Combination therapies

Abstract

Provided herein are combination therapies involving an AMPK activator, including compounds that are dual AMPK activators and mitochondrial uncouplers, dosed in combination with incretin-based therapies.

Description

Attorney Docket No.: 28650-20018.40COMBINATION THERAPIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 725,799, filed November 27, 2024, U.S. Provisional Application No. 63 / 725,900, filed November 27, 2024, U.S. Provisional Application No. 63 / 751,580, filed January 30, 2025, and U.S. Provisional Application No. 63 / 755,753, filed February 7, 2025, the entire contents of each of which are hereby incorporated by reference.FIELD

[0002] The present disclosure relates generally to combination therapies, and more specifically to combination therapies involving an AMPK activator dosed in combination with an incretin-based therapy.BACKGROUND

[0003] With the recent regulatory approvals of WEGOVY® (Novo Nordisk; Semaglutide, a Glucagon-Like Peptide 1 (GLP-1) receptor agonist) and ZEPBOUND® (Eli Lilly; Tirzepatide, a dual GLP-l / Gastric Inhibitory Polypeptide (GIP) receptor agonist), obesity has emerged as a central modifiable risk factor of multiple cardiometabolic diseases. Additional incretin poly-agonists are in clinical trials, with expected weight-loss effects beyond these observed with semaglutide and tirzepatide.

[0004] In particular, many of the current appetite-reducing anti-obesity treatments, such as semaglutide, show promise in achieving weight loss of 15% or more. However, one challenge with current anti-obesity treatments is maintaining the lost weight. In fact, the body weight lost is commonly regained within a year of stopping incretin-based treatment. Substantial weight regain is observed with other pharmacotherapies or following diet and / or exercise regimens. Thus, preventing weight regain after weight loss is commonly considered one of the biggest challenges in obesity treatments. See generally Obesity (Silver Spring), 2022 Apr; 30(4):841-857. Further, most of the weight loss via GLP-1 has been found to be attributable to fat mass and is accompanied by an unwanted reduction in lean mass. After weight loss, most of the weight regained is typically fat mass, leading to a progressive decline in lean mass in patients.1MF-364661167Attorney Docket No.: 28650-20018.40

[0005] What is desired in the art are additional therapies suitable for use in weight management, with increased efficacy and reduced side effects. In particular, what is desired are therapies that not only induce weight loss, but also help to maintain weight loss and address concerns associated with lean mass loss.BRIEF SUMMARY

[0006] In some aspects, provided is a method of managing body weight in a subject in need thereof. In some embodiments, the method comprises administering an AMPK activator, such as the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in combination with an incretin-based therapy. The compound of formula (I) has the following the structure:

[0007] In some embodiments, the AMPK activator is a sodium salt of the compound of formula (I). In some embodiments, the incretin-based therapy comprises at least one agent effective against a Glucagon-Like Peptide 1 (GLP-1) receptor. In other embodiments, the incretin-based therapy comprises: a GLP-1 receptor agonist. In other embodiments, the incretin-based therapy activates at least a GLP-1 receptor. In certain variations, the incretinbased therapy improves the efficiency of incretin function by activating at least a GLP-1 receptor.DESCRIPTION OF THE FIGURES

[0008] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0009] FIGS. 1-4 relate to data from Example 1. FIGS. 5-7 relate to data from Example 2. FIG. 8 compares results from Examples 1 and 2.

[0010] FIG. 1 depicts a graph that shows mean bodyweight change.

[0011] FIG. 2 depicts a graph that shows daily mean food intake.2MF-364661167Attorney Docket No.: 28650-20018.40

[0012] FIG. 3 depicts a graph that shows change in body composition, in which fat and lean mass are measured via EchoMRI.

[0013] FIG. 4 depicts a graph that shows change in lean mass as percentage of total body mass, in which fat and lean mass are measured via EchoMRI.

[0014] FIG. 5 depicts a graph showing food intake with sequential treatment after incretin withdrawal, based on food consumption (grams / day).

[0015] FIG. 6 depicts a graph showing weight maintenance with sequential treatment, based on mean % body weight change vs. Day 1.

[0016] FIG. 7 depicts a graph that shows change in body composition (Day 32 vs. Day 1), in which fat and lean mass are measured via EcoMRI.

