Non-naturally occurring melanocortin analogs and uses thereof for modulating weight gain

Abstract

Provided herein are 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 alone or in combination with a weight loss agent. The methods reduce lean mass loss, maintain lean mass, or promote lean mass gain in the subject. The methods also reduce adverse effects associated with weight loss agents and / or melanocortin analogs.

Description

Docket No.: 146316.8017.WO00 NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND USES THEREOF FOR MODULATING WEIGHT GAIN CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 607,500, filed December 7, 2023, U.S. Provisional Patent Application No. 63 / 618,843, filed January 8, 2024, U.S. Provisional Patent Application No.63 / 557,385, filed February 23, 2024, U.S. Provisional Patent Application No. 63 / 573,429, filed April 2, 2024, U.S. Provisional Patent Application No.63 / 650,705, filed May 22, 2024, U.S. Provisional Patent Application No.63 / 656,583, filed June 5, 2025, and U.S. Provisional Patent Application No. 63 / 663,648, filed June 24, 2024, all of which applications 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 created on December 9, 2024, is titled “146316_8017_WO00_SL.xml” and is 421,967 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.

[0004] Accordingly, despite recent advances treatment for obesity, diabetes, and metabolic syndrome, there is a demand for novel approaches to make weight loss agents more effective.Docket No.: 146316.8017.WO00 SUMMARY

[0005] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, including administering to the subject: (a) a GLP-1 receptor agonist; 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.

[0006] In some embodiments, the present technology comprises use of (a) a non- naturally occurring melanocortin analog and (b) a GLP-1 receptor agonist for reducing body weight and / or fat mass in a subject in need thereof 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 reducing body weight and / or fat mass in a subject in need thereof, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4- guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridgeDocket No.: 146316.8017.WO00 between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal- dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0008] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9;Docket No.: 146316.8017.WO00 when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal- dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0009] In some embodiments, the present technology comprises a method or the use, wherein the method further includes reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

[0010] In some embodiments, the present technology comprises a method 5, wherein the lean mass is lean muscle mass.

[0011] In some embodiments, the present technology comprises a method or the use, wherein the method further includes treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.

[0012] In some embodiments, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, including administering to the subject: (a) a GLP-1 receptor agonist; 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.

[0013] In some embodiments, the present technology comprises use of (a) a non- naturally occurring melanocortin analog and (b) a GLP-1 receptor agonist for treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof to produce a synergistic or additive effect on glucose intolerance and / or diabetes mellitus in the subject

[0014] In some embodiments, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula: X1-R1-R2-R3-R4-R5-R6-R7-R8-R9- Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys),Docket No.: 146316.8017.WO00 proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C- terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0015] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog for treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1-R1-R2-R3-R4-R5- R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanineDocket No.: 146316.8017.WO00 (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C- terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0016] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

[0017] In some embodiments, the present technology comprises a method or the use, wherein the lean mass is lean muscle mass.

[0018] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes reducing body weight and / or fat mass in the subject.

[0019] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes treating, preventing, reducing, or otherwise ameliorating a sleep disorder in the subject.Docket No.: 146316.8017.WO00

[0020] In some embodiments, the present technology comprises a method or the use, wherein the sleep disorder is sleep apnea.

[0021] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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.

[0022] In some embodiments, the present technology comprises a method or the use, 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 GLP-1 receptor agonist or the dual GLP-1 / GIP receptor agonist.

[0023] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is semaglutide and is administered at a dose of about 0.01 mg to about 10 mg once per week.

[0024] In some embodiments, the present technology comprises a method or the use, 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.

[0025] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is semaglutide and is administered at a dose of about 0.5 mg to about 40 mg once daily.

[0026] In some embodiments, the present technology comprises a method or the use, wherein semaglutide is administered orally at a dose of less than 3 mg, 7 mg or 14 mg once daily.

[0027] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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.

[0028] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is exenatide and is administered at a dose of about 0.5 mg to about 100 mg twice daily.Docket No.: 146316.8017.WO00

[0029] In some embodiments, the present technology comprises a method or the use, wherein exenatide is administered subcutaneously at a dose of less than 5 mg or 10 mg twice daily.

[0030] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is exenatide and is administered at a dose of about 0.5 mg to about 50 mg once per week.

[0031] In some embodiments, the present technology comprises a method or the use, wherein exenatide is administered subcutaneously at a dose of less 2 mg once per week.

[0032] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is dulaglutide and is administered at a dose of about 0.05 mg to about 50 mg once per week.

[0033] In some embodiments, the present technology comprises a method or the use, 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.

[0034] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is orforglipron and is administered at a dose of about 0.01 mg to about 100 mg once daily.

[0035] In some embodiments, the present technology comprises a method or the use, 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.

[0036] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is a dual GLP-1 / GIP receptor agonist.

[0037] In some embodiments, the present technology comprises a method or the use, 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.

[0038] In some embodiments, the present technology comprises a method or the use, 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.Docket No.: 146316.8017.WO00

[0039] In some embodiments, the present technology comprises a method or the use, 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 body weight of the subject once every three days.

[0040] In some embodiments, the present technology comprises a method or the use, 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.

[0041] In some embodiments, the present technology comprises a method or the use, 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.

[0042] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

[0043] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0044] In some embodiments, the present technology comprises a method or the use, wherein the melanocortin 4 receptor agonist is an agonist of the melanocortin 3 receptor.

[0045] In some embodiments, the present technology comprises a method or the use, wherein the melanocortin 4 receptor agonist is a full agonist of the melanocortin 3 receptor.

[0046] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin agonist includes no melanocortin 3 receptor antagonist activity.

[0047] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to administration of the GLP-1 receptor agonist, and wherein administration of the non- naturally occurring melanocortin analog makes the subject more responsive to the GLP-1 receptor agonist, compared to a subject who has not been administered the non-naturally occurring melanocortin 4 receptor analog.Docket No.: 146316.8017.WO00

[0048] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin agonist is administered to the subject after administration of the GLP-1 receptor agonist, and wherein the subject failed to lose sufficient body weight and / or fat mass following administration with the GLP-1 receptor agonist without the non-naturally occurring melanocortin analog.

[0049] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered to the subject after administration of the GLP-1 receptor agonist for one dose, one week, or one cycle.

[0050] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered to the subject after treatment with the GLP-1 receptor agonist is complete.

[0051] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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 GLP-1 receptor agonist is paused, and wherein, when administration of the non-naturally occurring melanocortin analog is completed, administration of the GLP-1 receptor agonist is resumed.

[0052] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog is administered to the subject for a period of time before administration of the GLP-1 receptor agonist, and wherein, while the non-GLP-1 receptor agonist is administered to the subject, administration of the non- naturally occurring melanocortin analog is paused, and wherein, when administration of the GLP-1 receptor agonist is completed, administration of the non-naturally occurring melanocortin analog is resumed.

[0053] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes preventing or reducing one or more side effects associated with the GLP-1 receptor agonist.Docket No.: 146316.8017.WO00

[0054] In some embodiments, the present technology comprises a method or the use, wherein the one or more side effects associated with the GLP-1 receptor agonist is a gastrointestinal effect.

[0055] In some embodiments, the present technology comprises a method or the use, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea.

[0056] In some embodiments, the present technology comprises a method or the use, wherein the one or more side effects associated with the GLP-1 receptor agonist is an adverse cardiovascular event.

[0057] In some embodiments, the present technology comprises a method or the use, 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.

[0058] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes preventing or reducing one or more side effects associated with the non-naturally occurring melanocortin analog.

[0059] In some embodiments, the present technology comprises a method or the use, wherein the one or more side effects associated with the non-naturally occurring melanocortin analog is an adverse cardiovascular event.

[0060] In some embodiments, the present technology comprises a method or the use, wherein the adverse cardiovascular event is sinus tachycardia.

[0061] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes reducing obesity-related inflammation in the subject.

[0062] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes preserving or improving kidney function in the subject.Docket No.: 146316.8017.WO00

[0063] In some embodiments, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with the use of a GLP-1 receptor agonist in a subject, including administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the GLP-1 receptor agonist.

[0064] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin receptor agonist for treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with the use of a GLP-1 receptor agonist in a subject, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the GLP-1 receptor agonist.

[0065] In some embodiments, the present technology comprises a method or the use, 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 GLP-1 receptor agonist required to elicit weight loss in the subject without the non-naturally occurring melanocortin analog.

[0066] In some embodiments, the present technology comprises a method or the use, wherein the one or more side effects associated with the use of a GLP-1 receptor agonist is an adverse cardiovascular event.

[0067] In some embodiments, the present technology comprises a method or the use, 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.

[0068] In some embodiments, the present technology comprises a method or the use, wherein the one or more side effects associated with the use of the GLP-1 receptor agonist is a gastrointestinal effect.

[0069] In some embodiments, the present technology comprises a method or the use, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea.Docket No.: 146316.8017.WO00

[0070] In some embodiments, the present technology comprises a method of reducing obesity-related inflammation in a subject in need thereof, including administering to the subject: (a) a GLP-1 receptor agonist; 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 GLP-1 receptor agonist

[0071] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist 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 GLP-1 receptor agonist.

[0072] In some embodiments, the present technology comprises a method of reducing obesity-related inflammation in a subject in need thereof, including administering to the subject a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4- guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 orDocket No.: 146316.8017.WO00 R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal- dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0073] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog for reducing obesity-related inflammation in a subject in need thereof, wherein the non-naturally occurring melanocortin analog includes a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3Docket No.: 146316.8017.WO00 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0074] In some embodiments, the present technology comprises a method of preserving or improving kidney function in a subject in need thereof, including administering to the subject: (a) a GLP-1 receptor agonist; 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 GLP-1 receptor agonist.

[0075] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist 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 GLP-1 receptor agonist.

[0076] In some embodiments, the present technology comprises a method of preserving or improving kidney function in a subject in need thereof, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal,Docket No.: 146316.8017.WO00 dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0077] In some embodiments, the present technology comprises use of 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 includes a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, andDocket No.: 146316.8017.WO00 R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0078] In some embodiments, the present technology comprises a method or the use, 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.

[0079] In some embodiments, the present technology comprises a method or the use, wherein the method or the use increases tolerance for the GLP-1 receptor agonist relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0080] In some embodiments, the present technology comprises a method or the use, wherein the increased tolerance includes reduced nausea.

[0081] In some embodiments, the present technology comprises a method or the use, wherein the method or the use maintains or increases a muscle mass level relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0082] In some embodiments, the present technology comprises a method or the use, wherein the muscle mass includes lean muscle mass.

[0083] In some embodiments, the present technology comprises a method or the use, wherein the method or the use increases a preference level or a compliance level for the GLP-1 receptor agonist relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.Docket No.: 146316.8017.WO00

[0084] In some embodiments, the present technology comprises a method or the use, wherein the method or the use includes increasing a weight loss level for the GLP-1 receptor agonist relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0085] In some embodiments, the present technology comprises a method or the use, wherein the method or the use includes a reduction in one or more side effects associated with the GLP-1 receptor agonist relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0086] In some embodiments, the present technology comprises a method or the use, wherein the method or the use includes reducing a weight loss plateau for the GLP-1 receptor agonist relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0087] In some embodiments, the present technology comprises a method or the use, wherein the method or the use reduces an appetite level or a weight gain level relative to a treatment including administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

[0088] In some embodiments, the present technology comprises a method or the use, wherein the method or the use does not reduce efficacy of the GLP-1 receptor agonist relative to a control.

[0089] In some embodiments, the present technology comprises a method or the use, wherein the method or the use increases efficacy of the GLP-1 receptor agonist relative to a control.

[0090] In some embodiments, the present technology comprises a method or the use, wherein the method or the use does not plateau body weight loss in the subject.

[0091] In some embodiments, the present technology comprises a method or the use, wherein the method or the use does not plateau fat mass loss in the subject.Docket No.: 146316.8017.WO00

[0092] In some embodiments, the present technology comprises a method or the use, wherein the method or the use prevents fat mass gain after administration of the GLP-1 receptor agonist relative to a control.

[0093] In some embodiments, the present technology comprises a method or the use, wherein the method or the use prevents body weight gain after administration of the GLP-1 receptor agonist relative to a control.

