Methods for stimulating appetite and / or increasing weight in subjects with fibrotic diseases using non-naturally occurring melanocortin analogs

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Non-naturally occurring melanocortin analogs are administered to patients with kidney and liver disease to address appetite loss and weight loss, enhancing food intake and weight gain, thus improving treatment tolerance and quality of life.

JP2026507646APending Publication Date: 2026-03-04ENDEVICA BIO INC

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Authority / Receiving Office: JP · JP
Patent Type: Applications
Current Assignee / Owner
Filing Date: 2024-02-17
Publication Date: 2026-03-04

Application Information

Patent Timeline

17 Feb 2024

Application

04 Mar 2026

Publication

JP2026507646A

IPC: C07K14/665; A61K38/33; A61P43/00; A61K9/08; C12N15/16

CPC: A61P13/12; A61P3/00; A61K38/34; C07K14/68

Inventors: ポッターフィールド,ラッセル; デレフ,ジョーダン

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AI Technical Summary

Technical Problem

There is a need for more effective therapeutic agents to stimulate appetite and increase weight in patients with kidney disease and/or liver disease, as loss of appetite and weight loss can lead to malnutrition, muscle loss, and a decline in physical condition, which can hinder medical treatment and reduce quality of life.

Method used

Administration of a therapeutically effective amount of a non-naturally occurring melanocortin analog, such as those with specific amino acid sequences and modifications, to stimulate appetite and increase weight in subjects with kidney and/or liver disease.

Benefits of technology

The non-naturally occurring melanocortin analogs effectively stimulate appetite, increase food consumption, and promote weight gain, including muscle and fat mass, thereby improving the subjects' ability to tolerate and benefit from medical treatment.

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Abstract

Methods are provided for increasing body weight and / or food consumption in subjects with kidney disease and / or liver disease (e.g., chronic kidney disease, renal failure, nonalcoholic fatty liver disease (NAFLD)) using a non-naturally occurring melanocortin analog. Methods are also provided for stimulating a subject's appetite by administering a non-naturally occurring melanocortin analog. The non-naturally occurring melanocortin analog can be present in a pharmaceutical composition and can be delivered via parenteral administration (e.g., subcutaneous injection). The methods improve a subject's appetite, increase food consumption, and increase body weight, muscle mass, and / or fat mass.

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Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 486,232, filed February 21, 2023, and U.S. Provisional Patent Application No. 63 / 541,394, filed September 29, 2023, which are incorporated by reference herein in their entireties.

[0002] SEQUENCE LISTING INCORPORATED BY REFERENCE This application contains a Sequence Listing in accordance with ST.26, which was simultaneously filed via the Patent Center in xml format and is incorporated herein by reference in its entirety. The .xml copy, created on February 16, 2024, is named 146316_8006_WO00_SL.xml and is 1,552,278 bytes in size. [Background technology]

[0003] Melanocortin analogs have been synthesized for the potential treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormone secretion and secretion deficiencies of many exocrine glands (e.g., Sjögren's syndrome), immune-related conditions, and sexual dysfunction.

[0004] Patients suffering from kidney disease (e.g., chronic kidney disease, renal failure) and liver disease (e.g., nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH)) often exhibit symptoms such as vomiting, loss of appetite or appetite loss, and weight loss. If left untreated, loss of appetite or appetite loss (e.g., anorexia) can lead to fatigue, malnutrition, weight loss, loss of muscle mass and / or fat mass, and a decline in overall physical condition. Loss of appetite and / or weight loss are also symptoms of cachexia, a wasting disease that adversely affects a patient's quality of life and survival. The aforementioned symptoms and cachexia may prevent a patient from receiving appropriate medical care or may shorten or reduce the duration or intensity of treatment for treating kidney disease and / or liver disease.

