Combination of GLP-1 receptor agonist, MC4r agonist, and HCAR2 agonist for use in weight loss

Abstract

Provided herein is the use of a triple combination comprising a glucagon-like peptide-1 (GLP-1) receptor agonist, a melanocortin-4 receptor (MC4R) agonist, and a hydroxycarboxylic acid receptor 2 (HCAR2) agonist for weight loss. The use of the triple combination leads to weight loss with reduced side effects typically associated with the GLP-1 receptor agonist.

Description

Attorney Docket No. 300902000540COMBINATION OF GLP-1 RECEPTOR AGONIST, MC4R AGONIST, AND HCAR2AGONIST FOR USE IN WEIGHT LOSSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 776,912, filed March 24, 2025, the entire content of which is incorporated herein by reference for all purposes.FIELD

[0002] The present disclosure relates generally to therapies for weight loss and weight management, and more specifically to the use of a triple combination comprising a glucagon-like peptide-1 (GLP-1) receptor agonist, a melanocortin-4 receptor (MC4R) agonist, and a hydroxy carboxylic acid receptor 2 (HCAR2) agonist for weight loss.BACKGROUND

[0003] Glucagon-like peptide-1 (GLP-1) is a hormone produced by the small intestine that plays several roles in the body. The hormone (a) triggers insulin release from the pancreas, (b) blocks glucagon secretion, thereby preventing more glucose from going into the bloodstream, (c) slows stomach emptying, thereby releasing less glucose / sugar from the food eaten into the bloodstream, and (d) affects the parts of the brain that processes hunger and satiety, increasing how full a person feels after eating.

[0004] Currently, several GLP-1 receptor agonists have been found to have weight loss effects and are approved to help treat obesity. Roughly 9-12% of the US population have tried a GLP-1 and this number is projected to rise. Despite their success, side effects plague many people taking these drugs. Nausea and vomiting are some of the most common adverse events reported both in clinical trials and in the real world. About 40% of people who have gone on a GLP-1 agonist have stopped, citing these side effects as the reason they stopped taking the medication.

[0005] Thus, what is desired in the art are methods to achieve clinically significant weight loss using GLP-1 receptor agonists in a way that reduce nausea and vomiting.1MF-368017554Attorney Docket No. 300902000540BRIEF SUMMARY

[0006] In some aspects, provided is a pharmaceutical combination, comprising: a glucagon-like peptide-1 (GLP-1) receptor agonist, a melanocortin-4 receptor (MC4R) agonist, and a hydroxycarboxylic acid receptor 2 (HCAR2) agonist, formulated for administration to a subject. In some embodiments, at least two or all three of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose.

[0007] In certain aspects, provided is a fixed dose pharmaceutical composition, comprising: a therapeutically effective dose of the pharmaceutical combination described herein, including the combination of GLP-1 receptor agonist, MC4R agonist and HCAR2 agonist; and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated as a solution for injection, such as subcutaneous injection.

[0008] In some aspects, provided is a method of reducing bodyweight or managing weight in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective dose of the pharmaceutical combination or the pharmaceutical composition as described herein, including the combination of GLP-1 receptor agonist, MC4R agonist and HCAR2 agonist.

[0009] In other aspects, provided is a method of reducing bodyweight or managing weight in a subject taking a glucagon-like peptide-1 (GLP-1) receptor agonist, comprising administering to the subject a combination of (i) a therapeutically effective dose of a melanocortin-4 receptor (MC4R) agonist, and (ii) a therapeutically effective dose a hydroxycarboxylic acid receptor 2 (HCAR2) agonist, wherein the combination serves as an adjuvant to the GLP-1 receptor agonist to reduce side effects experienced by the subject taking the GLP-1 receptor agonist.

[0010] In some variations, the use of such triple combination yields a synergistic effect on reducing bodyweight in the subject with reduced side effects compared to administration of each agonist alone, particularly with respect to the side effects experienced by the subject taking the GLP-1 receptor agonist. In other variations, the use of such triple combination unexpectedly improves the ratio of weight loss to nausea, e.g., as compared to the GLP-1 receptor agonist alone. In certain variations, the use of such triple combination unexpectedly2MF-368017554Attorney Docket No. 300902000540allows for reduction in the GLP-1 agonist used for weight loss and lower nausea, which may be beneficial for subjects (e.g., humans) who are generally intolerant of GLP-1 drugs.DESCRIPTION OF THE FIGURES

[0011] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0012] FIG. 1 is a graph that shows different doses of semaglutide and locomotion binned hourly.DETAILED DESCRIPTION

[0013] The following description sets forth exemplary compositions, methods, parameters, kits and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0014] Provided herein is the use of a triple combination of agonists suitable for use in weight loss or weight management therapies. In some aspects, provided is a pharmaceutical combination comprising a glucagon-like peptide-1 (GLP-1) receptor agonist, a melanocortin-4 receptor (MC4R) agonist, and a hydroxy carboxylic acid receptor 2 (HCAR2) agonist, formulated for administration to a subject.GLP-1 receptor agonists

[0015] GLP-1 receptor agonists bind and activate the GLP-1 receptor, thereby enhancing insulin secretion and slowing gastric emptying. GLP-1 may also interact with the parts of the brain that help to reduce appetite and signal a feeling of fullness.