[0017] FIG. 8 depicts a graph of change in body composition comparing Compound A alone, semaglutide alone, co-administration of Compound A and semaglutide (Example 1) and Compound A following cessation of semaglutide (Example 2).DETAILED DESCRIPTION

[0018] The following description sets forth exemplary compositions, methods, parameters 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.

[0019] In some aspects, provided herein are methods for managing body weight in a subject in need thereof. In some embodiments, the method comprises administering (1) an AMPK activator (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) in combination with (2) an incretin-based therapy. When the AMPK activator is administered in combination with the incretin-based therapy, the methods also include the coadministration of the AMPK activator and the incretin-based therapy. In some variations, such methods may involve administering the AMPK activator by one mode of administration, and administering the incretin-based therapy by a different mode of administration. For instance, in one variation, the methods may involve orally administering the AMPK activator, and subcutaneously administering the incretin-based therapy. In other variations, such methods may involve administering the AMPK activator by one mode of administration, and3MF-364661167Attorney Docket No.: 28650-20018.40 administering the incretin-based therapy by the same mode of administration. For instance, in another variation, the methods may involve orally administering the AMPK activator and orally administering the incretin-based therapy.

[0020] In some variations, the methods provided herein comprise administering the AMPK activator and the incretin-based therapy simultaneously. For instance, in one variation, the AMPK activator is orally administered at the same time as the incretin-based therapy is subcutaneously administered. In other variations, the methods provided herein comprise administering the AMPK activator and the incretin-based therapy at different times according to the dosing regimen for the AMPK activator and the incretin-based therapy, respectively. For instance, in one variation, the method may involve orally administering the AMPK activator twice or three times daily, and subcutaneously administering the incretinbased therapy once weekly.

[0021] In some embodiments, the administration of the compound that is an AMPK activator (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) further induces weight loss via increased energy expenditure, e.g., relative to the administration of the incretin-based therapy. Further, in some variations, the weight loss is restricted or substantially restricted to fat mass, and involves minimal to no reduction in lean mass or even an increase in lean mass in the subject. Hence, in some variations, the method reverses lean mass loss or preserves lean mass in the subject. In one variation, the method preserves lean mass in the subject.

[0022] Unexpected effects were observed when the compound of formula (I), or a pharmaceutically acceptable salt thereof, were administered in combination with an incretinbased therapy that targets at least GLP-1, such as semaglutide. In some embodiments, the total weight loss achieved with the combination therapy exceeds the weight loss that can be achieved with the incretin-based therapy administered alone. Therefore, the combination therapy is capable of overcoming the plateauing effect often observed with incretin-based therapies, even when such incretin-based therapies are administered at higher doses. In addition, the incretin-based therapy can be administered at lower doses when administered in combination with the GLP-1 compound, hence averting or mitigating side effects commonly associated with incretin-based therapies such as gastrointestinal side effects. Furthermore, faster weight loss is observed in subjects taking the disclosed combination therapy then when taking the incretin-based therapy alone.4MF-364661167Attorney Docket No.: 28650-20018.40

[0023] Subjects taking incretin-based therapy generally experience significant weight loss at levels that also impact lean mass loss. For instance, subjects (e.g., human subjects) on such incretin-based therapies commonly experience at least 5% reduction, or between 5-30% or between 5-15% reduction, in bodyweight, and also experience loss in lean mass (or muscle mass). In some variations, the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., a sodium salt) to a subject, in combination with such incretin-based therapy, reduces bodyweight, and also preserves lean mass in the subject. Accordingly, the disclosure provides methods of reducing weight of a subject or suppressing weight gain in a subject while preserving lean mass in the subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with an incretin-based therapy. In some embodiments, the subject is an obese subject, such as an obese human subject. Therefore, the combination therapies of the disclosure are capable of treating obesity. In other embodiments, the subject (e.g., human subject) is not obese.

[0024] Furthermore, it has been surprisingly found that a subject taking the combination therapy of the disclosure leads to preservation of lean mass. In some embodiments, the percentage of lean mass as a percentage of total body mass increases from about to 10% to about 30% in a subject taking the combination therapy.

[0025] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject (e.g., human subject) at the same time the incretin-based therapy begins. As an example, several of the incretin-based therapies, including semaglutide, are administered subcutaneously on a once weekly dosing schedule, and the dose is often increased at particular weeks following onset of administration. In some embodiments, the first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered on the same day when the incretin-based therapy commences. The particular dosing schedule of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided herein.