[0094] In some embodiments, the present technology comprises a method or the use, wherein the method or the use reduces body weight gain after administration of the GLP-1 receptor agonist relative to a control.

[0095] In some embodiments, the present technology comprises a method or the use, wherein the method or the use reduces fat mass gain after administration of the GLP-1 receptor agonist relative to a control.

[0096] In some embodiments, the present technology comprises a method or the use, wherein the method or the use reduces a blood sugar level in the subject relative to a control.

[0097] In some embodiments, the present technology comprises a method or the use, wherein the method or the use prevents a blood sugar elevation in the subject after administration of the GLP-1 receptor agonist relative to a control.

[0098] In some embodiments, the present technology comprises a method or the use, wherein the method or the use reduces a blood sugar elevation in the subject after administration of the GLP-1 receptor agonist relative to a control.

[0099] In some embodiments, the present technology comprises a method or the use, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the GLP-1 receptor agonist relative to a control.

[0100] In some embodiments, the present technology comprises a method or the use, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the GLP-1 receptor agonist relative to a control.

[0101] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence of FormulaDocket No.: 146316.8017.WO00 (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that: when one or both of R2 and R3 is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1 and Lys a R9; when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present and Y4 is absent, or (ii) X1, Y3, and Y4 are absent, R1 is Nle, R4 is dPhe, R5 is Arg, R6 is Trp, Y1Y2 is dVal- dPro, and the C-terminus is amidated; and when R2 is Ala, then X1 is Nle.

[0102] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is 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); R2 is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3 is selected from the groupDocket No.: 146316.8017.WO00 consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4 is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2'-D-naphthylalanine (dNal(2')); R7 is selected from the group consisting of Arg, Pro, cysteine (Cys) and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 or R8 is Lys; and a lactam bridge between R1 and R9 when R1 is Asp, R6 is dPhe, and R9 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412); Ac-Nle- c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423); Ac-Nle-c[Asp-Phe- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c[Asp-Phe-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 225); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 306); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac- dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Lys-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-His-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-Docket No.: 146316.8017.WO00 NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c[Asp-Pro- dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 437); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440); Ac-dHis- c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441); Ac-Nle-Nle-c[Asp- Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c[Asp-Pro-p(F)dPhe- His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')- Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle- dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal- dVal-dPro-NH2 (SEQ ID NO: 447); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal- dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg- c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-Arg-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg- Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 456); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 457); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-Nle-Docket No.: 146316.8017.WO00 c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597); Ac-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); Ac- Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); Ac-dLys-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); Ac-His-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 646); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

[0103] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4 (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3 is His or dHis; R4 is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5 is His or Arg; R6 is tryptophan (Trp); R7 is Pro or lysine (Lys); R8 is absent or lysine (Lys); Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is dVal or dPro; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; provided that when R2 is Ala, then X1 is Nle.

[0104] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);Docket No.: 146316.8017.WO00 R2 is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3 is His or dHis; R4 is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5 is His or Arg; R6 is tryptophan (Trp); R7 is Pro or lysine (Lys); R8 is absent or lysine (Lys); Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is dVal or dPro; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; provided that the non-naturally occurring melanocortin analog does not include the sequence: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 382).

[0105] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB): X1-R1-R2-His-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4 (IB), wherein: X1 is absent or is norleucine (Nle); R1 is selected from the group consisting of Nle, Arg, dArg, alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is Asp; R4 is D- phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5 is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl- proline (transPro(guan)); R6 is tryptophan (Trp) or 2'-D-naphthylalanine (dNal(2')); R7 is Pro or Lys; R8 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R7 or R8 when R2 is Asp, and R7 or R8 is Lys.

[0106] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB), wherein: X1 is absent or is norleucine (Nle); R1 is selected from the group consisting of Nle, Arg, lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is Asp; R4 is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5 is His or Arg; R6 is tryptophan (Trp); R7 is Pro or Lys; R8 is absent or Lys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 isDocket No.: 146316.8017.WO00 dVal or dPro; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R7 or R8 when R2 is Asp, and R7 or R8 is Lys.

[0107] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC): X1-R1-R2-His-R4-R5-R6-R7-Y1-Y2 (IC), wherein: X1 is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1 is aspartic acid (Asp); R2 is alanine (Ala) or D-alanine (dAla); R4 is D-phenylalanine (dPhe); R5 is Arg; R6 is tryptophan (Trp); R7 is Lys; Y1 is D- valine (dVal); Y2 is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2 and Lys at R7; provided that when R2 is Ala, then X1 is Nle.

[0108] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC), wherein: X1 is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1 is aspartic acid (Asp); R2 is alanine (Ala) or D-alanine (dAla); R4 is D-phenylalanine (dPhe); R5 is Arg; R6 is tryptophan (Trp); R7 is Lys; Y1 is D-valine (dVal); Y2 is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2 and Lys at R7; provided that the non-naturally occurring melanocortin analog does not include a sequence of: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

[0109] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3 (ID), wherein: X1 is absent or is norleucine (Nle); R1 is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2 is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro); R3 is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4 is selected from the group consisting of D- phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D- phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, cis-4-guanidinyl-Docket No.: 146316.8017.WO00 proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is tryptophan (Trp) or 2'-D-naphthylalanine (dNal(2')); R7 is cysteine (Cys) or lysine (Lys); Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; and a lactam bridge between R1 or R2 and R7 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 is Lys; provided that: when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are present, or (ii) X1 and Y3 are absent, R1 is Nle, R5 is Arg, R6 is Trp, Y1Y2 is dVal-dPro, and the C-terminus is amidated; when R4 is dPhe, then (i) R3 is not His or Gln or (ii) R3 is His and either R2 is Pro or R5 is transPro(guan) or cisPro(guan); and when R4 is p(F)dPhe, R3 is His, and R1 is Nle, then (i) R6 is not Trp or (ii) Y3 is dVal.

[0110] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID), wherein: X1 is absent or is norleucine (Nle); R1 is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2 is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro); R3 is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4 is selected from the group consisting of D-phenylalanine (dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6 is tryptophan (Trp) or 2'-D-naphthylalanine (dNal(2')); R7 is cysteine (Cys) or lysine (Lys); Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; and a lactam bridge between R1 or R2 and R7 when R1 or R2 is Asp, R4 is dPhe or p(F)dPhe, and R7 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:Docket No.: 146316.8017.WO00 225); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle- c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp- Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp- Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 453); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 641); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle- c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621); Ac-Nle-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-Nle-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]- dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-Docket No.: 146316.8017.WO00 dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro- dVal-dPro-NH2 (SEQ ID NO: 478).

[0111] In some embodiments, the present technology comprises a method or the use, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

[0112] In some embodiments, the present technology comprises a method or the use, wherein the acyl group is an acetyl group.

[0113] In some embodiments, the present technology comprises a method or the use, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0114] In some embodiments, the present technology comprises a method or the use, wherein a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

[0115] In some embodiments, the present technology comprises a method or the use, wherein a C-terminus of the non-naturally occurring melanocortin analog is not modified.

[0116] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond.

[0117] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R2 and R7.

[0118] In some embodiments, the present technology comprises a method or the use, wherein R4 is dPhe or p(F)dPhe.

[0119] In some embodiments, the present technology comprises a method or the use, wherein R3 is His.

[0120] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-c[Asp-His-Docket No.: 146316.8017.WO00 dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp- Lys]-dPro-dVal-NH2 (SEQ ID NO: 621), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0121] In some embodiments, the present technology comprises a method or the use, wherein R4 is p(F)dPhe.

[0122] In some embodiments, the present technology comprises a method or the use, wherein R1 is selected from the group consisting of Ala, Arg, dArg, Lys, dLys, His, and dHis.

[0123] In some embodiments, the present technology comprises a method or the use, wherein Y1 is dVal and Y2 is dPro.

[0124] In some embodiments, the present technology comprises a method or the use and 117-119, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Arg- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 467); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 468), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0125] In some embodiments, the present technology comprises a method or the use, wherein Y1 is dTle and Y2 is dPro.

[0126] In some embodiments, the present technology comprises a method or the use, 117, 118, and 121, wherein the sequence according of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 479); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481); Ac- Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp- His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Docket No.: 146316.8017.WO00 Lys]-dTle-dPro-NH2 (SEQ ID NO: 485), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0127] In some embodiments, the present technology comprises a method or the use, wherein R4 is p(F)dPhe.

[0128] In some embodiments, the present technology comprises a method or the use, wherein at least one of X1, Y3, and Y4 is present.

[0129] In some embodiments, the present technology comprises a method or the use, 124, and 123, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474); Ac- Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp- His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0130] In some embodiments, the present technology comprises a method or the use, wherein R5 is selected from the group consisting of His, transPro(guan) and cisPro(gaun).

[0131] In some embodiments, the present technology comprises a method or the use and 126, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229); and Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0132] In some embodiments, the present technology comprises a method or the use, wherein R6 is dNal(2').

[0133] In some embodiments, the present technology comprises a method or the use and 128, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-His- p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 471), wherein c represents cyclization through R2 and R7 via a lactam bond.Docket No.: 146316.8017.WO00

[0134] In some embodiments, the present technology comprises a method or the use, wherein R3 is not His.

[0135] In some embodiments, the present technology comprises a method or the use and 130, wherein R3 is selected from the group consisting of dHis, Gln, and Pro.

[0136] In some embodiments, the present technology comprises a method or the use, 130, and 131, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle- c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c[Asp-Gln- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491); and Ac-Nle-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0137] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R1 and R7 or R2 and R8.

[0138] In some embodiments, the present technology comprises a method or the use and 133, wherein R4 is dPhe.

[0139] In some embodiments, the present technology comprises a method or the use, 133, and 134, wherein R3 is His.

[0140] In some embodiments, the present technology comprises a method or the use and 133-135, wherein X1 and R1 are present.

[0141] In some embodiments, the present technology comprises a method or the use and 133-136, wherein R2 is Ala or dAla.

[0142] In some embodiments, the present technology comprises a method or the use and 133-137, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378); Ac- dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);and Ac-Nle-Docket No.: 146316.8017.WO00 c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380), wherein c represents cyclization through R1 and R7 via a lactam bond.

[0143] In some embodiments, the present technology comprises a method or the use and 133-135, wherein either R2 of R7 is Pro.

[0144] In some embodiments, the present technology comprises a method or the use, 133-135, and 139, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418). wherein c represents cyclization through R2 and R7 via a lactam bond.

[0145] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R1 and R9.

[0146] In some embodiments, the present technology comprises a method or the use and 141, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-Phe-Phe- Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 420), wherein c represents cyclization through R1 and R9 via a lactam bond.

[0147] In some embodiments, the present technology comprises a method or the use, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a disulfide bond.

[0148] In some embodiments, the present technology comprises a method or the use and 142, wherein R4 is p(Cl)dPhe.

[0149] In some embodiments, the present technology comprises a method or the use, 142, and 143, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[dCys-His- p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498), wherein c represents cyclization through R2 and R7 via a disulfide bond.

[0150] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498.Docket No.: 146316.8017.WO00

[0151] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486.

[0152] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621.

[0153] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621.

[0154] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 268 and 378-380.

[0155] In some embodiments, the present technology comprises a method or the use, wherein the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498.

[0156] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is present in a first pharmaceutical composition.

[0157] In some embodiments, the present technology comprises a method or the use, wherein the first pharmaceutical composition includes one or more pharmaceutically acceptable excipients and / or carriers.

[0158] In some embodiments, the present technology comprises a method or the use, wherein the one or more pharmaceutically acceptable excipients and / or carriers of the first pharmaceutical composition include water.

[0159] In some embodiments, the present technology comprises a method or the use, wherein 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, relative to a total volume of the first pharmaceutical composition.Docket No.: 146316.8017.WO00

[0160] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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.

[0161] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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.

[0162] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is exenatide, and is present in the first pharmaceutical composition in a concentration of 5 mg / mL to 1000 mg / mL, 10 mg / mL to 900 mg / mL, 20 mg / mL to 800 mg / mL, 50 mg / mL to 700 mg / mL, 70 mg / mL to 600 mg / mL, 90 mg / mL to 550 mg / mL, 100 mg / mL to 500 mg / mL, 110 mg / mL to 450 mg / mL, 120 mg / mL to 400 mg / mL, 130 mg / mL to 350 mg / mL, 140 mg / mL to 350 mg / mL, 150 mg / mL to 300 mg / mL, 200 mg / mL to 300 mg / mL, or 200 mg / mL to 250 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0163] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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 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.