[0016] In some variations, the GLP-1 receptor agonist activates at least a GLP-1 receptor or causes GLP-1 agonism. In certain variations, the GLP-1 receptor agonist targets one or more additional receptors (e.g., in addition to targeting a GLP-1 receptor). For example, in certain variations, such additional receptors may include a glucose-dependent insulinotropic polypeptide (GIP) receptor, or a glucagon (GCG) receptor, or a combination thereof. In one variation, the GLP-1 receptor agonist is a dual GLP-l / GIP agonist, or a dual GLP-1GCG agonist.3MF-368017554Attorney Docket No. 300902000540

[0017] In some variations of the foregoing, the GLP-1 receptor agonist leads to clinically significant weight loss. In certain variations, the GLP-1 receptor agonist leads to at least 5%, or between 5% and 30% reduction in body weight in the subject.

[0018] Suitable GLP-1 receptor agonists for use in the combinations described herein include, for example, liraglutide, exenatide, dulaglutide, tirzepatide, retatrutide, semaglutide, VK2735, MET-097, orforglipron, and survodutide.

[0019] In some variations of the foregoing, a therapeutically effective dose of the GLP-1 receptor agonist is used in the combination. In certain variations, when the GLP-1 receptor agonist is used in the combination, a reduced dose may be used to achieve weight loss with lower nausea, thereby making the combination suitable for subjects (e.g., humans) who may be intolerant of GLP-1 receptor agonists. In certain variations, the dose of GLP-1 receptor agonist is between 0.25 mg and 5 mg. In one variation, the total daily dose of GLP-1 receptor agonist is between 0.25 mg and 5 mg.

[0020] In one variation, the GLP-1 receptor agonist is semaglutide. In some embodiments of the foregoing, the therapeutically effective dose for semaglutide formulated for subcutaneous injection is between 0.25 mg / 0.5mL and 2.4 mg / 0.75 mL once weekly, or at about 0.25 mg / 0.5mL, 0.5 mg / 0.5 mL, 1 mg / 0.5 mL, 1.7 mg / 0.75 mL, or 2.4 mg / 0.75 mL once weekly. In certain variations, the therapeutically effective dose of semaglutide formulated for subcutaneous injection used in the combinations herein is below 2.4 mg / 0.75 mL or 1.7 mg / 0.75 mL once weekly.

[0021] In other embodiments, the therapeutically effective dose for semaglutide formulated for oral administration is between 3 mg and 14 mg once daily, or at about 3 mg, 7 mg or 14 mg once daily. In certain variations, the therapeutically effective dose of semaglutide formulated for oral administration used in the combinations herein is below 4 mg once daily.

[0022] In another variation, the GLP-1 receptor agonist is liraglutide. In some embodiments of the foregoing, the therapeutically effective dose for liraglutide formulated for subcutaneous injection is between 0.6 mg and 3 mg daily, or at about 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg daily. In certain variations, the therapeutically effective dose of liraglutide formulated for subcutaneous injection is below 3 mg daily.4MF-368017554Attorney Docket No. 300902000540

[0023] In another variation, the GLP-1 receptor agonist is tirzepatide. In some embodiments of the foregoing, the therapeutically effective dose for tirzepatide formulated for subcutaneous injection is between 2.5 mg / 0.5mL and 15 mg / 0.5 mL once weekly, or at about 2.5 mg / 0.5mL, 5 mg / 0.5 mL, 7.5 mg / 0.5 mL, 10 mg / 0.5 mL, 12.5 mg / 0.5 mL or 15 mg / 0.5 mL once weekly. In certain variations, the therapeutically effective dose of tirzepatide formulated for subcutaneous injection is below 15 mg / 0.5 mL once weekly.

[0024] In another variation, the GLP-1 receptor agonist is exenatide. In some embodiments of the foregoing, the therapeutically effective dose for exenatide formulated for subcutaneous injection is between 5 mcg per dose twice daily and 10 mcg twice daily, or at about 5 mcg or 10 mcg twice daily. In certain variations, the therapeutically effective dose for exenatide formulated for subcutaneous injection is below 10 mcg twice daily.

[0025] In other embodiments of the foregoing, the therapeutically effective dose for exenatide formulated for subcutaneous injection is 2 mg once weekly. In certain variations, the therapeutically effective dose for exenatide formulated for subcutaneous injection is below 2 mg once weekly.

[0026] In another variation, the GLP-1 receptor agonist is dulaglutide. In some embodiments of the foregoing, the therapeutically effective dose for dulaglutide formulated for subcutaneous injection is between 0.75 mg / 0.5mL and 4.5 mg / 0.5 mL once weekly, or at about 0.75 mg / 0.5mL, 1.5 mg / 0.5 mL, 3 mg / 0.5 mL, or 4.5 mg / 0.5 mL once weekly. In certain variations, the therapeutically effective dose for dulaglutide formulated for subcutaneous injection is below 0.75 mg / 0.5mL, 1.5 mg / 0.5 mL, 3 mg / 0.5 mL, or 4.5 mg / 0.5 mL once weekly.

[0027] In another variation, the GLP-1 receptor agonist is retatrutide. In some embodiments of the foregoing, the therapeutically effective dose for retatrutide formulated for subcutaneous injection is between 1 mg and 12 mg weekly, or at about 1 mg, 4 mg, 8 mg, or 12 mg weekly. In certain variations, the therapeutically effective dose for retatrutide formulated for subcutaneous injection is below 12 mg weekly.