[0005] Despite recent progress, there is still a need to develop more effective therapeutic agents for treating the appetite loss and / or weight loss of patients with kidney disease and / or liver disease.There is also a need for the appetite stimulating method, which can effectively promote appetite, increase food consumption, and increase body weight (for example, muscle mass, fat mass) in patients with kidney disease and / or liver disease.This therapeutic agent can make patients more likely to tolerate and benefit from the therapeutic agent that treats kidney disease and / or liver disease. Summary of the Invention [Means for solving the problem]

[0006] In some embodiments, the subject technology provides a method of stimulating appetite and / or increasing weight in a subject with kidney disease and / or liver disease, comprising: administering to a subject a therapeutically effective amount of a non-naturally occurring melanocortin analog comprising a sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1 is absent or selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (transPro(guan)), cis-4-guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R 2 is absent or selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R 3 is absent or contains histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-( selected from the group consisting of 1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc); R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R 5 is absent or selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R 6 is absent or selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R 7 is absent or selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 is absent or is lysine; R 9 ~R 20 But he is absent, X 1is absent or selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X 2 is absent or is D-proline; X 3 But he is absent, Y 1 is absent or selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y 2 is absent or selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y 3 is absent or selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-aspartic acid or aspartic acid; Y 5 ~Y 8 But he is absent, Non-naturally occurring melanocortin analogs include R 1 is cysteine and R 7 is cysteine, R 1 and R 7 The disulfide bond between R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 7 If is lysine or Dap, R 1 or R 2 and R 7 A side chain lactam bridge between R 2 is lysine and R 7 If is glutamic acid or aspartic acid, R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y 1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 3 is Aba, Ata, or Aia, and R 6 If Aia, then R 4 is not dNal(2') or R4 is dNal(2'), and R 5 is not Arg, R 4 If p(Cl)dPhe, R 3 is not Pro or His, R 4 When is p(I)dPhe, there is no naturally occurring melanocortin analogue R 1 and R 7 is cyclized via a side chain lactam bridge between R 2 and R 3 At least one of the above is Pro, Y 2 ~Y 4 If is absent, Y 1 is absent or is norleucine; R 2 is Pro or Y 2 If is Hyp, then R 3 is not Pro, R 3 , R 5 , or R 6 In the absence of R, the naturally occurring melanocortin analog is 1 and R 7 or cyclized via a lactam bridge between X 1 ~X 2 exists and Ac-dVal-dPro, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro-dNal(2')-Arg-Trp-Cys (SEQ ID NO: 527), 1 is not Ac-Nle or Y 1 ~Y 2 is not dVal-dPro, dVal-dVal, or dPro-dPro; and A naturally occurring melanocortin analogue is R 2 and R 8 If R is cyclized via a lactam bridge between 3 is not His or Y1 is not dVal.

[0007] In some embodiments, the present technology provides for the use of a non-naturally occurring melanocortin analog to stimulate appetite and / or increase weight in a subject with kidney disease and / or liver disease, comprising: A non-naturally occurring melanocortin analog comprises a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1is absent or selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (transPro(guan)), cis-4-guanidinyl-proline (cisPro(guan)), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), tyrosine, D-tyrosine, dimethyltyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R 2 is absent or selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R 3 is absent or contains histidine, L-proline, transPro(guan), cisPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-( selected from the group consisting of 1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (Ioc); R 4is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R 5 is absent or selected from the group consisting of arginine, homoarginine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(I)dPhe; R 6 is absent or selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1'), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R 7 is absent or selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2′), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 is absent or is lysine; R 9 ~R 20 But he is absent, X 1is absent or selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X 2 is absent or is D-proline; X 3 But he is absent, Y 1 is absent or selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y 2 is absent or selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y 3 is absent or selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-aspartic acid or aspartic acid; Y 5 ~Y 8 But he is absent, Non-naturally occurring melanocortin analogs include R 1 is cysteine and R 7 is cysteine, R 1 and R 7 The disulfide bond between R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 7 If is lysine or Dap, R 1 or R 2 and R 7 A side chain lactam bridge between R 2 is lysine and R 7 If is glutamic acid or aspartic acid, R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y 1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 3 is Aba, Ata, or Aia, and R 6 If Aia, then R 4 is not dNal(2') or R4 is dNal(2'), and R 5 is not Arg, R 4 If p(Cl)dPhe, R 3 is not Pro or His, R 4 When is p(I)dPhe, there is no naturally occurring melanocortin analogue R 1 and R 7 is cyclized via a side chain lactam bridge between R 2 and R 3 At least one of the above is Pro, Y 2 ~Y 4 If is absent, Y 1 is absent or is norleucine; R 2 is Pro or Y 2 If is Hyp, then R 3 is not Pro, R 3 , R 5 , or R 6 In the absence of R, the naturally occurring melanocortin analog is 1 and R 7 or cyclized via a lactam bridge between X 1 ~X 2 exists and Ac-dVal-dPro, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys or Cys-Pro-dNal(2')-Arg-Trp-Cys, R 1 is not Ac-Nle or Y 1 ~Y 2 is not dVal-dPro, dVal-dVal, or dPro-dPro; and A naturally occurring melanocortin analogue is R 2 and R 8 If R is cyclized via a lactam bridge between 3 is not His or Y 1This includes use, provided that is not dVal.