[0026] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered throughout the course of the incretin-based therapy. In other embodiments, the incretin-based therapy is stopped at some point after a particular desired weight loss is observed and the subject continues administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, continuation of administration of the compound of formula (I) following cessation of5MF-364661167Attorney Docket No.: 28650-20018.40 treatment with the incretin-based therapy preserves the weight loss observed when the subject was taking the combination therapy. In some embodiments, the subject observes additional weight loss following cessation of treatment with the incretin-based therapy. In some embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be reduced following cessation of the incretin-based therapy and the subject still maintains the same weight or even continues to lose weight. In any of the foregoing embodiments, the subject preserves lean mass despite the reduction in body weight. For instance, the subject may not undergo loss of lean mass or undergo loss of lean mass significantly reduced relative to lean-mass loss observed on the incretin-based therapy alone.

[0027] In some embodiments, the weight of the subject does not substantially increase, remains constant, or continues to decrease after the subject stops taking the incretin-based therapy, provided that the subject keeps taking the compound of formula (I), or a pharmaceutically acceptable salt thereof. Surprisingly, following cessation of treatment of the incretin-based therapy, the amount of food taken by the subject increases and potentially returns to the level prior to treatment with the combination therapy even though the subject does not continue to gain weight, provided that the subject keeps taking the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0028] In other embodiments, co-administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof and the incretin-based therapy leads to comparable or increased weight loss in the subject as compared to administration of the compound of formula (I) alone or administration of the incretin-based therapy alone; however, coadministration preserves lean mass loss as compared to administration of the incretin-based therapy alone (or incretin-based monotherapy). Accordingly, the methods disclosed herein solve a significant problem associated with incretin-based therapies, namely an increase in weight following cessation of the incretin-based therapy.

[0029] In some embodiments, the dose of the compound of formula (I), when administered in combination with an incretin-based therapy, is administered at a dose that is less than the dose usually administered to induce weight loss or treat obesity. For instance, in certain embodiments, a sodium salt of the compound of formula (I) can be administered to the human subject at a dose of from about 100 mg to about 600 mg, or from about 200 mg to about 400 mg. In other embodiments, the subject will be administered a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that is typically used6MF-364661167Attorney Docket No.: 28650-20018.40 to induce weight loss or treat obesity. For instance, in certain embodiments, the compound of formula (I) can be administered to the human subject at a dose of from about 600 mg to about 1,000 mg, or a dose of 700 mg to 900 mg. In any of the foregoing embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered as a tablet to a human subject. In some variations of the foregoing, the dose is administered once daily. In other variations, the dose is administered twice or three times daily.

[0030] In some embodiments, the total daily dose of the compound of formula (I), when administered in combination with an incretin-based therapy, is administered at a total daily dose that is less than the total daily dose usually administered to induce weight loss or treat obesity. For instance, in certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to the human subject at a total daily dose of from about 400 mg to about 1200 mg, or from about 400 mg to about 1000 mg. In other embodiments, the subject will be administered a total daily dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that is typically used to induce weight loss or treat obesity. For instance, in certain embodiments, the compound of formula (I) can be administered to the human subject at a total daily dose of from about 600 mg to about 1,000 mg, or a dose of 700 mg to 900 mg. In any of the foregoing embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered as a tablet to a human subject. In some variations of the foregoing, the total daily dose is achieved by administering one dose, e.g., the dose is administered once daily. In other variations, the total daily dose is achieved by administering multiple doses, e.g., the dose is administered twice or three times daily.

[0031] In some embodiments, the dose of the incretin-based therapy is progressively increased on particular weeks until a maintenance dose is reached. In some embodiments, the dose escalation regimen is reflected on the product label of the commercially approved incretin-based therapy. In some embodiments, when a subject is administered the combination therapy disclosed herein, the final maintenance dose reached is lower than final recommended maintenance dose reflected on the product label of the incretin-based therapy. In some embodiments, the maintenance dose of the incretin-based therapy is about 75% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance dose of the incretin-based therapy is about 50% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance7MF-364661167Attorney Docket No.: 28650-20018.40 dose of the incretin-based therapy is about 25% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance dose of the incretinbased therapy is about 10% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance dose of the incretin-based therapy is from about 10% to about 80% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance dose of the incretin-based therapy is from about 20% to about 75% of the recommended maintenance dose reflected on the product label. In some embodiments, the maintenance dose of the incretin-based therapy is from about 30% to about 60% of the recommended maintenance dose reflected on the product label.