[0028] In another variations, the GLP-1 receptor agonist is survodutide. In some embodiments of the foregoing, the therapeutically effective dose for survodutide formulated for subcutaneous injection is between 0.5 mg and 5 mg once weekly, or at about 0.6 mg, 2.4 mg, 3.6 mg, 4.8 mg, or 6 mg once weekly. In certain variations, the therapeutically effective 5MF-368017554Attorney Docket No. 300902000540dose for survodutide formulated for subcutaneous injection is below 3.6 mg, 4.8 mg or 6 mg once weekly.MC4R agonist

[0029] MC4R agonists activates the melanocortin 4 receptor, which is involved in regulating adipose tissue formation and energy homeostasis. MC4R agonists have been implicated in the homeostatic control of food intake and bodyweight.

[0030] In some variations, the MC4R agonist crosses the blood brain barrier in the subject.

[0031] In some variations, the MC4R agonist activates at least MC4R or causes MC4R agonism. In certain variations, the MC4R agonist targets one or more additional receptors (e.g., in addition to targeting MC4R). For example, in certain variations, such additional receptors may include a melanocortin- 1 receptor (MC1R), a melanocortin-3 receptor (MC3R), or a melanocortin-5 receptor (MC5R), or any combination thereof.

[0032] Suitable MC4R agonists for use in the combinations described herein include, for example, setmelanotide, bremelanotide, or PL-8905.

[0033] In some variations of the foregoing, a therapeutically effective dose of the MC4R agonist is used in the combination. In certain variations, the dose of MC4R agonist is between 0.1 mg and 2 mg. In certain variations, the total daily dose of MC4R agonist is between 0.1 mg and 2 mg.

[0034] In one variation, the MC4R agonist is setmelanotide. In some embodiments of the foregoing, the therapeutically effective dose for setmelanotide formulated for subcutaneous injection is between 1 mg and 3 mg once daily, or at about 1 mg, 2 mg or 3 mg once daily.

[0035] In another variation, the MC4R agonist is bremelanotide. In some embodiments of the foregoing, the therapeutically effective dose for subcutaneous injection is about 1.75 mg / 0.3 mL.

[0036] In another variation, the MC4R agonist is PL-8905. In some embodiments of the foregoing, the therapeutically effective dose for PL-8905 formulated for subcutaneous6MF-368017554Attorney Docket No. 300902000540injection is between 0.1 mg / kg and 5 mg / kg, or between 0.3 mg / kg and 3 mg / kg, or at about 0.3 mg / kg, 1 mg / kg or 3 mg / kg.HCAR2 agonist

[0037] HCAR2 agonists activate the GI protein signaling pathway, and have observed to show anti-inflammatory effects.

[0038] In some variations, the HCAR2 agonist crosses the blood brain barrier in the subject.

[0039] Suitable HCAR2 agonists for use in the combinations described herein include, for example, agonists for use in the combinations described herein include, for example, GSK256073, MK6892, or SCH900271.

[0040] In some variations of the foregoing, a therapeutically effective dose of the HCAR2 agonist is used in the combination. In certain variations, the dose of HCAR2 agonist is between 0.1 mg and 100 mg, between 1 mg and 75 mg, or between 5 mg and 50 mg. In certain variations, the total daily dose of HCAR2 agonist is between 0.1 mg and 100 mg, between 1 mg and 75 mg, or between 5 mg and 50 mg.

[0041] In one variation, the HCAR2 agonist is GSK256073. In some embodiments of the foregoing, the therapeutically effective dose for GSK256073 is between 1 mg and 50 mg once daily or twice daily, or at about 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg once daily or twice daily.

[0042] In another variation, the HCAR2 agonist is MK6892. In some embodiments of the foregoing, the therapeutically effective dose for MK6892 is between 1 mg / kg and 100 mg / kg.

[0043] In another variation, the HCAR2 agonist is SCH900271. In some embodiments of the foregoing, the therapeutically effective dose for SCH900271 is between 1 mg / kg and 10 mg / kg.Exemplary Combinations

[0044] In one aspect, the pharmaceutical combination comprises: retatrutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).7MF-368017554Attorney Docket No. 300902000540

[0045] In another aspect, the pharmaceutical combination comprises: semaglutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).

[0046] In another aspect, the pharmaceutical combination comprises: tirzepatide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).

[0047] In another aspect, the pharmaceutical combination comprises: liraglutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).

[0048] In another aspect, the pharmaceutical combination comprises: retatrutide (GLP-1 receptor agonist), bremelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).

[0049] In another aspect, the pharmaceutical combination comprises: retatrutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and MK6892 (HCAR2 agonist).

[0050] In another aspect, the pharmaceutical combination comprises: retatrutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and SCH900271 (HCAR2 agonist).

[0051] In yet another aspect, the pharmaceutical combination comprises: survodutide (GLP-1 receptor agonist), setmelanotide (MC4R agonist) and GSK256073 (HCAR2 agonist).Fixed Dose Combinations

[0052] A fixed dose combination (FDC) is a combination of two or more active drugs in a single dosage form.

[0053] In some embodiments, at least two or all three of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination. In certain embodiments, two of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination for subcutaneous administration, and the remaining of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist is formulated for oral administration. In other embodiments, two of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination for oral administration, and the remaining of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist is formulated for subcutaneous administration.8MF-368017554Attorney Docket No. 300902000540

[0054] In some variations, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination, and separately administered from the GLP-1 receptor agonist to the subject.Pharmaceutical Compositions

[0055] In some embodiments, the combination of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist is formulated as a fixed dose combination, further comprising at least one pharmaceutically acceptable carrier or excipient. Any suitable carriers and excipients may be used. In some variations, the pharmaceutical composition is a solution formulated for injection, such as subcutaneous injection. In other variations, the pharmaceutical composition is formulated for oral administration, e.g., in the form of a tablet or capsule.