[0008] In some embodiments, the N-terminus, if present, is modified with a functional group selected from the group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

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

[0010] In some embodiments, the acyl group is an acetyl group.

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

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

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

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

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

[0016] In some embodiments, the N-terminus, if present, is unmodified.

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

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

[0019] In some embodiments, the amide group is an -NH alkylamide group or an -NH arylamide group.

[0020] In some embodiments, the -NH arylamide group is a p-nitroanilide group or 7-amino-4-methylcoumarin.

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

[0022] In some embodiments, the C-terminus is unmodified.

[0023] In some embodiments, R 1 is absent, and R 2 is D-aspartic acid.

[0024] In some embodiments, X 1 , X 2 , and X 3 is absent.

[0025] In some embodiments, R 4 is D-Nal(2').

[0026] In some embodiments, Y 3 ~Y 8 is absent.

[0027] In some embodiments, Y 1 is D-valine, and Y 2 is D-proline, or Y 1 is D-proline, and Y 2 is D-valine.

[0028] In some embodiments, Y 3 exists and Y 4 ~Y 8 is absent.

[0029] In some embodiments, Y1 is D-valine or D-proline, Y2 is D-valine or D-proline, and / or Y3 is D-valine or D-proline.

[0030] In some embodiments, Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-proline or Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-valine or Y 1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, or Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-proline.

[0031] In some embodiments, Y 3 and Y 4 exists and Y 5 ~Y 8 is absent.

[0032] In some embodiments, Y 1 is D-valine or D-proline, Y 2 is D-valine or D-proline, Y 3 is D-valine or D-proline, and / or Y 4 is D-valine or D-proline.

[0033] In some embodiments, Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-valine, and Y 4 is D-proline or Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-valine, and Y 4 is D-valine or Y1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, and Y 4 is D-valine or Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-proline, and Y 4 is D-valine, or Y 1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, and Y 4 is D-proline.

[0034] In some embodiments, R 1 , R 2 , and R 7 exists and R 8 ~R 20 is absent and the sequence of formula (I) is connected to R via a lactam bond 2 and R 7 It is cyclized through

[0035] In some embodiments, R 1 , R 2 , R 7 , and R 8 exists and R 9 ~R 20 is absent and the sequence of formula (I) is connected to R via a lactam bond 2 and R 8 It is cyclized through In some embodiments, R 1 is acetylated norleucine, R 2 is aspartic acid, R 3 is selected from the group consisting of proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine; R 4 is histidine or dNal(2'), R 5 is dNal(2') or arginine, R6 is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan; R 7 is tryptophan or proline, R 8 is lysine, Y 1 is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y 2 is D-proline.

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

[0037] In some embodiments, a non-naturally occurring melanocortin analog is present in the composition.

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

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

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

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

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

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

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

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

[0046] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is between 0.001 mg / kg and 25 mg / kg of subject body weight.

[0047] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is between 0.5 mg / kg and 10 mg / kg of the subject's body weight.

[0048] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg of subject body weight.

[0049] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg of subject body weight.

[0050] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0051] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

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

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

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

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

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

[0057] In some embodiments, the NAFLD is non-alcoholic steatohepatitis (NASH).

[0058] In some embodiments, the subject experiences decreased appetite, loss of appetite, decreased food consumption, and / or weight loss prior to administration of the non-naturally occurring melanocortin analog.

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

[0060] In some embodiments, the loss of appetite, decreased appetite, decreased food consumption, and / or weight loss is caused by cachexia.

[0061] In some embodiments, the method or use (i) stimulates the appetite of a subject, (ii) increases food consumption by a subject, (iii) prevents or alleviates nausea, vomiting, and / or anorexia in a subject, (iv) increases or maintains the body weight of a subject, (v) prevents or reduces weight loss in a subject, (vi) increases or maintains muscle mass in a subject, (vii) prevents or reduces muscle mass loss in a subject, (viii) increases or maintains fat mass in a subject, and / or (ix) prevents or reduces fat mass loss in a subject.

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

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

[0064] In some embodiments, the subject's appetite is increased by at least 25% to 100% after administration of the non-naturally occurring melanocortin analog.