[0164] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is dulaglutide and is present in the first pharmaceuticalDocket No.: 146316.8017.WO00 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.

[0165] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist 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.

[0166] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor 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.

[0167] In some embodiments, the present technology comprises a method or the use, 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.

[0168] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0169] In some embodiments, the present technology comprises a method or the use, wherein the first pharmaceutical composition including the GLP-1 receptor agonist is administered to the subject parenterally.Docket No.: 146316.8017.WO00

[0170] In some embodiments, the present technology comprises a method or the use, wherein the first pharmaceutical composition including the GLP-1 receptor agonist is administered to a subject subcutaneously.

[0171] In some embodiments, the present technology comprises a method or the use, 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.

[0172] In some embodiments, the present technology comprises a method or the use, 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.

[0173] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, including: administering a GLP-1 receptor agonist 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 GLP-1 receptor agonist for the at least one treatment cycle; and administering a non-naturally occurring melanocortin analog including a sequence of SEQ ID NO: 295 to the subject after administration of the GLP-1 receptor agonist, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

[0174] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog including a sequence of SEQ ID NO: 295 for reducing body weight and / or fat mass in a subject in need thereof who has failed to lose sufficient body weight and / or fat mass following administration of a GLP-1 receptor agonist for at least one treatment cycle, wherein the non-naturally occurring melanocortin analog is administered after administration of the GLP-1 receptor agonist such that the subject loses a sufficient amount of body weight and / or fat mass.Docket No.: 146316.8017.WO00

[0175] In some embodiments, the present technology comprises a method of promoting weight loss in a subject currently being administered a GLP-1 receptor agonist, the method including administering to the subject a non-naturally occurring melanocortin analog, 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.

[0176] In some embodiments, the present technology comprises use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist for reducing body weight and / or fat mass in a subject in need thereof, 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.

[0177] In some embodiments, the present technology comprises a method or the use, wherein the method or the use further includes treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.

[0178] In some embodiments, the present technology comprises a method or the use, 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.

[0179] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, including: administering a combination therapy including: (a) GLP-1 receptor agonist; and (b) a non-naturally occurring melanocortin analog including a sequence of SEQ ID NO: 295, 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.

[0180] In some embodiments, the present technology comprises use of a combination therapy including: (a) a GLP-1 receptor agonist; and (b) a non-naturally occurring melanocortin analog including a sequence of SEQ ID NO: 295, for reducing body weight and / or fat mass in a subject in need thereof, 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.Docket No.: 146316.8017.WO00

[0181] In some embodiments, the present technology comprises a method or the use, wherein a blood glucose level of the subject is decreased following administration of a first dose of the combination therapy.

[0182] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is semaglutide and the combination therapy has an additive effect on the subject's weight loss.

[0183] In some embodiments, the present technology comprises a method or the use, wherein the combination therapy has an additive effect on the subject's fat mass loss.

[0184] In some embodiments, the present technology comprises the method or the use of clam 282 or 283, wherein a percent lean mass of the subject is increased following administration of a first dose of the combination therapy.

[0185] In some embodiments, the present technology comprises a method or the use, wherein the combination therapy has an additive effect on suppressing the subject's appetite

[0186] In some embodiments, the present technology comprises a method or the use, wherein the GLP-1 receptor agonist is a dual GLP-1 / GIP receptor agonist.

[0187] In some embodiments, the present technology comprises a method or the use, wherein the dual GLP-1 / GIP receptor agonist is tirzepatide and the combination therapy has a synergistic effect on the subject's weight loss.

[0188] In some embodiments, the present technology comprises a method or the use, wherein the combination therapy has a synergistic effect on the subject's fat mass loss.

[0189] In some embodiments, the present technology comprises a method or the use, wherein the combination therapy has a synergistic effect on the suppressing the subject's appetite.

[0190] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.Docket No.: 146316.8017.WO00

[0191] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.

[0192] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.

[0193] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.

[0194] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.

[0195] In some embodiments, the present technology comprises a method or the use, 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 the combination therapy.Docket No.: 146316.8017.WO00 BRIEF DESCRIPTION OF THE DRAWINGS

[0196] FIGS.1A-1C show the cardiac data for melanocortin agonist A07D (“E2”; SEQ ID NO: 295) up to 180 minutes after subcutaneous injection.

[0197] FIGS.2A-2C show the body weight and food intake of rats administered saline, 3 mg / kg (mpk) E2, 10 mg / kg E2, or 1 mg / kg setmelanotide up to 24 hours after subcutaneous injection.

[0198] FIGS.3A and 3B show the plasma insulin levels of rats pre and post injection of melanocortin antagonist B07 (SEQ ID NO: 3).

[0199] FIGS. 4A-4N show the change in body weight of rats administered 3 mpk (mg / kg) E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg semaglutide (“Sema”; Group 4) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Sema (Group 5) after treatment.

[0200] FIGS.5A-5I show the mass distribution of rats administered 3 mpk (mg / kg) E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Sema (Group 4) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Sema (Group 5) after seven days of treatment and up to week 5 of treatment.

[0201] FIGS. 6A-6E show the cumulative food consumption, daily food intake, and kaolin intake in rats administered 3 mpk (mg / kg) E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Sema (Group 4) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Sema (Group 5).

[0202] FIGS. 7A-7D show the blood glucose levels as measured by an oral glucose tolerance test (OGTT) of rats administered 3 mpk (mg / kg) E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Sema (Group 4) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Sema (Group 5) on day 0 and day 8 of treatment.

[0203] FIGS. 8A-8N show the change in body weight of rats administered 3 mpk E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg tirzepatide (“Tirzep”; Group 7) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Tirzep (Group 6) after treatment.Docket No.: 146316.8017.WO00

[0204] FIGS.9A-9I show the mass distribution of rats administered 3 mpk E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Tirzep (Group 7) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Tirzep (Group 6) after seven days of treatment and up to week 5 of treatment.

[0205] FIGS.10A-10E show the cumulative food consumption, daily food intake, and kaolin intake in rats administered 3 mpk E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Tirzep (Group 7) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Tirzep (Group 6).

[0206] FIGS. 11A-11D show the blood glucose levels of rats administered 3 mpk E2 (Group 2), saline (Group 3), 12.5 / 25 nmol / kg Tirzep (Group 7) and a combination of 3 mpk E2 and 12.5 / 25 nmol / kg Tirzep (Group 6) on day 0, day 8, and day 19 of treatment.

[0207] FIGS.12A-12F show the change in body weight of rats administered 1 mpk E2 (Group 1), 3 mpk E2 (Group 2), and saline (Group 3) after treatment.

[0208] FIGS. 13A-13F show the mass distribution of rats administered 1 mpk E2 (Group 1), 3 mpk E2 (Group 2), and saline (Group 3) after seven days of treatment.

[0209] FIGS.14A-14C show the cumulative food consumption and kaolin intake over 11 days of treatment of rats administered 1 mpk E2 (Group 1), 3 mpk E2 (Group 2), and saline (Group 3).

[0210] FIGS. 15A-15D show the blood glucose levels of rats administered 1 mpk E2 (Group 1), 3 mpk E2 (Group 2), and saline (Group 3) on days 0 through up to day 120.

[0211] FIGS.16A and 16B show gastrocnemius muscle mass as a percentage of body weight (FIG. 16A and brain mass as a percentage of body weight (FIG. 16B) in rats administered saline vehicle, sema (12.5 / 25 nmol / kg), A07D (“E2”; SEQ ID NO: 295) (3mpk), A07D (3mpk) + sema (12.5 / 25 nmol / kg), sema (12.5 / 25 nmol / kg) followed by saline alone at day 21, A07D (3mpk) followed by saline alone at day 21, and A07D (3mpk) + sema (12.5 / 25 nmol / kg) followed by A07D alone at day 21.

[0212] FIGS.17A and 17B show gastrocnemius muscle mass as a percentage of body weight (FIG. 17A) and brain mass as a percentage of body weight (FIG. 17B) in rats administered saline vehicle, tirzep (12.5 / 25 nmol / kg), A07D (“E2”; SEQ ID NO: 295) (3mpk),Docket No.: 146316.8017.WO00 A07D (3mpk) + tirzep (12.5 / 25 nmol / kg), tirzep (12.5 / 25 nmol / kg) followed by saline alone at day 21, A07D (3mpk) followed by saline alone at day 21, and A07D (3mpk) + tirzep (12.5 / 25 nmol / kg) followed by A07D alone at day 21.

[0213] FIGS. 18A and 18B show gastrocnemius muscle mass (FIG. 18A) and brain mass (FIG.18B) as a percentage of body weight in rats administered saline vehicle, A07D (“E2”; SEQ ID NO: 295) (3mpk), A07D (1mpk), A07D (3mpk) followed by saline alone at day 21, and A07D (1mpk) followed by saline alone at day 21.

[0214] FIGS.19A-19D show perirenal fat mass (g) (FIG.19A), perirenal fat mass as a percentage of body weight (FIG.19B), epididymal fat mass (g) (FIG.19C), and epididymal fat mass as a percentage of body weight (FIG. 19D) in rats administered saline vehicle, sema (12.5 / 25 nmol / kg), A07D (“E2”; SEQ ID NO: 295) (3mpk), A07D (3mpk) + sema (12.5 / 25 nmol / kg), sema (12.5 / 25 nmol / kg) followed by saline alone at day 21, A07D (3mpk) followed by saline alone at day 21, and A07D (3mpk) + sema (12.5 / 25 nmol / kg) followed by A07D alone at day 21.

[0215] FIGS.20A-20D show perirenal fat mass (g) (FIG.20A), perirenal fat mass as a percentage of body weight (FIG.20B), epididymal fat mass (g) (FIG.20C), and epididymal fat mass as a percentage of body weight (FIG. 20D) in rats administered saline vehicle, tirzep (12.5 / 25 nmol / kg), A07D (“E2”; SEQ ID NO: 295) (3mpk), A07D (3mpk) + tirzep (12.5 / 25 nmol / kg), tirzep (12.5 / 25 nmol / kg) followed by saline alone at day 21, A07D (3mpk) followed by saline alone at day 21, and A07D (3mpk) + tirzep (12.5 / 25 nmol / kg) followed by A07D alone at day 21.

[0216] FIGS.21A and 21B show perirenal fat mass (FIG.21A) and epididymal fat mass (FIG.21B) as a percentage of body weight in rats administered saline vehicle, A07D (“E2”; SEQ ID NO: 295) (3mpk), A07D (1mpk), A07D (3mpk) followed by saline alone at day 21, and A07D (1mpk) followed by saline alone at day 21.

[0217] FIGS. 22A-22D show the plasma and cerebrospinal fluid (CSF) concentration of A07D (“E2”; SEQ ID NO: 295) in rats over time following subcutaneous administration.Docket No.: 146316.8017.WO00

[0218] FIGS.23A-23C show representative images of pancreas (FIG.23A), heart (FIG. 23B), and liver (FIG. 23C) sections of rats fed a high fat diet and subcutaneously administered saline daily for 5 weeks.

[0219] FIGS. 24A and 24B show representative images of pancreas (FIG. 24A) and heart (FIG.24B) sections of rats fed a high fat diet and subcutaneously administered 3 mg / kg A07D daily for 5 weeks.

[0220] FIGS.25A-25D show changes in body weight and food intake at the beginning of treatment (FIGS. 25A and 25B) relative to the 4 weeks after removal of semaglutide (sema), tirzepatide (tirz), A07D, or saline administration (FIGS.25C and 25D).