[0056] In such pharmaceutical compositions, each of the GLP-1 receptor agonist, the MC4R agonist, and the HCAR2 agonist is present in the composition at a therapeutically effective dose. As used herein, a “therapeutically effective dose” refers to an amount of the compound or composition that is sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect. The effective dose will vary with the age or general condition of the individual or subject (e.g., a human), the severity of the condition being treated, the particular agents administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art.

[0057] In some variations, the dose of the GLP-1 receptor agonist, the MC4R agonist, and the HCAR2 agonist used in combination is lower than the amount of each individual agonist used alone to achieve a therapeutic and / or beneficial effect. In certain variations, the GLP-1 receptor agonist is present in the composition at a dose between 0.025mg and 0.25mg. In certain variations, the MC4R agonist is present in the composition at a dose between 0. Img and Img. In certain variations, the HCAR2 agonist is present in the composition at a dose between 0.5mg and 5mg.Modes of Administration

[0058] In some embodiments, the combination described herein may be administered orally or by injection. In other embodiments where two of the three agonists are formulated9MF-368017554Attorney Docket No. 300902000540as a fixed dose combination, the fixed dose combination may be administered orally and the remaining agonist may be formulated for administration by injection, and vice versa.

[0059] In the embodiment where administration is by injection, the pharmaceutical composition is formulated as a solution for injection, such as subcutaneous injection. Any suitable methods and devices may be employed to administer the solution for injection. For instance, an injection pen may be used. In certain variations, the injection pen is a singledose pen. In one variation, the injection pen is a pre-filled with the pharmaceutical combination or the pharmaceutical composition.

[0060] In the embodiment where administration is oral, the pharmaceutical composition is formulated as a solid dosage form, such as a tablet or capsule, or as a liquid form.Treatment Methods

[0061] In some aspects, provided is a method of reducing bodyweight or managing weight in a subject. In other aspects, provided is a method of treating obesity. In some variations of the foregoing aspects, the method comprises: administering to the subject a therapeutically effective dose of the pharmaceutical combination or the pharmaceutical composition as described herein. The administration of the combination of the GLP-1 receptor agonist, the MC4R agonist, and the HCAR2 agonist was observed to yield a synergistic effect on reducing bodyweight in the subject with reduced side effects compared to administration of each agonist alone.

[0062] In some variations, “treatment” or “treating” includes an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.10MF-368017554Attorney Docket No. 300902000540

[0063] In some embodiments, the pharmaceutical combination or the pharmaceutical composition is administered as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management. In some variations, the subject is obese. In certain variations, the subject suffers from diabetes, e.g., type 2 diabetes. In one variation, the subject is obese and diabetic.

[0064] In some variations, the subject is a human. In certain variations, the subject is an adult human. In one variation, the adult human has an initial BMI of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition. In other variations, the subject is a pediatric human. In certain variations, the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity). In other variations, the pediatric human is aged 12 years and older with a body weight above 60 kg and an initial BMI corresponding to 30 kg / m2for adults (obese) by international cut-offs.

[0065] In some embodiments, the pharmaceutical combination or the pharmaceutical composition described herein is administered is administered once daily, once weekly or once monthly to the subject.Use as Adjuvant

[0066] In other aspects, provided is a method of reducing bodyweight or managing weight in a subject taking a GLP-1 receptor agonist. In some embodiments, the method comprises administering to the subject a combination of (i) a therapeutically effective dose of a MC4R agonist, and (ii) a therapeutically effective dose a HCAR2 agonist. Such combination may serve as an adjuvant to the GLP-1 receptor agonist to reduce side effects experienced by the subject taking the GLP-1 receptor agonist.

[0067] In some embodiments, the MC4R agonist and the HCAR2 agonist are formulated in a fixed dose pharmaceutical composition. In certain embodiments, the MC4R agonist and the HCAR2 agonist are formulated in a fixed dose pharmaceutical composition for injection; and the GLP-1 receptor agonist is formulated for oral or subcutaneous administration. In one embodiment, the MC4R agonist and the HCAR2 agonist are formulated for subcutaneous administration. In one variation, the GLP-1 receptor agonist is formulated for oral administration. In another variation, the GLP-1 receptor agonist is formulated for subcutaneous administration.11MF-368017554Attorney Docket No. 300902000540

[0068] In yet other aspects, provided is a pharmaceutical composition, comprising a melanocortin-4 receptor (MC4R) agonist and a hydroxy carboxylic acid receptor 2 (HCAR2) agonist, formulated for administration to a subject taking a glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, the MC4R and the HCAR2 is formulated as a fixed dose combination.Articles of Manufacture and Kits

[0069] The present disclosure also provides articles of manufacture and / or kits containing any of the pharmaceutical combinations or pharmaceutical compositions described herein. Articles of manufacture and / or kits of the present disclosure may include container(s) comprising the combination of the present disclosure. Suitable containers may include, for example, bottles, vials, syringes, and IV solution bags. The containers may be formed from a variety of materials such as glass or plastic. In some embodiments, the articles of manufacture and / or kits further include instructions for use in accordance with any of the methods of the present disclosure. In some embodiments, these instructions comprise a description of administration of any of the pharmaceutical combinations or pharmaceutical compositions described herein, to reduce body weight or manage weight in a subject, or treat obesity in a subject in need thereof. The article of manufacture and / or kit may further comprise a description of selecting a subject suitable for treatment using the combination herein.