[0065] In some embodiments, appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during administration of the non-naturally occurring melanocortin analog.

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

[0067] In some embodiments, the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after administration of the non-naturally occurring melanocortin analog is discontinued.

[0068] In some embodiments, appetite is assessed by a scale to measure desire to eat, hunger, and / or satiety levels.

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

[0070] In some embodiments, the subjects include two or more subjects and the appetite is the average appetite of the two or more subjects.

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

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

[0073] In some embodiments, food consumption is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during administration of the non-naturally occurring melanocortin analog.

[0074] In some embodiments, food consumption is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during administration of the non-naturally occurring melanocortin analog.

[0075] In some embodiments, the increased food consumption is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after administration of the non-naturally occurring melanocortin analog is discontinued.

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

[0077] In some embodiments, the loss of appetite is determined by food consumption.

[0078] In some embodiments, the subject's body weight increases by at least 5% to 200% after administration of the non-naturally occurring melanocortin analog.

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

[0080] In some embodiments, the subject's body weight increases by at least 20% to 100% after administration of the non-naturally occurring melanocortin analog.

[0081] In some embodiments, the gained weight is maintained for at least 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 is discontinued.

[0082] In some embodiments, the subject's muscle mass is increased by at least 1% to 100% following administration of the non-naturally occurring melanocortin analog.

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

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

[0085] In some embodiments, the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after administration of the non-naturally occurring melanocortin analog is discontinued.

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

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

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

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

[0090] In some embodiments, the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years after administration of the non-naturally occurring melanocortin analog is discontinued.

[0091] In some embodiments, the method or use stimulates appetite in a subject relative to a control subject with renal or liver disease, wherein the control subject is not administered the non-naturally occurring melanocortin analogue.

[0092] In some embodiments, the control subject experiences decreased appetite, loss of appetite, decreased food consumption, and / or weight loss.

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

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

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

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

[0097] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m 2 to 35 kg / m 2 .

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

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

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

[0101] In some embodiments, the subject experiences no adverse events following administration of the non-naturally occurring melanocortin analog.

[0102] In some embodiments, the subject experiences no adverse events attributable to the non-naturally occurring melanocortin analog following administration.

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

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

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

[0106] In some embodiments, the subject is cachectic before the non-naturally occurring melanocortin analog is administered.

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

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

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

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

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

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

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

[0114] In some embodiments, the subject does not meet the Fearon weight loss criteria. [Brief explanation of the drawings]

[0115] [Figure 1A]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included HS024 (TFA) (SEQ ID NO: 525). [Figure 1B]

[0023] Figure 3 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E1 (Figure 3B, SEQ ID NO: 15). [Figure 1C]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E2 (SEQ ID NO: 16). [Figure 1D]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E3 (SEQ ID NO: 17). [Figure 1E]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E4 (SEQ ID NO: 18). [Figure 1F]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E5 (SEQ ID NO: 19). [Figure 1G]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E6 (SEQ ID NO: 20). [Figure 1H]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E7 (SEQ ID NO: 21). [Figure 1I]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E8 (SEQ ID NO: 22). [Figure 1J]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E9 (SEQ ID NO: 23). [Figure 1K]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E10 (SEQ ID NO: 24). [Figure 1L]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E11 (SEQ ID NO: 25). [Figure 1M]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E12 (SEQ ID NO: 26). [Figure 1N]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E13 (SEQ ID NO: 27). [Figure 1O]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E14 (SEQ ID NO: 28). [Figure 1P]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E15 (SEQ ID NO: 29). [Figure 1Q]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E16 (SEQ ID NO: 30). [Figure 1R]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E17 (SEQ ID NO: 31). [Figure 1S]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E18 (SEQ ID NO: 32). [Figure 1T]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E19 (SEQ ID NO: 35). [Figure 1U]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E20 (SEQ ID NO: 36). [Figure 1V]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included E21 (SEQ ID NO: 37). [Figure 1W]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F1 (SEQ ID NO: 40). [Figure 1X]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F2 (SEQ ID NO: 41). [Figure 1Y]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F3 (SEQ ID NO: 42). [Figure 1Z]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F4 (SEQ ID NO: 43). [Figure 1AA]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F5 (SEQ ID NO: 44). [Figure 1BB]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F6 (SEQ ID NO: 50). [Figure 1CC]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F7 (SEQ ID NO: 51). [Figure 1DD]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F8 (SEQ ID NO: 52). [Figure 1EE]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F9 (SEQ ID NO: 53). [Figure 1FF]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F10 (SEQ ID NO: 54). [Figure 1GG]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F11 (SEQ ID NO: 55). [Figure 1HH]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F12 (SEQ ID NO: 56). [Figure 1II]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F13 (SEQ ID NO: 57). [Figure 1JJ]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F14 (SEQ ID NO: 58). [Figure 1KK]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F15 (SEQ ID NO: 59). [Figure 1LL]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F16 (SEQ ID NO: 60). [Figure 1MM]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F17 (SEQ ID NO: 61). [Figure 1NN]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F18 (SEQ ID NO: 62). [Figure 100]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F19 (SEQ ID NO: 63). [Figure 1PP]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F20 (SEQ ID NO: 64). [Figure 1QQ]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F21 (SEQ ID NO: 65). [Figure 1RR]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F22 (SEQ ID NO: 45). [Figure 1SS]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F23 (SEQ ID NO: 46). [Figure 1TT]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F24 (SEQ ID NO: 47). [Figure 1UU]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F25 (SEQ ID NO: 48). [Figure 1VV]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F26 (SEQ ID NO: 49). [Figure 1WW]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F28 (SEQ ID NO: 67). [Figure 1XX]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F29 (SEQ ID NO: 68). [Figure 1YY]