[0221] FIG. 26 shows plasma concentration of A07D administered at 1mg / kg intravenously, 10 mg / kg orally, or 30 mg / kg orally to fasted male cynomolgus monkeys. DETAILED DESCRIPTION

[0222] The present technology comprises non-naturally occurring melanocortin analogs, or a pharmaceutically acceptable salts, solvates, or stereoisomers thereof, collectively referred to herein as melanocortin analogs, for reducing weight and / or preventing weight gain in a subject in need thereof. In some embodiments the present technology comprises combination therapies (e.g., pharmaceutical combinations) having a non-naturally occurring melanocortin analog and a weight loss agent. Use of the non- naturally occurring melanocortin analogs and the combination therapies in accordance with the present technology may be useful in treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction. For example, the methods of the present technology may reduce body weight and / or fat mass in a subject in need thereof.

[0223] In some embodiments, the non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin receptor antagonist and / or a melanocortin receptor agonist. The non-naturally occurring melanocortin analogs or the combinations comprising weight loss agents and non-naturally occurring melanocortin antagonists in accordance with the present technology may be useful in treating, preventing, reducing, or otherwise ameliorating one or more conditions, associated with a weight loss agent in a subject in needDocket No.: 146316.8017.WO00 thereof using non-naturally occurring melanocortin analogs. For example, combination therapies of the present technology may be useful in preventing or reducing lean mass loss (e.g., muscle, organ, and bone mass) associated with use of a weight loss agent in a subject in need thereof.

[0224] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof using a non-naturally occurring melanocortin analog or a weight loss agent in combination with the non-naturally occurring melanocortin analog. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a combination comprising a non-naturally occurring melanocortin analog of the present technology or a weight loss agent in combination with the non-naturally occurring melanocortin analog. In some embodiments, the method comprises promoting fat loss in a subject in need thereof using a combination comprising a non-naturally occurring melanocortin analog of the present technology or a weight loss agent in combination with the non-naturally occurring melanocortin analog In some embodiments, the method comprises reducing body weight and / or fat mass in a subject in need thereof using one or more a pharmaceutical compositions or the present technology.

[0225] 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 disclosed herein. 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.

[0226] 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 embodimentsDocket No.: 146316.8017.WO00 may be realized, and that logical 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, recited in any method or process may be executed in any order and are not limited to the order presented. Moreover, any of the steps thereof may be outsourced to or performed by one or more third parties. Definitions

[0227] 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.

[0228] 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.

[0229] 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, 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.

[0230] 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 non-naturally occurring melanocortin analogs), 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 orDocket No.: 146316.8017.WO00 intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

[0231] 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.

[0232] 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.

[0233] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.),Docket No.: 146316.8017.WO00 polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0234] 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.

[0235] 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 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%,Docket No.: 146316.8017.WO00 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.

[0236] 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.

[0237] As used herein, the terms “effective amount” or “therapeutically effective amount”, refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0238] 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 otherwiseDocket No.: 146316.8017.WO00 specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0239] 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.

[0240] 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.

[0241] 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. A control may reference to a measurement from the same subject as the subject being treated (e.g., a measurement at baseline or an intermediate timepoint), or from a different subject (e.g., a subject not having the same treatment or condition as the subject being treated).

[0242] “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,” consistsDocket No.: 146316.8017.WO00 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.

[0243] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0244] 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.

[0245] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.Docket No.: 146316.8017.WO00

[0246] 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.

[0247] 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.

[0248] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0249] “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. SeeDocket No.: 146316.8017.WO00 generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non- protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J.268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res.35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0250] 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 disclosed herein 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.

[0251] 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.

[0252] 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” isDocket No.: 146316.8017.WO00 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.

[0253] 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.

[0254] 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 β3 peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2 amino acids.

[0255] 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.

[0256] 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 as “c.” “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: Nle is norleucine; Nal(2’) is 2′-naphthylalanine; Nal(1') is 1′- naphthylalanine; Tle is tert-leucine; Nva is norvaline; Orn is ornithine; Bip is biphenylalanine; Hyp is hydroxyproline; Mamb is 3-aminomethyl-benzoic acid; Pen is Penicillamine; Tic is 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid; Aba is 4-amino-1,2,4,5-tetra-hydro-2- benzazepin-3-one; Oic is octohydroindole-2-carboxylic acid; Atc is 2-aminotetraline-2-Docket No.: 146316.8017.WO00 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; Ata is 7-amino-7,8-dihydro-4H-[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; Che is 1-amino-1-cyclohexanecarboxylic acid Ioc is indoline-2-carboxylic acid, Aic is 2- aminoindone-2-carboxylic acid; Cpe is 1-amino-1-cyclopentane carboxylic; and p(Cl)dPhe is para-chloro-phenylalanine (I – iodo, F – fluoro, Br – bromo, CF3 – trifluoromethyl).

[0257] 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.”

[0258] 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.

[0259] An “amine” includes compounds that contain an amine group (—NH2).

[0260] 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.

[0261] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0262] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some aspects, no more than 25% of theDocket No.: 146316.8017.WO00 administered peptide causes side effects and / or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and / or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0263] As used herein, a “composition” refers to a mixture of the active ingredient with other chemical components.

[0264] 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

[0265] 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.

[0266] 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%.

[0267] 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%.

[0268] 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).Docket No.: 146316.8017.WO00

[0269] 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.

[0270] The non-naturally occurring melanocortin analogs in accordance with the present technology may have certain 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 melanocortin 4 receptor and / or melanocortin 3 receptor. 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, Aia, Aba, Ata, Hyp, dHyp, 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, dMet and disulfide bridges (e.g., cyclization via disulfide bond), as well as Pro-Gly and Gly-Gly linkers may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0271] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I):Docket No.: 146316.8017.WO00 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:Docket No.: 146316.8017.WO00 a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

[0272] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’));Docket No.: 146316.8017.WO00 R7is selected from the group consisting of Arg, Pro, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 447); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

[0273] In some embodiments, R9is absent. 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 norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3is His or dHis; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or lysine (Lys);Docket No.: 146316.8017.WO00 R8is absent or lysine (Lys); Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; provided that when R2is Ala, then X1is Nle.

[0274] 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 norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3is His or dHis; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or lysine (Lys); R8is absent or lysine (Lys); Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro;Docket No.: 146316.8017.WO00 Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; provided that the non-naturally occurring melanocortin analog does not comprise the sequence: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

[0275] In some embodiments, R3is His. In further embodiments, R3and R4form the moiety His-p(X)dPhe, where X is H or F. In still further embodiments, R3and R4form the moiety His-dPhe or His-p(F)dPhe.

[0276] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): X1-R1-R2-His-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, Arg, dArg, alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is Asp; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is Pro or Lys; R8is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle);Docket No.: 146316.8017.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 lactam bridge between R2and R7or R8when R2is Asp, and R7or R8is Lys;

[0277] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein: wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, Arg, lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is Asp; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or Lys; R8is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R7or R8when R2is Asp, and R7or R8is Lys.Docket No.: 146316.8017.WO00

[0278] In some embodiments, R3is His and R4is dPhe. In further embodiments, R2is Ala or dAla. In still further embodiments, R2, R3, and R4, form the moiety Ala-His-dPhe or dAla-His-dPhe.

[0279] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC): X1-R1-R2-His-R4-R5-R6-R7-Y1-Y2(IC), wherein: X1is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1is aspartic acid (Asp); R2is alanine (Ala) or D-alanine (dAla); R4is D-phenylalanine (dPhe); R5is Arg; R6is tryptophan (Trp); R7is Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2and Lys at R7; provided that when R2is Ala, then X1is Nle.

[0280] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein: X1is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1is aspartic acid (Asp); R2is alanine (Ala) or D-alanine (dAla); R4is D-phenylalanine (dPhe); R5is Arg;Docket No.: 146316.8017.WO00 R6is tryptophan (Trp); R7is Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2and Lys at R7; provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

[0281] In some embodiments, R8is absent. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3(ID), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro); R3is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4is selected from the group consisting of D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is cysteine (Cys) or lysine (Lys);Docket No.: 146316.8017.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; 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; and a lactam bridge between R1or R2and R7when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7is Lys; provided that: when R3is Pro, then R4is dPhe and either (i) X1and Y3are present, or (ii) X1and Y3are absent, R1is Nle, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; when R4is dPhe, then (i) R3is not His or Gln or (ii) R3is His and either R2is Pro or R5is transPro(guan) or cisPro(guan); and when R4is p(F)dPhe, R3is His, and R1is Nle, then (i) R6is not Trp or (ii) Y3is dVal.

[0282] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro); R3is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4is selected from the group consisting of D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe);Docket No.: 146316.8017.WO00 R5is selected from the group consisting of Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is cysteine (Cys) or lysine (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; 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; and a lactam bridge between R1or R2and R7when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);Docket No.: 146316.8017.WO00 Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478).

[0283] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (I)-(ID) has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, the presence of Pro, cisPro(guan) and / or transPro(guan) in the melanocortin analog 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.

[0284] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(ID), 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)-(ID) 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)-(ID) may be at any of R7, R8, R9, Y1, Y2, Y3, and Y4.

[0285] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified by an acyl group. In some embodiments, the acyl group is acetyl group ).Docket No.: 146316.8017.WO00

[0286] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is not modified.

[0287] In the sequence of any one of Formulae (I)-(ID), Y1Y2Y3Y4represents 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.

[0288] In some embodiments, Y1-Y3are present and Y4is absent. In some embodiments, Y4is absent and (i) Y1is D-proline, (ii) Y2is D-valine, and (iii) Y3is D-proline. In some embodiments, Y4is absent, and (i) Y1is D-tert-leucine, Y2is D-tert-leucine, and Y3is D-valine.

[0289] In some embodiments, Y1-Y4are present. In some embodiments, Y1-Y4are present and (i) Y1is D-valine, (ii) Y2is D-valine, (iii) Y3is D-valine, and (iv) Y4is D-proline.

[0290] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of Formula (I), a non-naturally occurringmodified by an amide may be represented by a terminal -NH2.

[0291] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of Formula (I), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH.

[0292] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(ID) 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys.Docket No.: 146316.8017.WO00

[0293] In some embodiments of the sequence of Formulae (I)-(ID), R3is His. In some embodiments, when R3is His, then X1is absent and R1is present. In some embodiments, R1is norleucine. In further embodiments, R2is Asp, R4is dPhe or p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. In some embodiments, Y1and Y2are each independently dVal or dPro. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621), wherein c represents cyclization through R2and R7via a lactam bond.

[0294] Alternatively, in some embodiments, R1is an amino acid other than norleucine. In some embodiments, R1is selected from Ala, Arg, dArg, Lys, dLys, His, or dHis. In further embodiments, R2is Asp, R4is p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468), wherein c represents cyclization through R2and R7via a lactam bond.Docket No.: 146316.8017.WO00

[0295] In some embodiments, R1is selected from Arg, Lys, dLys, His, or dHis. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468), wherein c represents cyclization through R2and R7via a lactam bond.

[0296] In some embodiments, R1is Ala or dArg. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); or Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463), wherein c represents cyclization through R2and R7via a lactam bond.

[0297] In some embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formula (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485), wherein c represents cyclization through R2and R7via a lactam bond.Docket No.: 146316.8017.WO00

[0298] In some embodiments, R1is selected from Arg, Lys, dLys, His, or dHis. In some embodiments, the sequence of any one of Formula (I)-(ID) is selected from the group consisting of: Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485), wherein c represents cyclization through R2and R7via a lactam bond.

[0299] In some embodiments, R1is Ala or dArg. In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479); or Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480), wherein c represents cyclization through R2and R7via a lactam bond.

[0300] . In some embodiments, when R3is His, then X1and R1are present. In some embodiments, when X1and R1are present, then R2is Ala or dAla. In some embodiments, X1is Nle or dArg, R1is Asp, R4is dPhe, R5is Arg, R6is Trp, and R7is Lys. some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380), wherein c represents cyclization through R1and R7via a lactam bond.

[0301] In some embodiments, when R3is His, then at least one of X1, Y3, and Y4are present. In some embodiments, X1is absent. In other embodiments, X1is Nle. In someDocket No.: 146316.8017.WO00 embodiments, Y3-Y4are absent. In some embodiments, Y3is dVal or dPro and Y4is absent. In some embodiments, Y3is dVal and Y4is dPro. In some embodiments, R2is Asp, R4is p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478), wherein c represents cyclization through R2and R7via a lactam bond.

[0302] In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478), wherein c represents cyclization through R2and R7via a lactam bond.