[0070] The instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the articles of manufacture and / or kits of the present disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the article of manufacture and / or kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. The label or package insert also provides instructions for practicing any of the methods described herein.

[0071] The articles of manufacture and / or kits of the present disclosure may be in suitable packaging. Suitable packaging includes, for example, vials, pre-filled syringes, bottles, jars, and flexible packaging (e.g., sealed Mylar or plastic bags). Also contemplated are packages for use in combination with a specific device, such as an injection pen. In one embodiment,12MF-368017554Attorney Docket No. 300902000540the injection pen is a single-dose pen. In some variations, the injection pen is pre-filled with the pharmaceutical composition herein.

[0072] An article of manufacture and / or kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).

[0073] Articles of manufacture and / or kits may optionally provide additional components such as buffers and interpretive information. Normally, the article of manufacture and / or kit comprises a container and a label or package insert(s) on or associated with the container.EXAMPLES

[0074] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Example 1: Combination Screening

[0075] This Example tests various combinations of GLP-1 receptor agonists, MC4R agonists and HCAR2 agonists in a rodent model.Materials and Methods

[0076] Animals: Male and female mice were obtained from commercially available sources at age 8 to 12 weeks. Mice were habituated in behavior boxes equipped with a running wheel in a 12 / 12 light cycle for 10 days and fed ad libitum water, high fat diet (HFD) and regular chow in separate hoppers. Each box housed 2 mice of the same sex, with equal distribution between sexes. At 10 days mice are eligible for drug injection.

[0077] Experiment design: Mice were randomly assigned to an injection group and would receive an IP injection of a different, randomized drug or drug combination with a minimum of 3 days between injections. Post injection, behavior and physiological parameters are monitored via video, thermal camera, CO2 sensor and humidity sensor for 12 hours. Body weights, food weight in the hoppers and water weight in water bottles were measured just prior to injection. At the end of 24 hours, all weights were measured again. Mice were always 13MF-368017554Attorney Docket No. 300902000540injected at the same time of day and total injection volumes were kept below 0.3 ml, with 0.1ml median injection volume.

[0078] Behavioral quantification: Video footage of mice was captured using cameras positioned on the ceilings of each experimental apparatus. To extract relevant frame-by-frame information from the video data, deep learning models that inferred bounding boxes surrounding each mouse and keypoint locations across various body parts were employed. These model-derived predictions were then processed to analyze numerous dimensions of mouse behavior. Specifically, features encompassing movement dynamics (e.g., locomotion and turn biases) and social interaction metrics (e.g., inter-mouse distances and relative orientations) were computed. In total, 14 distinct behavioral features were extracted for each video frame within each experiment.

[0079] To generate a summary representation of behavior, behavioral features were then binned into hourly intervals, and the median feature values were computed across the two mice sharing each experimental apparatus. Analysis focused exclusively on the 12 hours immediately following dosing to capture peak drug-induced behavioral effects. FIG. 1 provides an example of different doses of semaglutide and locomotion binned hourly.

[0080] Human nausea prediction: To build a prediction from behavioral data to human nausea in the field, clinical trial data were surveyed for the top available and late stage GLP-1 -based obesity drugs: liraglutide, semaglutide, tirzepatide, retatrutide. The timepoints used were limited to between 40 and 70 weeks to ensure similar reporting opportunities.Table 1. Summary of clinical trial data usedDrug Dose Timepoint (wks) Body weight change (%) Nausea Liraglutide 3 68 -6.4 59.1 Liraglutide 3 56 -8 40.2 Placebo 0 68 -2 17.4 Placebo 0 48 -2.1 11 Placebo 0 56 -2.6 14.7 Placebo 0 68 -3.4 9.214MF-368017554Attorney Docket No. 300902000540Placebo 0 68 -5.7 22.1 Placebo 0 68 -2.2 22.4 Retatrutide 1 48 -8.7 14 Retatrutide 4 48 -16.3 18 Retatrutide 4 48 -17.8 36 Retatrutide 8 48 -21.7 17 Retatrutide 8 48 -23.9 60 Retatrutide 12 48 -24.2 45 Semaglutide 1 68 -7 32.1 Semaglutide 1 40 -5.6 15 Semaglutide 1 40 -6.7 17.9 Semaglutide 1.7 68 -9.6 18 Semaglutide 2.4 68 -13.2 18 Semaglutide 2.4 68 -9.6 33.7 Semaglutide 2.4 68 -16 58.2 Semaglutide 2.4 68 -15.8 61.1 Semaglutide 2.4 40 -6.4 14 Semaglutide 2.4 68 -14.9 44.2 Tirzepatide 5 40 -8.5 17.4 Tirzepatide 10 40 -11 19.2 Tirzepatide 15 40 -13.1 22.1

[0081] The data in Table 1 may be plotted, with the median of each dosing level as a dot, and lines connecting different doses of the same drug. The more ideal the drug, the further down and to the left the drug will appear.

