim 132, wherein the dual GLP-1 / GIP receptor agonist is tirzepatide and is present in the first pharmaceutical composition in a concentration of 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, or 30 mg / mL, relative to a total volume of the first pharmaceutical composition. -359- 180085204.4Docket No.: 146316.8032.WO00 134. The method or the use of any one of claims 1 to 122, wherein the weight loss agent is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

135. The method or the use of any one of claims 122-133, wherein the first pharmaceutical composition comprising the weight loss agent is administered to the subject parenterally.

136. The method or the use or the use of any one of claims 122-133, wherein the first pharmaceutical composition comprising the weight loss agent is administered to a subject subcutaneously.

137. The method or the use of any one of claims 1-136, wherein, after administration of the non-naturally occurring melanocortin analog, the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

138. The method or the use of any one of claims 1-137, wherein, after administration of the non-naturally occurring melanocortin analog, the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

139. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a weight loss agent to the subject for at least one treatment cycle, wherein the subject failed to lose sufficient body weight and / or fat mass following administration of the weight loss agent for the at least one treatment cycle; and administering a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) to the subject -360- 180085204.4Docket No.: 146316.8032.WO00 after administration of the weight loss agent, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

140. Use of a non-naturally occurring melanocortin analog and a weight loss agent for reducing body weight and / or fat mass in a subject in need thereof, wherein (i) the weight loss agent is administered to the subject for at least one treatment cycle, wherein the subject failed to lose sufficient body weight and / or fat mass following administration of the weight loss agent for the at least one treatment cycle; and (ii) the non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) is administered to the subject after administration of the weight loss agent, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

141. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a weight loss agent to the subject for at least one treatment cycle, wherein the subject failed to lose sufficient body weight and / or fat mass following administration of the weight loss agent for the at least one treatment cycle; and administering a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) to the subject after administration of the weight loss agent, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

142. Use of a non-naturally occurring melanocortin analog and a weight loss agent for reducing body weight and / or fat mass in a subject in need thereof, wherein: -361- 180085204.4Docket No.: 146316.8032.WO00 (i) the weight loss agent is administered to the subject for at least one treatment cycle, wherein the subject failed to lose sufficient body weight and / or fat mass following administration of the weight loss agent for the at least one treatment cycle; and (ii) non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) is administered to the subject after administration of the weight loss agent, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

143. The method or the use of any one of claims 139-142, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.

144. The method or the use of any one of claims 139-143, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

145. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) to the subject to sensitize the subject to a weight loss agent; and during or after administration of the non-naturally occurring melanocortin analog, administering to the subject the weight loss agent.

146. Use of a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) for reducing body weight and / or fat mass in a subject in need thereof, wherein the non-naturally occurring melanocortin analog is administered to the subject to sensitize the subject to a weight loss agent; and -362- 180085204.4Docket No.: 146316.8032.WO00 during or after administration of the non-naturally occurring melanocortin analog, the weight loss agent is administered to the subject.

147. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) to the subject to sensitize the subject to a weight loss agent; and during or after administration of the non-naturally occurring melanocortin analog, administering to the subject the weight loss agent.

148. Use of a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) for reducing body weight and / or fat mass in a subject in need thereof, wherein the non-naturally occurring melanocortin analog is administered to the subject to sensitize the subject to a weight loss agent; and during or after administration of the non-naturally occurring melanocortin analog, the weight loss agent is administered to the subject.

149. The method or the use of any one of claims 145-148, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.

150. The method or the use of any one of claims 145-149, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

151. A method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent. -363- 180085204.4Docket No.: 146316.8032.WO00 152. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

153. A method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

154. Use of non-naturally occurring melanocortin analog for treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

155. The method or the use of claim 153 or 154, wherein the method or the use further comprises reducing a risk of the cancer.

156. A method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

157. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

158. A method of reducing body weight and / or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent. -364- 180085204.4Docket No.: 146316.8032.WO00 159. Use of a non-naturally occurring melanocortin analog and a weight loss agent for reducing body weight and / or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

160. A method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

161. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

162. A method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

163. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

164. A method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

165. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non- -365- 180085204.4Docket No.: 146316.8032.WO00 naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

166. A method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

167. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

168. A method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

169. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

170. A method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

171. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent. -366- 180085204.4Docket No.: 146316.8032.WO00 172. A method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

173. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing Type 2 Diabetes in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

174. A method of treating, preventing, or reducing Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

175. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing weight gain after a weight loss or a weight loss plateau a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

176. A method of treating, preventing, or reducing weight gain after a weight loss or a weight loss plateau in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

177. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I) and a weight loss agent.