[0023] Figure 1 illustrates the percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to an embodiment of the present technology. Examples of non-naturally occurring melanocortin analogs included F30 (SEQ ID NO: 69). [Figure 2A]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G5 (SEQ ID NO: 77). [Figure 2B]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G6 (SEQ ID NO: 78). [Figure 2C]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G7 (SEQ ID NO: 75). [Figure 2D]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G8 (SEQ ID NO: 74). [Figure 2E]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G9 (SEQ ID NO: 79). [Figure 2F]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G10 (SEQ ID NO: 80). [Figure 2G]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G11 (SEQ ID NO: 81). [Figure 2H]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G12 (SEQ ID NO: 82). [Figure 2I]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G13 (SEQ ID NO: 83). [Figure 2J]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G15 (SEQ ID NO: 85). [Figure 2K]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G17 (SEQ ID NO: 211). [Figure 2L]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G18 (SEQ ID NO: 212). [Figure 2M]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G19 (SEQ ID NO: 213). [Figure 2N]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: G20 (SEQ ID NO: 214). [Figure 2O]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H1 (SEQ ID NO: 97). [Figure 2P]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H2 (SEQ ID NO: 98). [Figure 2Q]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H3 (SEQ ID NO: 99). [Figure 2R]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H4 (SEQ ID NO: 100). [Figure 2S]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H5 (SEQ ID NO: 101). [Figure 2T]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H6 (SEQ ID NO: 102). [Figure 2U]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H7 (SEQ ID NO: 103). [Figure 2V]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H8 (SEQ ID NO: 104). [Figure 2W]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H9 (SEQ ID NO: 105). [Figure 2X]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H10 (SEQ ID NO: 106). [Figure 2Y]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H11 (SEQ ID NO: 107). [Figure 2Z]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H12 (SEQ ID NO: 108). [Figure 2AA]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H13 (SEQ ID NO: 109). [Figure 2BB]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H14 (SEQ ID NO: 110). [Figure 2CC]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: H15 (SEQ ID NO: 111). [Figure 2DD]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I1 (SEQ ID NO: 112). [Figure 2EE]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I2 (SEQ ID NO: 113). [Figure 2FF]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I3 (SEQ ID NO: 119). [Figure 2GG]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I4 (SEQ ID NO: 115). [Figure 2HH]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I5 (SEQ ID NO: 120). [Figure 2II]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included:

[0025] I6 (SEQ ID NO: 121). [Figure 2JJ]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I7 (SEQ ID NO: 116). [Figure 2KK]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I8 (SEQ ID NO: 117). [Figure 2LL]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I9 (SEQ ID NO: 122). [Figure 2MM]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I10 (SEQ ID NO: 123). [Figure 2NN]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I11 (SEQ ID NO: 118). [Figure 2OO]

[0023] Figure 1 illustrates percent activation of MC3R after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Examples of non-naturally occurring melanocortin analogs included:

[0024] Examples of non-naturally occurring melanocortin analogs included: I12 (SEQ ID NO: 124). [Figure 3A]