[0082] Human doses were mapped back to mouse dose via literature, as set forth in Table 2 below.15MF-368017554Attorney Docket No. 300902000540Table 2. Human dose to mouse dose mappingMouse DoseDrug Human Dose (mg) (mg / kg)Liraglutide 3 0.134Placebo 0 73Retatrutide 4 0.005Retatrutide 8 0.015Retatrutide 12 0.045Semaglutide 1 0.01Semaglutide 2.4 0.03Tirzepatide 5 0.003Tirzepatide 10 0.01Tirzepatide 15 0.03

[0083] ElasticNet regression was used to create a transform between mouse behavior and human nausea for a given dose. Leave-One-Out cross validation was used to ensure models were performing well. Spearman correlations of 0.8 and Pearson R2of 0.73 were achieved with this method. See Table 3.Table 3. Data for Leave-One-Out Cross Validation: Nausea PredictionDrug Dose Actual Nausea Rate Predicted Nausea Rate Placebo 0.0 0.14 0.21 Semaglutide 2.4 0.40 0.43 Semaglutide 1.0 0.22 0.30 Tirzepatide 10.0 0.26 0.24 Retatrutide 8.0 0.39 0.34 Tirzepatide 15.0 0.27 0.30 Tirzepatide 5.0 0.21 0.25 Retatrutide 4.0 0.27 0.18 Retatrutide 12.0 0.45 0.43 Liraglutide 1.8 0.31 0.32Liraglutide 3.0 0.50 0.4116MF-368017554Attorney Docket No. 300902000540

[0084] The feature importance (beta coefficients) is provided in Table 4 below. In general, movement features were negatively correlated with human nausea prediction (time spent on the running wheel, move, locomotion) while time spent being social (defined by the two mice touching) was positively correlated. This model was then used to predict nausea for different drugs and drug combinations (see results).Table 4. Feature importance (beta coefficients)Features Beta coefficientswheel -0.069move -0.054locomotion -0.050right rotation -0.042left rotation -0.037social 0.013foodhopper 0.000right rotation amount 0.000right rotation speed 0.000left rotation speed 0.000left rotation amount 0.000water 0.000left angle 0.000otherhopper 0.000left speed 0.000right speed 0.000social distance 0.000locomotor speed 0.000right angle 0.000Results

[0085] Computationally deriving combinations: We used a proprietary algorithm to obtain predictions of Efficacy / Safety for weight loss (“optimal therapeutic profile” in the figure). See Table 5. We had the algorithm make predictions for current obesity drugs tirzepatide and semaglutide, an older GLP-1 agonist liraglutide, and the next generation triple agonist obesity drug retatrutide. We then made an optimized combination by permutating known drugs and observing the Efficacy / Safety value. The best permutation was moved on for testing in mice.17MF-368017554Attorney Docket No. 300902000540Table 5. Computational results for predicted Efficacy / SafetyDrug Efficacy / Safety (more negative is better) Liraglutide -0.29Semaglutide -0.34Tirzepatide -0.42Retatrutide -0.51Top combination -0.72

[0086] The top combination was made from retatrutide, setmelanotide, and GSK256073.

[0087] Comparison with existing drugs in mice: Using the mouse experimental paradigm we tested liraglutide, tirzepatide, semaglutide, retatrutide, and setmelanotide alone, the top computationally predicted combination, and two permutations of pairs of molecules from the combination (retatrutide + setmelanotide and retatrutide + GSK256073). Each drug was tested at multiple, therapeutically relevant doses mapped back to human doses, results are plotted based on the data in Table 6, with numbers in mg / kg (also see Table 2).Table 6. Mouse % weight change vs. predicted nausea %Mouse Weight Predicted Nausea Drug(s) Dose(s) (mg / kg)Change (%) Rate Saline 0 0.811 0.186 Semaglutide 0.003 0.036 0.159 Semaglutide 0.01 -3.530 0.279 Semaglutide 0.03 -6.356 0.410 Tirzepatide 0.003 -0.833 0.239 Tirzepatide 0.01 -3.082 0.247 Tirzepatide 0.03 -6.153 0.285 Liraglutide 0.06 -2.033 0.308 Liraglutide 0.134 -3.933 0.411 Retatrutide 0.005 -2.236 0.201 Retatrutide 0.015 -7.956 0.356 Retatrutide 0.045 -10.706 0.418 Setmelanotide 0.3 -1.026 0.230 Setmelanotide 1 -2.896 0.330 Retatrutide / Setmelanotide / 0.005 / 0.07 / 3 -6.368 0.260GSK25607318MF-368017554Attorney Docket No. 300902000540Retatrutide / Setmelanotide / 0.015 / 0.2 / 9 -10.572 0.397 GSK256073Retatrutide / 0.005 / 0.07 -6.747 0.373 SetmelanotideRetatrutide / 0.005 / 3 -7.118 0.402 GSK256073Retatrutide / 0.015 / 9 -7.802 0.406GSK256073

[0088] Based on the data in Table 6, the triple combination was significantly shifted down and left relative to all drugs and drug combinations tested (p < .01 for both doses).

[0089] The triple combination more than doubled weight loss for the same 0.005 mg / kg dose of retatrutide while maintaining a better nausea prediction (less) than 0.015 mg / kg of retatrutide.