[0032] In some embodiments of the methods disclosed herein where a particular maintenance dose of the incretin-based therapy is reached, the method further comprises lowering the maintenance dose of the incretin-based therapy over a period of time, and optionally stopping the incretin-based therapy while maintaining administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. For instance, where the incretin-based therapy is semaglutide, in some variations, the recommended maintenance dose of semaglutide on the Wegovy® product label is 2.4 mg once weekly, or perhaps lower if the subject shows complications; and the maintenance dose may be lowered and ultimately stopped over time while maintaining administration of the AMPK activator (e.g., a compound of formula (I), or pharmaceutically acceptable salt thereof).

[0033] In some embodiments of the combination therapy disclosed herein, where the incretin-based therapy is semaglutide, the maintenance dose of semaglutide administered to the subject is less than 2.4 mg once weekly, the recommended maintenance dose on the Wegovy® product label. In some embodiments, the maintenance dose of semaglutide is from about 0.25 mg once weekly to about 2 mg once weekly. In some embodiments, the maintenance dose of semaglutide is from about 0.5 mg once weekly to about 1.75 mg once weekly. In some embodiments, the maintenance dose of semaglutide is from about 0.75 mg once weekly to about 1.5 mg once weekly. In some embodiments, the maintenance dose of semaglutide is from about 1 mg once weekly to about 2 mg once weekly. In some embodiments, the semaglutide can be administered at a maintenance dose of less than once weekly, for instance twice monthly or once monthly.8MF-364661167Attorney Docket No.: 28650-20018.40

[0034] In some embodiments of the combination therapy disclosed herein, where the incretin-based therapy is tirzepatide, the maintenance dose of tirzepatide administered to the subject is less than 15 mg once weekly, the maximum recommended maintenance dose on the Mounjaro® product label. In some embodiments, the maintenance dose of tirzepatide is from about 2 mg once weekly to about 12 mg once weekly. In some embodiments, the maintenance dose of tirzepatide is from about 2.5 mg once weekly to about 10 mg once weekly. In some embodiments, the maintenance dose of tirzepatide is from about 2.5 mg once weekly to about 5 mg once weekly. In some embodiments, the tirzepatide can be administered at a maintenance dose of less than once weekly, for instance twice monthly or once monthly.

[0035] In some embodiments of the combination therapy disclosed herein, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be decreased following a particular weight loss, irrespective of whether the incretin-based therapy is still being administered to the subject. For instance, in certain embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be reduced by from about 20% to about 70% or from about 30% to about 50% following a particular desired amount of weight loss. In some such embodiments, the incretin-based therapy is removed from the dosing regimen.

[0036] In some embodiments where the incretin-based therapy is substantially reduced from or eliminated from the dosing regimen, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be increased to compensate for the removal of the incretin-based therapy. For instance, in some embodiments, the starting dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, when administered as a part of the combination therapy disclosed herein, is lower than required for weight loss as when the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by itself. In some such embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be increased to ensure maintenance of the current weight or continued reduction in weight.

[0037] In certain embodiments, the method comprises administering an initial dose of an incretin-based therapy to the subject to induce initial weight loss in the subject; and upon observing the initial weight loss in the subject, reducing or eliminating the initial dose of the incretin-based therapy and administering a therapeutically effective dose of the compound of9MF-364661167Attorney Docket No.: 28650-20018.40 formula (I), or a pharmaceutically acceptable salt thereof, to the subject to further induce weight loss and / or minimize or prevent against body weight regain. In some such embodiments, the dose of the incretin-based inhibitor is not increased prior to the administration of the compound of formula (I), or pharmaceutically acceptable salt thereof. In other such embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, preserves lean mass in the subject or completely or partially reverses the reduction of lean mass from administration of the incretin-based therapy.