178. A method of promoting weight loss in a subject receiving a weight loss agent, the method comprising administering to the subject a non-naturally occurring melanocortin -367- 180085204.4Docket No.: 146316.8032.WO00 analog comprising Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43) wherein the subject’s weight is decreased by inducing and / or increasing loss of fat mass while maintaining or increasing muscle mass of the subject.

179. Use of a non-naturally occurring melanocortin analog comprising Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43)) for promoting weight loss in a subject receiving a weight loss agent, wherein the non-naturally occurring melanocortin analog is administered to the subject and the subject’s weight is decreased by inducing and / or increasing loss of fat mass while maintaining or increasing muscle mass of the subject.

180. The method or the use of claim 178 or 179, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

181. The method or the use of claim 178 or 179, wherein a plasma insulin level of the subject following administration of the non-naturally occurring melanocortin analog is substantially the same as a plasma insulin level of the subject prior to administration of the non-naturally occurring melanocortin analog.

182. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a combination therapy comprising: (a) weight loss agent; and (b) a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), wherein the subject’s weight is decreased by inducing and / or increasing loss of fat mass while maintaining or increasing muscle mass of the subject.

183. Use of a combination therapy comprising: (a) weight loss agent; and -368- 180085204.4Docket No.: 146316.8032.WO00 (b) a non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), for reducing body weight and / or fat mass in a subject in need thereof, wherein the combination therapy is administered to the subject and the subject’s weight is decreased by inducing and / or increasing loss of fat mass while maintaining or increasing muscle mass of the subject.

184. The method or the use of claim 182 or 183, wherein a blood glucose level of the subject is decreased following administration of a first dose of the combination therapy.

185. The method or the use of any one of claims 182-184, wherein the weight loss agent is semaglutide and the combination therapy has an additive effect on the subject’s weight loss.

186. The method or the use of claim 185, wherein the combination therapy has an additive effect on the subject’s fat mass loss.

187. The method or the use of any one of claims 182-186, wherein a percent lean mass of the subject is increased following administration of a first dose of the combination therapy.

188. The method or the use of claim 185, wherein the combination therapy has an additive effect on suppressing an appetite in the subject.

189. The method or the use of any one of claims 182-184, wherein the weight loss agent is a dual GLP-1 / GIP receptor agonist.

190. The method or the use of claim 189, wherein the dual GLP-1 / GIP receptor agonist is tirzepatide and the combination therapy has a synergistic effect on the subject’s weight loss. -369- 180085204.4Docket No.: 146316.8032.WO00 191. The method or the use of claim 190, wherein the combination therapy has a synergistic effect on the subject’s fat mass loss.

192. The method or the use of any one of claims 120-191, wherein a percent lean mass of the subject is increased following administration of a first dose of the combination therapy.

193. The method or the use of claim 190, wherein the combination therapy has a synergistic effect on the suppressing an appetite level in the subject.

194. The method or the use of any one of claims 1-193, wherein the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in body weight about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non-naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent.

195. The method or the use of any one of claims 1-194, wherein the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, or about a 30% reduction in fat mass about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non-naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent.

196. The method or the use of any one of claims 1-195, wherein the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non- naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent. -370- 180085204.4Docket No.: 146316.8032.WO00 197. The method or the use of any one of claims 1-196, wherein the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% increase in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non- naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent.

198. The method or the use of any one of claims 1-197, wherein the subject exhibits about a 5%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 60%, or about a 70% reduction, in food intake per day about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non-naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent.

199. The method or the use of any one of claims 1-198, wherein the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in blood glucose level about 10 days, about 20 days, or about 30 days after administration of a first dose of (i) the non- naturally occurring melanocortin analog or (ii) a combination of the non-naturally occurring melanocortin analog and the weight loss agent.

200. The method or the use of any one of claims 1-199, wherein the method of the use further comprises one or more of (i) reducing a lipid droplets size (e.g., an average lipid droplet size); (ii) increasing an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; (iv) increasing, maintaining, or preventing a reduction of a beige or brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing, maintaining, or preventing reduction of an insulin sensitivity level, relative to a control. -371- 180085204.4Docket No.: 146316.8032.WO00 201. The method or the use of any one of claims 1-200, wherein the non-naturally occurring melanocortin analog comprises a reduced clearance, and increased concentration, or an increased distribution during or after administration to the subject, relative to a control.

202. The method or the use of claim 201, wherein the clearance is a liver or a liver microsome clearance.

203. The method or the use of claim 201, wherein the concentration is an aqueous concentration.

204. The method or the use of claim 203, wherein the aqueous concentration comprises an intestinal fluid concentration or a gastric fluid concentration. -372- 180085204.4

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