[0090] The combination of all three drugs was found to yield unexpected results for weight loss and nausea reduction. Combining retatrutide and either GSK256073 or setmelanotide alone resulted in similar weight loss at 0.005 mg / kg of retatrutide, however the predicted nausea rates were much worse for both cases. In addition, increasing the dose of both retatrutide and GSK256073 did not result in a similar increase in weight loss seen when all three drugs were combined. Taken together the combination of these three drug classes was observed to be important to decreasing predicted nausea rate while increasing efficacy. See Table 7.Table 7. Experiment results, percent weight change and predicted nausea rates Percent weight Predicted Nausea Rate Drug Dose (mg / kg) change (%) (%) N Saline 0 0.8 19 582 Semaglutide 0.03 -6.4 41 33 Semaglutide 0.01 -3.5 28 97 Semaglutide 0.003 0.0 16 114 Liraglutide 0.06 -2.0 31 8 Liraglutide 0.134 -3.9 41 819MF-368017554Attorney Docket No. 300902000540Tirzepatide 0.01 -3.1 25 83 Tirzepatide 0.03 -6.2 28 53 Tirzepatide 0.003 -0.8 24 52 Setmelanotide 0.3 -1.0 23 8 Setmelanotide 1 -2.9 33 8 Retatrutide 0.005 -2.2 20 54 Retatrutide 0.015 -8.0 36 76 Retatrutide 0.045 -10.7 42 38 RetSetGSK (0.005, 0.07, 3.0) -6.4 26 78 RetSetGSK (0.015, 0.2, 9.0) -10.6 40 75 RetSet (0.005, 0.07) -6.7 37 8 RetGSK (0.005, 3.0) -7.1 40 18 RetGSK (0.015, 9.0) -7.8 41 18Example 2: Combination Screening

[0091] This Example tests various combinations of GLP-1 receptor agonists, MC4R agonists and HCAR2 agonists in a rodent model. The methods set forth in Example 1 are performed for the following combinations:1. Semaglutide, Setmelanotide, GSK2560732. Tirzepatide, Setmelanotide, GSK2560733. Liraglutide, Setmelanotide, GSK2560734. Retatrutide, Bremelanotide, GSK2560735. Retatrutide, Setmelanotide, MK68926. Retatrutide, Setmelanotide, SCH9002717. Survodutide, Setmelanotide, GSK25607320MF-368017554Attorney Docket No. 300902000540Example 3: Dosing Study

[0092] This Example provides a 3-week dosing study for four groups: Semaglutide only, Tirzepatide only, Saline, Combination. The drug combination is Semaglutide, Setmelanotide, GSK256073. Thes study involves 8 mice each group, split male and female. The mice are dosed daily, and weights measured daily. MRI is taken every other day to assess lean muscle mass loss.21MF-368017554

Claims

Attorney Docket No. 300902000540CLAIMSWhat is claimed is:

1. A pharmaceutical combination, comprising:a glucagon-like peptide-1 (GLP-1) receptor agonist, a melanocortin-4 receptor (MC4R) agonist, and a hydroxy carboxylic acid receptor 2 (HCAR2) agonist, formulated for administration to a subject.

2. The pharmaceutical combination of claim 1, wherein at least two or all three of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination.

3. The pharmaceutical combination of claim 1, wherein two of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination for subcutaneous administration, and the remaining of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist is formulated for oral administration.

4. The pharmaceutical combination of claim 1, wherein two of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination for oral administration, and the remaining of the GLP-1 receptor agonist, the MC4R agonist and the HCAR2 agonist is formulated for subcutaneous administration.

5. The pharmaceutical combination of claim 1, wherein the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose combination.

6. The pharmaceutical combination of claim 5, wherein the MC4R agonist and the HCAR2 agonist are separately administered from the GLP-1 receptor agonist to the subject.

7. The pharmaceutical combination of any one of claims 1 to 6, wherein the GLP-1 receptor agonist activates at least a GLP-1 receptor or causes GLP-1 agonism.

8. The pharmaceutical combination of any one of claims 1 to 6, wherein the GLP-1 receptor agonist targets one or more additional receptors, in addition to targeting a GLP-1 receptor.22MF-368017554Attorney Docket No. 3009020005409. The pharmaceutical composition of claim 8, wherein one or more of the additional receptors is a glucose-dependent insulinotropic polypeptide (GIP) receptor, or a glucagon (GCG) receptor, or a combination thereof.

10. The pharmaceutical combination of any one of claims 1 to 9, wherein the GLP-1 receptor agonist leads to clinically significant weight loss.

11. The pharmaceutical combination of any one of claims 1 to 9, wherein the GLP-1 receptor agonist leads to at least 5% reduction in bodyweight in the subject.

12. The pharmaceutical combination of any one of claims 1 to 9, wherein the GLP-1 receptor agonist leads to between 5% and 30% reduction in bodyweight in the subject.

13. The pharmaceutical combination of any one of claims 1 to 9, wherein the GLP-1 receptor agonist is liraglutide, exenatide, dulaglutide, tirzepatide, retatrutide, semaglutide, VK2735, MET-097, orforglipron, or servodutide.

14. The pharmaceutical combination of any one of claims 1 to 13, wherein the MC4R agonist crosses the blood brain barrier in the subject.

15. The pharmaceutical combination of any one of claims 1 to 14, wherein the MC4R agonist targets one or more additional receptors, in addition to targeting MC4R.

16. The pharmaceutical combination of claim 15, wherein one or more of the additional receptors is a melanocortin-1 receptor (MC1R), a melanocortin-3 receptor (MC3R), or a melanocortin-5 receptor (MC5R), or any combination thereof.

17. The pharmaceutical combination of any one of claims 1 to 13, wherein the MC4R agonist is setmelanotide, bremelanotide, or PL-8905.

18. The pharmaceutical combination of any one of claims 1 to 17, wherein the HCAR2 agonist crosses the blood brain barrier in the subject.