[0303] In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473), wherein c represents cyclization through R2and R7via a lactam bond.

[0304] In some embodiments, when R3is His, then R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In some embodiments, R5is selected from His, transPro(guan) and cisPro(gaun). In further embodiments, R2is Asp, R4is dPheDocket No.: 146316.8017.WO00 or p(F)dPhe, R6is Trp, and R7is Lys. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229); and Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470), wherein c represents cyclization through R2and R7via a lactam bond.

[0305] In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228) or Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229), wherein c represents cyclization through R2and R7via a lactam bond.

[0306] In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle- c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470), wherein c represents cyclization through R2and R7via a lactam bond.

[0307] In some embodiments, when R3is His, then R6is Trp. Alternatively, in some embodiments, R6is an amino acid other than Trp. In some embodiments, R6is dNal(2’). In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-His- p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 471), wherein c represents cyclization through R2and R7via a lactam bond.

[0308] 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, R6is Trp, and R7is Lys. In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491); and Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639), wherein c represents cyclization through R2and R7via a lactam bond.

[0309] In some embodiments, the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); and Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486), wherein c represents cyclization through R2and R7via a lactam bond.

[0310] In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491); or Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639), wherein c represents cyclization through R2and R7via a lactam bond.

[0311] In some embodiments of the sequence of any one of Formulae (I)-(ID), the non- naturally occurring melanocortin analog is cyclized through R2and R7via a lactam bond. In other embodiments, the non-naturally occurring melanocortin analog is cyclized through R2and R7via a disulfide bond. In some embodiments, the sequence of any one of Formulae (I)-(ID): Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498), wherein c represents cyclization through R2and R7via a disulfide bond.

[0312] In other embodiments, the non-naturally occurring melanocortin analog is cyclized through R1and R7or R2and R8via a lactam bond. In some embodiments, either R2or R7is Pro. In further embodiments, R1Nle or Asp, R2is Asp or Pro, R3is His, R4is dPhe, R6is Trp, and R7is Lys or Pro and R8is absent or Lys. In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418).Docket No.: 146316.8017.WO00 wherein c represents cyclization through R2and R7via a lactam bond.

[0313] In some embodiments, the sequence of any one of Formulae (I)-(ID) is Ac-Nle- c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297), wherein c represents cyclization through R2and R7via a lactam bond.

[0314] In some embodiments, the sequence of any one of Formulae (I)-(ID) is: Ac-Nle- c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418), wherein c represents cyclization through R2and R7via a lactam bond. In some embodiments of the sequence of Formula (I), R9is absent. Alternatively, in some embodiments, R9is present. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 420), wherein c represents cyclization through R1and R9via a lactam bond.

[0315] 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: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498.

[0316] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486.

[0317] 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: 223, 228-229, 363, 418, 462-485, and 621. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621.

[0318] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurringDocket No.: 146316.8017.WO00 melanocortin analog comprises any one of the sequences of SEQ ID NOs: 268 and 378- 380.

[0319] 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: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498.

[0320] Non-naturally occurring melanocortin analog of any one of Formulae (I)-(ID) 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)-(ID) 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)-(ID) are full agonists of the melanocortin 4 receptor and partial agonists of the melanocortin 3 receptor. Non-Naturally Occurring Melanocortin Analog Synthesis

[0321] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any 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.

[0322] 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 withDocket No.: 146316.8017.WO00 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.

[0323] 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).

[0324] 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.

[0325] 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.

[0326] 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.Docket No.: 146316.8017.WO00

[0327] 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.

[0328] 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.

[0329] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0330] 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-pyrrolidoneDocket No.: 146316.8017.WO00 (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).

[0331] 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

[0332] 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,Docket No.: 146316.8017.WO00 hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0333] When the peptides of the present technology are basic, acid addition salts may be prepared from non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, 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. Weight Loss Agents

[0334] The present technology comprises combination therapies including a non- naturally occurring melanocortin analog and a weight loss agent. In some embodiments, the non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin agonist analog. The combination therapy may be useful in effecting weight loss in a subject in need thereof. The combination therapy may further be useful in effecting weight loss in a subject in need thereof while preserving lean mass, e.g., muscle and bone mass in the subject. For example, subjects who achieve weight loss using pharmaceutical combinations of the present technology may shed less lean mass, e.g., muscle and bone mass, than subjects who achieve weight loss using a weight loss agent alone. Additionally, or alternatively, subjects who achieve weight loss using pharmaceutical combinations of the present technology may shed more fat mass, e.g., visceral fat mass, than subjects who achieve weight loss using a weight loss agent alone.Docket No.: 146316.8017.WO00

[0335] Combination therapies in accordance with the present technology comprise a weight loss agent. In some embodiments, the weight loss agent is useful for treating and / or preventing metabolic dysfunction or one or more symptoms of metabolic dysfunction in a subject. 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.

[0336] Combination therapies of the present technology may include any conventional weight loss agent 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; 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®).

[0337] 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 agentDocket No.: 146316.8017.WO00 known in the art may be used in the methods of the present technology. For example, when the weight loss agent is a salt form of setmelanotide, it may be setmelanotide acetate.

[0338] 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.

[0339] 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.

[0340] In some embodiments, the weight loss agent is a 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 (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®). InDocket No.: 146316.8017.WO00 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®).

[0341] 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 compounds 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, and WO2016 / 046753, which are incorporated herein by reference in their entireties.

[0342] 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.

[0343] 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 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.

[0344] 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 otherDocket No.: 146316.8017.WO00 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 disclosed in US 2023 / 0293638, the entirety of which is incorporated herein by reference in its entirety.

[0345] 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.

[0346] In some embodiments, the weight loss agent is an MC4 receptor agonist. In some embodiments, the weight loss agent is setmelanotide (e.g., Imcivree®). Pharmaceutical Compositions, Formulations, and Administration Pharmaceutical Compositions Non-Naturally Occurring Melanocortin Analogs

[0347] The non-naturally occurring melanocortin analogs of the present technology may be present in a pharmaceutical composition.

[0348] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 50 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 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 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 10 mg / mL, relative to a total volume of the pharmaceutical composition.

[0349] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 mg / mL, relative to a total volume of the pharmaceutical composition. In someDocket No.: 146316.8017.WO00 embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 mg / mL, about 0.5 mg / mL to about 40 mg / mL, about 1 mg / mL to about 30 mg / mL, about 2.5 mg / mL to about 20 mg / mL, about 5 mg / mL to about 15 mg / mL, or about 5 mg / mL to about 10 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, relative to a total volume of the pharmaceutical composition.

[0350] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least 0.1 mg / mL to at least 50 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 at least 0.1 mg / mL to at least 50 mg / mL, at least 0.5 mg / mL to at least 40 mg / mL, at least 1 mg / mL to at least 30 mg / mL, at least 2.5 mg / mL to at least 20 mg / mL, at least 5 mg / mL to at least 15 mg / mL, or at least 5 mg / mL to at least 10 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 at least 10 mg / mL, relative to a total volume of the pharmaceutical composition.

[0351] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least about 0.1 mg / mL to at least about 50 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 at least about 0.1 mg / mL to at least about 50 mg / mL, at least about 0.5 mg / mL to at least about 40 mg / mL, at least about 1 mg / mL to at least about 30 mg / mL, at least about 2.5 mg / mL to at least about 20 mg / mL, at least about 5 mg / mL to at least about 15 mg / mL, or at least about 5 mg / mL to at least about 10 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 aDocket No.: 146316.8017.WO00 concentration of at least about 10 mg / mL, relative to a total volume of the pharmaceutical composition. Weight Loss Agents & Combination Therapies

[0352] Combination therapies of the present technology may comprise the non- naturally occurring melanocortin analog and the weight loss agent 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.

[0353] 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.

[0354] 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.

[0355] 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 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.Docket No.: 146316.8017.WO00

[0356] In still other embodiments, the first pharmaceutical composition and the second pharmaceutical composition may be administered cyclically.

[0357] 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.

[0358] 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.

[0359] 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 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.Docket No.: 146316.8017.WO00

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

[0361] 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.

[0362] In some embodiments, the weight loss agent is Rybelsus®.

[0363] 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.

[0364] In some embodiments, the weight loss agent is Byetta®.

[0365] 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 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 firstDocket No.: 146316.8017.WO00 pharmaceutical composition in a concentration of about 2.35 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0366] In some embodiments, the weight loss agent is Bydureon®.

[0367] 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.

[0368] In some embodiments, the weight loss agent is Trulicity®.

[0369] 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.

[0370] 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 firstDocket No.: 146316.8017.WO00 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.

[0371] 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.

[0372] 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, 20 mg / mL, 25 mg / mL, or 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0373] In some embodiments, the weight loss agent is Mounjaro™. In some embodiments, the weight loss agent is Zepbound™.Docket No.: 146316.8017.WO00

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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, 2Docket No.: 146316.8017.WO00 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.

[0378] 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.

[0379] 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.

[0380] In some embodiments, the weight loss agent Imcivree®.

[0381] In some embodiments, the first pharmaceutical composition comprising the weight loss agent formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or oral administration. In some embodiments, theDocket No.: 146316.8017.WO00 first pharmaceutical composition comprising the weight loss agent is formulated for subcutaneous administration. Alternatively, in some embodiments, the first pharmaceutical composition comprising the weight loss agent is formulated for oral administration.

[0382] The first pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and / or excipients such as, for example, buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, and antioxidants. For example, when the first pharmaceutical composition is formulated for subcutaneous administration, the one or more pharmaceutically acceptable carriers and / or excipients may comprise water. In such embodiments, the first pharmaceutical composition contains 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 one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the first pharmaceutical composition.

[0383] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0384] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462- 471, 473-486, 491, and 498 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5Docket No.: 146316.8017.WO00 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0385] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474- 478, and 481-486 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0386] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.Docket No.: 146316.8017.WO00

[0387] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 223, 363, 418, 464-470, 474- 478, 481-485, and 621 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0388] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 268 and 378-380 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 268 and 378-380 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 268 and 378-380 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0389] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 and is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of theDocket No.: 146316.8017.WO00 second pharmaceutical composition. In some embodiments, any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0390] Formulations

[0391] The pharmaceutical composition comprising the non-naturally occurring melanocortin analog may be formulated for intraperitoneal, intravenous, parenteral, depot, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for depot administration. In some embodiments, the pharmaceutical composition comprising the non- naturally occurring melanocortin analog is present in a single composition with the weight loss agent. In some embodiments, the non-naturally occurring melanocortin analog and the weight loss agent are present in different pharmaceutical compositions (e.g., a first pharmaceutical composition and a second pharmaceutical composition) are formulated for the same route of administration or are formulated for different routes of administration.

[0392] 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.

[0393] Pharmaceutical compositions comprising the non-naturally occurring melanocortin analog may be administered using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. Compositions administered by injection may be formulated for depot injection.Docket No.: 146316.8017.WO00 Pharmaceutical compositions 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, antioxidants and other agents known in the art. In general, any route of administration by which the compositions are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. Administration includes delivery across the epithelium. Administration includes delivery through the gastrointestinal tract. 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.

[0394] In order to facilitate delivery of the active ingredients, to enhance dispersion, solubility, and stability of the active ingredients, and / or to reduce adverse injection site reactions, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers and / or excipients.

[0395] The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and / or excipients such as, for example, buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, and antioxidants. For example, when the first pharmaceutical composition is formulated for subcutaneous administration, the one or more pharmaceutically acceptable carriers and / or excipients may comprise water.

[0396] In some embodiments, the first pharmaceutical composition contains 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 one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the first pharmaceutical composition.

[0397] In some embodiments, the first pharmaceutical composition contains 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 one or moreDocket No.: 146316.8017.WO00 pharmaceutically acceptable carriers and / or excipients relative to a total weight of the first pharmaceutical composition.

[0398] In some embodiments, the first 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 the one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the first pharmaceutical composition.

[0399] In some embodiments, the first 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 the one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the first pharmaceutical composition.

[0400] 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.

[0401] To facilitate delivery of the non-naturally occurring melanocortin analog, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and / or excipients. Other pharmaceutically acceptable carriers and / or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.Docket No.: 146316.8017.WO00

[0402] In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients are isotonic.

[0403] 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.