19. The pharmaceutical combination of any one of claims 1 to 18, wherein the HCAR2 agonist is GSK256073, MK6892, or SCH900271.

20. The pharmaceutical combination of any one of claims 1 to 6, wherein:the GLP-1 receptor agonist is retatrutide,23MF-368017554Attorney Docket No. 300902000540the MC4R agonist is setmelanotide, andthe HCAR2 agonist is GSK256073.

21. The pharmaceutical combination of any one of claims 1 to 6, wherein:the GLP-1 receptor agonist is semaglutide,the MC4R agonist is setmelanotide, andthe HCAR2 agonist is GSK256073.

22. A fixed dose pharmaceutical composition, comprising:a therapeutically effective dose of the pharmaceutical combination of any one of claims 1 to 21; andat least one pharmaceutically acceptable carrier or excipient.

23. The pharmaceutical composition of claim 22, formulated as a solution for injection.

24. The pharmaceutical composition of claim 22, formulated as a solution for subcutaneous injection.

25. The pharmaceutical composition of any one of claims 22 to 24, wherein each of the GLP-1 receptor agonist, the MC4R agonist, and the HCAR2 agonist is present in the composition at a therapeutically effective dose.

26. The pharmaceutical composition of any one of claims 22 to 25, wherein the GLP-1 receptor agonist is present in the composition at a dose between 0.25 mg and 5 mg.

27. The pharmaceutical composition of any one of claims 22 to 26, wherein the MC4R agonist is present in the composition at a dose between 0.1 mg and 2 mg.

28. The pharmaceutical composition of any one of claims 22 to 27, wherein the HCAR2 agonist is present in the composition at a dose between 5 mg and 50 mg.

29. A method of reducing bodyweight or managing weight in a subject, comprising administering to the subject a therapeutically effective dose of the pharmaceutical24MF-368017554Attorney Docket No. 300902000540combination of any one of claims 1 to 21, or the pharmaceutical composition of any one of claims 22 to 28.

30. The method of claim 29, wherein administration of the pharmaceutical composition yields a synergistic effect on reducing bodyweight in the subject with reduced side effects compared to administration of each agonist alone.

31. The method of claim 29 or 30, wherein the pharmaceutical combination or the pharmaceutical composition is administered as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management.

32. The method of any one of claims 29 to 31, wherein the subject is a human.

33. The method of claim 32, wherein the subject is an adult human.

34. The method of claim 33, wherein the adult human has an initial BMI of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition.

35. The method of claim 32, wherein the subject is a pediatric human.

36. The method of claim 35, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).

37. The method of claim 36, wherein the pediatric human is aged 12 years and older with a body weight above 60 kg and an initial BMI corresponding to 30 kg / m2for adults (obese) by international cut-offs.

38. The method of any one of claims 29 to 37, wherein the pharmaceutical combination or the pharmaceutical composition is administered as a solution for injection.

39. The method of any one of claims 29 to 37, wherein the pharmaceutical combination or the pharmaceutical composition is administered as a solution for subcutaneous injection.

40. The method of any one of claims 29 to 37, wherein the pharmaceutical combination or the pharmaceutical composition is administered via an injection pen.

41. The method of claim 40, wherein the injection pen is a single-dose pen.25MF-368017554Attorney Docket No. 30090200054042. The method of claim 40 or 41, wherein the injection pen is pre-filled with the pharmaceutical combination or the pharmaceutical composition.

43. The method of any one of claims 29 to 42, wherein the pharmaceutical combination or the pharmaceutical composition is administered once daily, once weekly or once monthly to the subject.

44. The method of any one of claims 29 to 43, wherein the pharmaceutical combination is administered to the subject, andwherein the MC4R agonist and the HCAR2 agonist are formulated as a fixed dose pharmaceutical composition, and the GLP-1 receptor against is separately formulated as a pharmaceutical composition.

45. A method of reducing body weight or managing weight in a subject taking a glucagon-like peptide-1 (GLP-1) receptor agonist, comprising administering to the subject a combination of (i) a therapeutically effective dose of a melanocortin-4 receptor (MC4R) agonist, and (ii) a therapeutically effective dose of a hydroxycarboxylic acid receptor 2 (HCAR2) agonist, wherein the combination serves as an adjuvant to the GLP-1 receptor agonist to reduce side effects experienced by the subject taking the GLP-1 receptor agonist.

46. The method of claim 45, wherein the MC4R agonist and the HCAR2 agonist are formulated in a fixed dose pharmaceutical composition.

47. The method of claim 45, wherein the MC4R agonist and the HCAR2 agonist are formulated in a fixed dose pharmaceutical composition for injection.

48. The method of any one of claims 45 to 47, wherein the GLP-1 receptor agonist is formulated for oral or subcutaneous administration.

49. The method of any one of claims 45 to 47, wherein the MC4R agonist and the HCAR2 agonist are formulated for subcutaneous administration.

50. A kit comprising: an injection pen, and the pharmaceutical composition of any one of claims 22 to 28.

51. The kit of claim 50, wherein the injection pen is a single-dose pen.26MF-368017554Attorney Docket No. 30090200054052. The kit of claim 50 or 51, wherein the injection pen is pre-filled with the pharmaceutical composition.

53. A pharmaceutical composition, comprising a melanocortin-4 receptor (MC4R) agonist and a hydroxy carboxylic acid receptor 2 (HCAR2) agonist, formulated for administration to a subject taking a glucagon-like peptide-1 (GLP-1) receptor agonist.27MF-368017554

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