[0404] 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

[0405] In order to achieve a desirable tonicity, the pharmaceutical composition may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.

[0406] 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.

[0407] 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 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.

[0408] 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.Docket No.: 146316.8017.WO00

[0409] 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.

[0410] 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.

[0411] 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. 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.

[0412] 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.

[0413] 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.

[0414] 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 theDocket No.: 146316.8017.WO00 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.

[0415] 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.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] 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-naturallyDocket No.: 146316.8017.WO00 occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] In addition to sodium acetate and Tris, the pharmaceutical composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the pharmaceutical composition comprises acetic acid as an additional buffering agent.

[0424] 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.Docket No.: 146316.8017.WO00

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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 pharmaceuticalDocket No.: 146316.8017.WO00 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.

[0430] 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.

[0431] 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.

[0432] 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.

[0433] 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.Docket No.: 146316.8017.WO00

[0434] 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 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises sodium acetateDocket No.: 146316.8017.WO00 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.

[0439] 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.

[0440] Alternatively, in some embodiments, the pharmaceutical composition is formulated for intranasal administration. When the pharmaceutical composition is formulated for intranasal administration, the composition may comprise one or more pharmaceutically acceptable carriers and / or excipients to facilitate delivery and enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog.

[0441] The pharmaceutical 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 composition includes a propellant, such as hydrofluoroalkane.

[0442] When the pharmaceutical composition is formulated for intranasal administration, the active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the one or more pharmaceutically acceptable carriers and / or excipients. 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.Docket No.: 146316.8017.WO00

[0443] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises the 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.

[0444] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and is configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver about 1mg to about 100mg per spray. In some embodiments, the spray device or nasal inhaler is configured to deliver 1mg to 100mg, 5mg to 90mg, 10mg to 80mg, 15mg to 70mg, 20mg to 60mg, 25mg, to 50mg, or 30mg to 40mg per spray.

[0445] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and has a pH approximating the normal pH range of the nasal fluid. Accordingly, in some embodiments, the pharmaceutical composition has a pH ranging from about 5.5 to about 6.5. In some embodiments, the pharmaceutical composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0446] Pharmaceutically acceptable carriers and / or excipients that may be included in the pharmaceutical composition formulated for intranasal administration may generally include (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and / or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0447] In some embodiments, the pharmaceutically acceptable carriers and / or excipients are isotonic to nasal fluids.Docket No.: 146316.8017.WO00

[0448] In order to achieve a desirable tonicity, the pharmaceutical composition formulated for intranasal administration may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some embodiments, the salt is sodium chloride and is present in a concentration of 0.9% by weight.

[0449] When the pharmaceutical composition is formulated for intranasal administration, the composition may comprise a pH buffered aqueous solution as previously described.

[0450] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises sodium acetate in a concentration of about 80 mM to about 100 mM. For example, sodium acetate may be present in the pharmaceutical composition in a molar concentration of 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, or 100 mM.

[0451] In some embodiments, the pharmaceutical composition is formulated for intranasal 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.

[0452] Additionally, when the pharmaceutical composition is formulated for intranasal administration, the composition may further comprise a phosphate, e.g., sodium phosphate. In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises sodium phosphate in a molar concentration of about 5 mM to about 700 mM, relative to a total volume of the composition. For example, sodium phosphate 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.Docket No.: 146316.8017.WO00

[0453] In some embodiments, the pharmaceutical composition comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0454] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0455] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0456] 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%.

[0457] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 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 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 1 mg / mL to 30 mg / mL, 2.5 mg / mL to 20 mg / mL, 5 g / mL to 15 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the pharmaceutical composition. Any of the non-naturally occurring melanocortin analogs and corresponding concentrations described previously with reference to the pharmaceutical composition may be present in the pharmaceutical composition at the same or substantially similar concentrations. AdministrationDocket No.: 146316.8017.WO00

[0458] The pharmaceutical compositions of the present technology may be administered once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day.

[0459] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day.

[0460] 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 monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, 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 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, 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 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In some embodiments, the administration is performed once monthly.Docket No.: 146316.8017.WO00

[0461] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462- 471, 473-486, 491, and 498 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0462] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 andDocket No.: 146316.8017.WO00 is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0463] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times perDocket No.: 146316.8017.WO00 day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0464] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4Docket No.: 146316.8017.WO00 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0465] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 268 and 378-380 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 268 and 378-380 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 268 and 378-380 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks,Docket No.: 146316.8017.WO00 once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 268 and 378-380 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0466] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1Docket No.: 146316.8017.WO00 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.

[0467] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof 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.

[0468] 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).

[0469] 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. Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequenciesDocket No.: 146316.8017.WO00 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. 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. Dosing

[0470] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the non-naturally occurring melanocortin analog to the subject in need thereof.

[0471] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least 1 mg, at least 2 mg, at least 3 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, or at least 500 mg of the non-naturally occurring melanocortin analog to the subject in need thereof.

[0472] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least about 1 mg, at least about 2 mg, atDocket No.: 146316.8017.WO00 least about 3 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, or at least about 500 mg of the non- naturally occurring melanocortin analog to the subject in need thereof.

[0473] In some embodiments, the compositions of the present technology are administered to the subject at a dose that is based on the subject’s BMI. In some embodiments, two or more doses of the compositions of the present technology are administered to the subject, wherein the two or more doses are titrated (e.g., inversely titrated) based on the subject’s BMI at the time of each administration.

[0474] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.10 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, 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 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 75 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, about 300 mg / kg, about 325 mg / kg, about 350 mg / kg, about 375 mg / kg, about 400 mg / kg, about 425 mg / kg, about 450 mg / kg, about 475 mg / kg, or about 500 mg / kg of the non-naturally occurring melanocortin analog to the subject in need thereof.

[0475] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least 0.001 mg / kg, at least 0.005 mg / kg, at least 0.01 mg / kg, at least 0.05 mg / kg, at least 0.10 mg / kg, at least 0.5 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, 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 40 mg / kg, at least 50 mg / kg, at least 60 mg / kg, at least 75 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 225 mg / kg, at least 250 mg / kg,Docket No.: 146316.8017.WO00 at least 275 mg / kg, at least 300 mg / kg, at least 325 mg / kg, at least 350 mg / kg, at least 375 mg / kg, at least 400 mg / kg, at least 425 mg / kg, at least 450 mg / kg, at least 475 mg / kg, or at least 500 mg / kg of the non-naturally occurring melanocortin analog to the subject in need thereof. In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least about 0.001 mg / kg, at least about 0.005 mg / kg, at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.10 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, 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 40 mg / kg, at least about 50 mg / kg, at least about 60 mg / kg, at least about 75 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 225 mg / kg, at least about 250 mg / kg, at least about 275 mg / kg, at least about 300 mg / kg, at least about 325 mg / kg, at least about 350 mg / kg, at least about 375 mg / kg, at least about 400 mg / kg, at least about 425 mg / kg, at least about 450 mg / kg, at least about 475 mg / kg, or at least about 500 mg / kg of the non-naturally occurring melanocortin analog to the subject in need thereof.

[0476] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg to about 500 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 250 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.

[0477] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg to at least 500 mg / kg per body weight of theDocket No.: 146316.8017.WO00 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 250 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.

[0478] 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 500 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 250 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.

[0479] 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.

[0480] 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.Docket No.: 146316.8017.WO00

[0481] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from at least 0.5 mg / kg to at least 10 mg / kg, at least 1 mg / kg to at least 7.5 mg / kg, or at least 2.5 mg / kg to at least 5 mg / kg per body weight of the subject.

[0482] In some embodiments, the non-naturally occurring melanocortin analog is administered about 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.

[0483] 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 per body weight of the subject once daily.

[0484] 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 per body weight of the subject once daily.

[0485] 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 200Docket No.: 146316.8017.WO00 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 per body weight of the subject once daily.

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] 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.

[0492] 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.

[0493] 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.

[0494] 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.

[0495] 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.

[0496] 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.

[0497] 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.Docket No.: 146316.8017.WO00

[0498] 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.

[0499] 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] 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.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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. 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.

[0509] 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.Docket No.: 146316.8017.WO00

[0510] 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.

[0511] 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.

[0512] 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 per body weight of the subject twice daily.

[0513] 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 per body weight of the subject twice daily.

[0514] 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 per body weight of the subject twice daily.Docket No.: 146316.8017.WO00

[0515] 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.

[0516] 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.

[0517] 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.

[0518] 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.

[0519] 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.

[0520] 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.

[0521] 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.

[0522] 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.

[0523] 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.

[0524] 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.

[0525] 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.

[0526] 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.

[0527] 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.Docket No.: 146316.8017.WO00

[0528] 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.

[0529] 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.

[0530] 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.

[0531] 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.

[0532] 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.

[0533] 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 twice daily.

[0534] 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 twice daily.

[0535] 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 twice daily.

[0536] 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 twice daily.

[0537] 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 twice daily.

[0538] 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 twice daily.

[0539] 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 twice daily.

[0540] 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 twice daily.Docket No.: 146316.8017.WO00

[0541] 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 twice daily.

[0542] 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.

[0543] 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.

[0544] 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.

[0545] 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.

[0546] 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 15Docket No.: 146316.8017.WO00 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 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.

[0547] 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.

[0548] 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.

[0549] 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.

[0550] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462- 471, 473-486, 491, and 498and is administered at least once daily in an amount rangingDocket No.: 146316.8017.WO00 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 any one of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498 and 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.

[0551] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486 and 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 any one of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486and 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.

[0552] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 and 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 any one of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621 and is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, about 1 ...

Claims

Docket No.: 146316.8017.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 GLP-1 receptor agonist; 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 non-naturally occurring melanocortin analog and (b) a GLP-1 receptor agonist for reducing body weight and / or fat mass in a subject in need thereof to produce an additive or synergistic effect on body weight and / or fat mass loss in the subject.

3. A method 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 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe);Docket No.: 146316.8017.WO00 R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.Docket No.: 146316.8017.WO00 4. Use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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;Docket No.: 146316.8017.WO00 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

5. The method or the use of any one of claims 1-4, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

6. The method of the use of claim 5, wherein the lean mass is lean muscle mass.

7. The method or the use of any one of claims 1 to 6, wherein the method further comprises treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.Docket No.: 146316.8017.WO00 8. A method of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; 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.

9. Use of (a) a non-naturally occurring melanocortin analog and (b) a GLP-1 receptor agonist for treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof to produce a synergistic or additive effect on glucose intolerance and / or diabetes mellitus in the subject 10. A method of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula: 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan));Docket No.: 146316.8017.WO00 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, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.Docket No.: 146316.8017.WO00 11. Use of a non-naturally occurring melanocortin analog for treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in a subject in need thereof, 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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;Docket No.: 146316.8017.WO00 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

12. The method or the use of any one of claims 8-11, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

13. The method or the use of claim 12, wherein the lean mass is lean muscle mass.

14. The method or the use of any one of claims 8 to 13, wherein the method or the use further comprises reducing body weight and / or fat mass in the subject.Docket No.: 146316.8017.WO00 15. The method or the use of any one of claims 8 to 14, wherein the method or the use further comprises treating, preventing, reducing, or otherwise ameliorating a sleep disorder in the subject.

16. The method or the use of claim 15, wherein the sleep disorder is sleep apnea.

17. The method or the use of any one of claims 1 to 14, wherein the GLP-1 receptor agonist 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.

18. The method or the use of any one of claims 1 to 15, 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 GLP-1 receptor agonist or a dual GLP-1 / GIP receptor agonist.

19. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is semaglutide and is administered at a dose of about 0.01 mg to about 10 mg once per week.

20. The method or the use of claim 19, 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.

21. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is semaglutide and is administered at a dose of about 0.5 mg to about 40 mg once daily.

22. The method or the use of claim 21, wherein semaglutide is administered orally at a dose of less than 3 mg, 7 mg or 14 mg once daily.

23. The method or the use of any one of claims 1 to 16, wherein the GLP-1Docket No.: 146316.8017.WO00 receptor agonist 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.

24. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is exenatide and is administered at a dose of about 0.5 µg to about 100 µg twice daily.

25. The method or the use of claim 24, wherein exenatide is administered subcutaneously at a dose of less than 5 µg or 10 µg twice daily.

26. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is exenatide and is administered at a dose of about 0.5 mg to about 50 mg once per week.

27. The method or the use of claim 26, wherein exenatide is administered subcutaneously at a dose of less 2 mg once per week.

28. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is dulaglutide and is administered at a dose of about 0.05 mg to about 50 mg once per week.

29. The method or the use of claim 28, 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.

30. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is orforglipron and is administered at a dose of about 0.01 mg to about 100 mg once daily.

31. The method or the use of claim 30, 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.Docket No.: 146316.8017.WO00 32. The method or the use of any one of claims 1 to 16, wherein the GLP-1 receptor agonist is a dual GLP-1 / GIP receptor agonist.

33. The method or the use of claim 32, 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.

34. The method or the use of claim 33, 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.

35. The method or the use of claim 32, 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 body weight of the subject once every three days.

36. The method or the use of any one of claims 1 to 33, 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.

37. The method or the use of claim 36, 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.

38. The method or the use of any one of claims 1 to 33, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

39. The method or the use of any one of claims 1 to 33, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.Docket No.: 146316.8017.WO00 40. The method or the use of any one of claims 1 to 37, wherein the melanocortin 4 receptor agonist is an agonist of the melanocortin 3 receptor.

41. The method or the use of claim 40, wherein the melanocortin 4 receptor agonist is a full agonist of the melanocortin 3 receptor.

42. The method or the use of claim 40 or 41, wherein the non-naturally occurring melanocortin agonist comprises no melanocortin 3 receptor antagonist activity.

43. The method or the use of any one of claims 1 to 42, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to administration of the GLP-1 receptor agonist, and wherein administration of the non-naturally occurring melanocortin analog makes the subject more responsive to the GLP-1 receptor agonist, compared to a subject who has not been administered the non-naturally occurring melanocortin 4 receptor analog.

44. The method or the use of any one of claims 1 to 42, wherein the non-naturally occurring melanocortin agonist is administered to the subject after administration of the GLP- 1 receptor agonist, and wherein the subject failed to lose sufficient body weight and / or fat mass following administration with the GLP-1 receptor agonist without the non-naturally occurring melanocortin analog.

45. The method or the use of claim 44, wherein the non-naturally occurring melanocortin analog is administered to the subject after administration of the GLP-1 receptor agonist for one dose, one week, or one cycle.

46. The method or the use of claim 44, wherein the non-naturally occurring melanocortin analog is administered to the subject after treatment with the GLP-1 receptor agonist is complete.Docket No.: 146316.8017.WO00 47. The method or the use of any one of claims 1 to 42, wherein the GLP-1 receptor agonist 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 GLP-1 receptor agonist is paused, and wherein, when administration of the non-naturally occurring melanocortin analog is completed, administration of the GLP-1 receptor agonist is resumed.

48. The method or the use of any one of claims 1 to 42, wherein the non-naturally occurring melanocortin analog is administered to the subject for a period of time before administration of the GLP-1 receptor agonist, and wherein, while a non-GLP-1 receptor agonist is administered to the subject, administration of the non-naturally occurring melanocortin analog is paused, and wherein, when administration of the GLP-1 receptor agonist is completed, administration of the non-naturally occurring melanocortin analog is resumed.

49. The method or the use of any one of claims 1 to 46, wherein the method or the use further comprises preventing or reducing one or more side effects associated with the GLP-1 receptor agonist.

50. The method or the use of claim 49, wherein the one or more side effects associated with the GLP-1 receptor agonist is a gastrointestinal effect.

51. The method or the use of claim 50, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea.

52. The method or the use of any one of claims 49 to 51, wherein the one or more side effects associated with the GLP-1 receptor agonist is an adverse cardiovascular event.

53. The method or the use of claim 52, 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, percutaneousDocket No.: 146316.8017.WO00 coronary intervention, heart failure, carotid endarterectomy, and peripheral vascular disease.

54. The method or the use of any one of claims 1 to 51, wherein the method or the use further comprises preventing or reducing one or more side effects associated with the non-naturally occurring melanocortin analog.

55. The method or the use of any one of claims 54, wherein the one or more side effects associated with the non-naturally occurring melanocortin analog is an adverse cardiovascular event.

56. The method or the use of claim 55, wherein the adverse cardiovascular event is sinus tachycardia.

57. The method or the use of any one of claims 1 to 54, wherein the method or the use further comprises reducing obesity-related inflammation in the subject.

58. The method or the use of any one of claims 1 to 55, wherein the method or the use further comprises preserving or improving kidney function in the subject.

59. A method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with the use of a GLP-1 receptor agonist in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the GLP-1 receptor agonist.

60. Use of a non-naturally occurring melanocortin analog for treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with the use of a GLP-1 receptor agonist in a subject, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the GLP- 1 receptor agonist.Docket No.: 146316.8017.WO00 61. The method or the use of claim 59 or 60, 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 GLP-1 receptor agonist required to elicit weight loss in the subject without the non-naturally occurring melanocortin analog.

62. The method or the use of any one of claims 59-61, wherein the one or more side effects associated with the use of a GLP-1 receptor agonist is an adverse cardiovascular event.

63. The method or the use of claim 62, 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.

64. The method or the use of any one of claims 59-61, wherein the one or more side effects associated with the use of the GLP-1 receptor agonist is a gastrointestinal effect.

65. The method or the use of claim 64, wherein the gastrointestinal effect is one or more of nausea, vomiting, and diarrhea.

66. A method of reducing obesity-related inflammation in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; 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 GLP-1 receptor agonist 67. Use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist for reducing obesity-related inflammation in a subject in need thereof, wherein theDocket No.: 146316.8017.WO00 non-naturally occurring melanocortin analog is administered prior to, during, or after administration of the GLP-1 receptor agonist.

68. A method of reducing obesity-related inflammation in a subject in need thereof, comprising administering to the subject a 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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;Docket No.: 146316.8017.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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

69. Use of a non-naturally occurring melanocortin analog for reducing obesity- related inflammation in a subject in need thereof, wherein the non-naturally occurring melanocortin analog comprises 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);Docket No.: 146316.8017.WO00 R2is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that:Docket No.: 146316.8017.WO00 when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

70. A method of preserving or improving kidney function in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; 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 GLP-1 receptor agonist.

71. Use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist 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 GLP-1 receptor agonist.

72. A method of preserving or improving kidney function in a subject in need thereof, comprising administering to the subject: a 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);Docket No.: 146316.8017.WO00 R2is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that:Docket No.: 146316.8017.WO00 when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

73. Use of 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 comprises 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp;Docket No.: 146316.8017.WO00 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

74. The method or the use of any one of claims 1 to 73, 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.Docket No.: 146316.8017.WO00 75. The method or the use of any one of claims 1-74, wherein the method or the use increases tolerance for the GLP-1 receptor agonist relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

76. The method or the use of claim 75, wherein the increased tolerance comprises reduced nausea.

77. The method or the use of any one of claims 1-76, wherein the method or the use maintains or increases a muscle mass level relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

78. The method or the use of claim 77, wherein the muscle mass comprises lean muscle mass.

79. The method or the use of any one of claims 1-78, wherein the method or the use increases a preference level or a compliance level for the GLP-1 receptor agonist relative to a treatment comprising administration of a GLP-1 receptor agonist without a non- naturally occurring melanocortin analog.

80. The method or the use of any one of claims 1-79, wherein the method or the use comprises increasing a weight loss level for the GLP-1 receptor agonist relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.Docket No.: 146316.8017.WO00 81. The method or the use of any one of claims 1-80, wherein the method or the use comprises a reduction in one or more side effects associated with the GLP-1 receptor agonist relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

82. The method or the use of any one of claims 1-81, wherein the method or the use comprises reducing a weight loss plateau for the GLP-1 receptor agonist relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

83. The method or the use of any one of claims 1-82, wherein the method or the use reduces an appetite level or a weight gain level relative to a treatment comprising administration of a GLP-1 receptor agonist without a non-naturally occurring melanocortin analog.

84. The method or the use of any one of claims 1-83, wherein the method or the use does not reduce efficacy of the GLP-1 receptor agonist relative to a control.

85. The method or the use of any one of claims 1-83, wherein the method or the use increases efficacy of the GLP-1 receptor agonist relative to a control.

86. The method or the use of any one of claims 1-83, wherein the method or the use does not plateau body weight loss in the subject.

87. The method or the use of any one of claims 1-83, wherein the method or the use does not plateau fat mass loss in the subject.Docket No.: 146316.8017.WO00 88. The method or the use of any one of claims 1-87, wherein the method or the use prevents fat mass gain after administration of the GLP-1 receptor agonist relative to a control.

89. The method or the use of any one of claims 1-88, wherein the method or the use prevents body weight gain after administration of the GLP-1 receptor agonist relative to a control.

90. The method or the use of any one of claims 1-88, wherein the method or the use reduces body weight gain after administration of the GLP-1 receptor agonist relative to a control.

91. The method or the use of any one of claims 1-88, wherein the method or the use reduces fat mass gain after administration of the GLP-1 receptor agonist relative to a control.

92. The method or the use of any one of claims 1-91, wherein the method or the use reduces a blood sugar level in the subject relative to a control.

93. The method or the use of any one of claims 1-91, wherein the method or the use prevents a blood sugar elevation in the subject after administration of the GLP-1 receptor agonist relative to a control.

94. The method or the use of any one of claims 1-91, wherein the method or the use reduces a blood sugar elevation in the subject after administration of the GLP-1 receptor agonist relative to a control.Docket No.: 146316.8017.WO00 95. The method or the use of any one of claims 1-94, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the GLP-1 receptor agonist relative to a control.

96. The method or the use of any one of claims 1-94, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the GLP-1 receptor agonist relative to a control.

97. The method or the use of any one of claims 1-96, wherein the non-naturally occurring melanocortin analog comprises 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), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp;Docket No.: 146316.8017.WO00 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that: when one or both of R2and R3is Phe, then the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R1and Lys a R9; when R3is Pro, then R4is dPhe and either (i) X1and Y3are present and Y4is absent, or (ii) X1, Y3, and Y4are absent, R1is Nle, R4is dPhe, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; and when R2is Ala, then X1is Nle.

98. The method or the use of any one of claims 1-96, wherein 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);Docket No.: 146316.8017.WO00 R2is selected from the group consisting of Asp, D-cysteine (dCys), proline (Pro), Ala, D-alanine (dAla), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of Pro, D-phenylalanine (dPhe), para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-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, 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; 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 R7or R8when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7or R8is Lys; and a lactam bridge between R1and R9when R1is Asp, R6is dPhe, and R9is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);Docket No.: 146316.8017.WO00 Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 447); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

99. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), wherein:Docket No.: 146316.8017.WO00 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, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3is His or dHis; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or lysine (Lys); R8is absent or lysine (Lys); Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; provided that when R2is Ala, then X1is Nle.

100. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA), 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, aspartic acid (Asp), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);Docket No.: 146316.8017.WO00 R2is selected from the group consisting of Asp, Ala, and D-alanine (dAla); R3is His or dHis; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or lysine (Lys); R8is absent or lysine (Lys); Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; provided that the non-naturally occurring melanocortin analog does not comprise the sequence: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

101. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB): X1-R1-R2-His-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, Arg, dArg, alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);Docket No.: 146316.8017.WO00 R2is Asp; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of His, Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is Pro or Lys; R8is 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; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R7or R8when R2is Asp, and R7or R8is Lys.

102. The method or the use of claim 101, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, Arg, lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is Asp; R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe); R5is His or Arg; R6is tryptophan (Trp); R7is Pro or Lys; R8is absent or Lys;Docket No.: 146316.8017.WO00 Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is dVal or dPro; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2and R7or R8when R2is Asp, and R7or R8is Lys.

103. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC): X1-R1-R2-His-R4-R5-R6-R7-Y1-Y2(IC), wherein: X1is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1is aspartic acid (Asp); R2is alanine (Ala) or D-alanine (dAla); R4is D-phenylalanine (dPhe); R5is Arg; R6is tryptophan (Trp); R7is Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2and Lys at R7; provided that when R2is Ala, then X1is Nle.Docket No.: 146316.8017.WO00 104. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC), wherein: X1is norleucine (Nle), arginine (Arg) or D-arginine (dArg); R1is aspartic acid (Asp); R2is alanine (Ala) or D-alanine (dAla); R4is D-phenylalanine (dPhe); R5is Arg; R6is tryptophan (Trp); R7is Lys; Y1is D-valine (dVal); Y2is D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R2and Lys at R7; provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381); or Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382).

105. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3(ID), wherein: X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro);Docket No.: 146316.8017.WO00 R3is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4is selected from the group consisting of D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is cysteine (Cys) or lysine (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; 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; and a lactam bridge between R1or R2and R7when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7is Lys; provided that: when R3is Pro, then R4is dPhe and either (i) X1and Y3are present, or (ii) X1and Y3are absent, R1is Nle, R5is Arg, R6is Trp, Y1Y2is dVal-dPro, and the C-terminus is amidated; when R4is dPhe, then (i) R3is not His or Gln or (ii) R3is His and either R2is Pro or R5is transPro(guan) or cisPro(guan); and when R4is p(F)dPhe, R3is His, and R1is Nle, then (i) R6is not Trp or (ii) Y3is dVal.

106. The method or the use of any one of claims 1-98, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID), wherein:Docket No.: 146316.8017.WO00 X1is absent or is norleucine (Nle); R1is selected from the group consisting of Nle, D-arginine (dArg), aspartic acid (Asp), and alanine (Ala); R2is selected from the group consisting of Asp, D-cysteine (dCys), and proline (Pro); R3is selected from the group consisting of histidine (His), glutamine (Gln), and proline (Pro); R4is selected from the group consisting of D-phenylalanine (dPhe), para-fluoro-D- phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, cis-4-guanidinyl-proline (cisPro(guan)), and trans-4-guanidinyl-proline (transPro(guan)); R6is tryptophan (Trp) or 2’-D-naphthylalanine (dNal(2’)); R7is cysteine (Cys) or lysine (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; 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; and a lactam bridge between R1or R2and R7when R1or R2is Asp, R4is dPhe or p(F)dPhe, and R7is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592);Docket No.: 146316.8017.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478).

107. The method or the use of any one of claims 3-106, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

108. The method or the use of claim 107, wherein the acyl group is an acetyl group.

109. The method or the use of any one of claims 3-106, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

110. The method or the use of any one of claims 3-109, wherein a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

111. The method or the use of any one of claims 3-109, wherein a C-terminus of the non-naturally occurring melanocortin analog is not modified.Docket No.: 146316.8017.WO00 112. The method or the use of any one of claims 3-111, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond.

113. The method or the use of any one of claims 3-112, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R2and R7.

114. The method or the use of any one of claims 3-113, wherein R4is dPhe or p(F)dPhe.

115. The method or the use of any one of claims 3-114, wherein R3is His.

116. The method or the use of any one of claims 3-115, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); and Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621), wherein c represents cyclization through R2and R7via a lactam bond.

117. The method or the use of any one of claims 3-115, wherein R4is p(F)dPhe.

118. The method or the use of claim 117, wherein R1is selected from the group consisting of Ala, Arg, dArg, Lys, dLys, His, and dHis.

119. The method or the use of claim 117 or 118, wherein Y1is dVal and Y2is dPro.

120. The method or the use of any one of claims 3-115 and 117-119, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);Docket No.: 146316.8017.WO00 Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468), wherein c represents cyclization through R2and R7via a lactam bond.

121. The method or the use of claim 117 or 118, wherein Y1is dTle and Y2is dPro.

122. The method or the use of any one of claims 3-115, 117, 118, and 121, wherein the sequence according of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485), wherein c represents cyclization through R2and R7via a lactam bond.

123. The method or the use of any one of claims 3-115, wherein R4is p(F)dPhe.

124. The method or the use of claim 123, wherein at least one of X1, Y3, and Y4is present.Docket No.: 146316.8017.WO00 125. The method or the use of any one of claims 3-115, 124, and 123, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478), wherein c represents cyclization through R2and R7via a lactam bond.

126. The method or the use of any one of claims 3-115, wherein R5is selected from the group consisting of His, transPro(guan) and cisPro(gaun).

127. The method or the use of any one of claims 3-115 and 126, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229); and Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470), wherein c represents cyclization through R2and R7via a lactam bond.

128. The method or the use of any one of claims 3-115, wherein R6is dNal(2’).

129. The method or the use of any one of claims 3-115 and 128, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]- dVal-dPro-NH2 (SEQ ID NO: 471), wherein c represents cyclization through R2and R7via a lactam bond.Docket No.: 146316.8017.WO00 130. The method or the use of any one of claims 3-114, wherein R3is not His.

131. The method or the use of any one of claims 3-114 and 130, wherein R3is selected from the group consisting of dHis, Gln, and Pro.

132. The method or the use of any one of claims 3-115, 130, and 131, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491); and Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639), wherein c represents cyclization through R2and R7via a lactam bond.

133. The method or the use of any one of claims 3-112, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R1and R7or R2and R8.

134. The method or the use of any one of claims 3-112 and 133, wherein R4is dPhe.

135. The method or the use of any one of claims 3-112, 133, and 134, wherein R3is His.

136. The method or the use of any one of claims 3-112 and 133-135, wherein X1and R1are present.

137. The method or the use of any one of claims 3-112 and 133-136, wherein R2is Ala or dAla.Docket No.: 146316.8017.WO00 138. The method or the use of any one of claims 3-112 and 133-137, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380), wherein c represents cyclization through R1and R7via a lactam bond.

139. The method or the use of any one of claims 3-112 and 133-135, wherein either R2of R7is Pro.

140. The method or the use of any one of claims 3-112, 133-135, and 139, wherein the sequence of any one of Formulae (I)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418). wherein c represents cyclization through R2and R7via a lactam bond.

141. The method or the use of any one of claims 3-112, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a lactam bond between R1and R9.

142. The method or the use of any one of claims 3-112 and 141, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 420), wherein c represents cyclization through R1and R9via a lactam bond.

143. The method or the use of any one of claims 3-111, wherein the sequence of any one of Formulae (I)-(ID) is cyclized by a disulfide bond.Docket No.: 146316.8017.WO00 144. The method or the use of any one of claims 3-111 and 142, wherein R4is p(Cl)dPhe.

145. The method or the use of any one of claims 3-111, 142, and 143, wherein the sequence of any one of Formulae (I)-(ID) is: Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]- dVal-dPro-NH2 (SEQ ID NO: 498), wherein c represents cyclization through R2and R7via a disulfide bond.

146. The method or the use of any one of claims 1-96, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 228, 229, 268, 295, 297, 363, 365, 370, 378-380, 418, 420, 462-471, 473-486, 491, and 498.

147. The method or the use of claim 143, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 268, 363, 365, 378-380, 418, 464-470, 474-478, and 481-486.

148. The method or the use of claim 143, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 228-229, 363, 418, 462-485, and 621.

149. The method or the use of claim 143, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 223, 363, 418, 464-470, 474-478, 481-485, and 621.

150. The method or the use of claim 143, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 268 and 378- 380.

151. The method or the use of claim 143, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 228, 229, 295, 297, 462, 463, 471, 473, 479, 480, 491, and 498.Docket No.: 146316.8017.WO00 152. The method or the use of any one of claims 1-151, wherein the GLP-1 receptor agonist is present in a first pharmaceutical composition.

153. The method or the use of claim 152, wherein the first pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and / or carriers.

154. The method or the use of claim 153, wherein the one or more pharmaceutically acceptable excipients and / or carriers of the first pharmaceutical composition comprise water.

155. The method or the use of any one of claims 152-154, wherein 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, relative to a total volume of the first pharmaceutical composition.

156. The method or the use of claim 155, wherein the GLP-1 receptor agonist 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.

157. The method or the use of claim 155, wherein the GLP-1 receptor agonist 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.

158. The method or the use of claim 155, wherein the GLP-1 receptor agonist isDocket No.: 146316.8017.WO00 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.

159. The method or the use of claim 155, wherein the GLP-1 receptor agonist 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 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.

160. The method or the use of claim 155, wherein the GLP-1 receptor agonist 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.

161. The method or the use of claim 155, wherein the GLP-1 receptor agonist 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.

162. The method or the use of any one of claims 152-154, wherein the GLP-1 receptor is a dual GLP-1 / GIP receptor agonist and is present in the first pharmaceuticalDocket No.: 146316.8017.WO00 composition in a concentration of 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

163. The method or the use of claim 162, 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.

164. The method or the use of any one of claims 1 to 154, wherein the GLP-1 receptor agonist is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

165. The method or the use of any one of claims 152 to 155, wherein the first pharmaceutical composition comprising the GLP-1 receptor agonist is administered to the subject parenterally.

166. The method or the use of any one of claims 152 to 156, wherein the first pharmaceutical composition comprising the GLP-1 receptor agonist is administered to a subject subcutaneously.

167. The method or the use of any one of claims 1 to 157, 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.

168. The method or the use of any one of claims 1 to 158, 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.Docket No.: 146316.8017.WO00 169. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a GLP-1 receptor agonist 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 GLP-1 receptor agonist for the at least one treatment cycle; and administering a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 295 to the subject after administration of the GLP-1 receptor agonist, such that the subject loses a sufficient amount of body weight and / or fat mass following administration of the non-naturally occurring melanocortin analog.

170. Use of a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 295 for reducing body weight and / or fat mass in a subject in need thereof who has failed to lose sufficient body weight and / or fat mass following administration of a GLP-1 receptor agonist for at least one treatment cycle, wherein the non-naturally occurring melanocortin analog is administered after administration of the GLP-1 receptor agonist such that the subject loses a sufficient amount of body weight and / or fat mass.

171. A method of promoting weight loss in a subject currently being administered a GLP-1 receptor agonist, the method comprising administering to the subject a non-naturally occurring melanocortin analog, 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.

172. Use of a non-naturally occurring melanocortin analog and a GLP-1 receptor agonist for reducing body weight and / or fat mass in a subject in need thereof, 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.

173. The method or the use of claim 171 or 172, wherein the method or the use further comprises treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.Docket No.: 146316.8017.WO00 174. The method or the use of any one of claims 171-173, 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.

175. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising: administering a combination therapy comprising: (a) GLP-1 receptor agonist; and (b) a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 295, 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.

176. Use of a combination therapy comprising: (a) a GLP-1 receptor agonist; and (b) a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 295, for reducing body weight and / or fat mass in a subject in need thereof, 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.

177. The method or the use of any one of claims 1-175, wherein a blood glucose level of the subject is decreased following administration of a first dose of the combination therapy or of the non-naturally occurring melanocortin analog.

178. The method or the use of any one of claims 1-177, wherein the GLP-1 receptor agonist is semaglutide and the combination therapy comprising the GLP-1 receptor agonist and the non-naturally occurring melanocortin analog has an additive effect on the subject’s weight loss.Docket No.: 146316.8017.WO00 179. The method or the use of claim 178, wherein the combination therapy has an additive effect on the subject’s fat mass loss.

180. The method or the use of clam 282 or 283, wherein a percent lean mass of the subject is increased following administration of a first dose of the combination therapy.

181. The method or the use of claim 178, wherein the combination therapy has an additive effect on suppressing the subject’s appetite 182. The method or the use of any one of claims 1-181, wherein the GLP-1 receptor agonist is a dual GLP-1 / GIP receptor agonist.

183. The method or the use of claim 182, wherein the dual GLP-1 / GIP receptor agonist is tirzepatide and the combination therapy has a synergistic effect on the subject’s weight loss.

184. The method or the use of claim 183, wherein the combination therapy has a synergistic effect on the subject’s fat mass loss.

185. The method or the use of claim 183, wherein the combination therapy has a synergistic effect on the suppressing the subject’s appetite.

186. The method or the use of any one of claims 1-185, 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 the combination therapy.

187. The method or the use of any one of claims 1-185, 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%,Docket No.: 146316.8017.WO00 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 the combination therapy.

188. The method or the use of any one of claims 1-185, 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 the combination therapy.

189. The method or the use of any one of claims 1-185, 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 the combination therapy.

190. The method or the use of any one of claims 1-185, 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 the combination therapy.

191. The method or the use of any one of claims 1-185, 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 the combination therapy.