[0038] In some embodiments, the incretin-based therapy is stopped after observing initial weight loss in the subject, and then a therapeutically effective dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to maintain weight loss without the side effects of the incretin-based therapy. In some variations, no further loss of muscle mass is observed during the treatment with the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered, as compared to the incretin-based therapy. Further, in some variations, once the incretin-based therapy is stopped, appetite is regained and food intake resumes to normal, while still observing maintenance of weight loss. In some variations where the incretin-based therapy is stopped, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered at a daily dose that results in a Cmax and / or a steady state blood plasma concentration of from about 100 pg / mL to about 280 pg / mL. In certain variations where the incretin-based therapy is stopped, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a daily dose of at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, or at least 1000 mg, or between 400 mg and 1500 mg, between 400 mg and 1250 mg, between 400 mg and 1000 mg, between 500 mg and 1000 mg, between 600 mg and 800 mg, between 800 mg and 1250 mg, or between 800 mg and 1000 mg. In one variation, the daily dose is 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0039] In some embodiments, the incretin-based therapy is administered to a subject for a particular amount of time prior to the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. For instance, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is not administered to a subject until an appreciable amount of weight loss is observed. In some embodiments, the compound10MF-364661167Attorney Docket No.: 28650-20018.40 of formula (I), or a pharmaceutically acceptable salt thereof, is not administered until at least one day after treatment with the incretin-based therapy commences. For instance, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered three days, four days, one week, two weeks, three weeks or 1 month after the initial administration of the incretin-based therapy. In some embodiments, the dose of the incretin-based therapy is lowered immediately at the outset of administering the compound of formula (I), or a pharmaceutically acceptable salt thereof. For instance, the dose of the incretin-based therapy may be reduced by from about 20% to about 70% or from about 30% to about 50% upon administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In other embodiments, the dose of the incretin-based therapy is not lowered upon the onset of administering the compound of formula (I), or a pharmaceutically acceptable salt thereof. In some such embodiments, the dose of the incretin-based therapy can be reduced at some time following the onset of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In any of the foregoing embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, preserves lean mass in the subject or completely or partially reverses the reduction of lean mass from administration of the compound of incretin-based therapy in the absence of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0040] In some variations, the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure. In other variations, the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or stopped and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure. In certain variations, the dose of the incretin-based therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy. In one variation of the foregoing, the dose of the incretin-based therapy is reduced where the11MF-364661167Attorney Docket No.: 28650-20018.40 titration stops before the top dose. In another variation, the incretin-based therapy is stopped after initial weight loss in the subject is observed.

[0041] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a human subject that is already taking an incretinbased therapy. In some such embodiments, the dose incretin-based therapy is lowered prior to the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered prior to the first administration of the incretin-based therapy. In some such embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at least one day, one week, two weeks or one month prior to the first administration of the incretin-based therapy.

[0043] Furthermore, it has been surprisingly discovered that the combination of incretinbased therapy and a compound of formula (I), or a pharmaceutically acceptable salt thereof, substantially increases the feed efficiency ratio relative to monotherapy with the incretinbased therapy or a compound of formula (I), or a pharmaceutically acceptable salt thereof. Feed efficiency ratio is a measure of body weight loss (or gain) by energy intake (e.g., calories in) over a given period of time. In particular embodiments, the feed efficiency ratio exhibits a synergistic effect when the incretin-based therapy is administered in combination with the compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 25%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 30%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 35%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 40%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 50%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is greater than 60%. In some embodiments, the feed efficiency ratio exhibited when the subject is administered the combination therapy is from about 35% to about 60%. In some embodiments, the feed12MF-364661167Attorney Docket No.: 28650-20018.40 efficiency ratio exhibited when the subject is administered the combination therapy is from about 30% to about 50%.

[0044] In some variations, managing body weight in the subject may include one or more of the following: decreasing body weight; improving glycemic control; increasing energy expenditure; reducing food or caloric intake; reducing appetite; and signaling a feeling of fullness. In some embodiments, the reduction of food intake when a subject is administered the combination therapy is less than reduction of food intake when the subject is only taking the incretin-based monotherapy.

[0045] In some variations, the combination therapies described herein are an adjunct to a reduced calorie diet and increased physical activity for weight management. In certain variations, the combination therapies are an adjunct to a reduced calorie diet and increased physical activity for chronic weight management.

[0046] In some variations, the combination therapies are administered to an adult subject. In certain variations, the adult subject has an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight- related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia, kidney disease, or metabolic-associated liver disease).

[0047] In other variations, the combination therapies are administered to a pediatric subject. In certain variations, the pediatric subject is aged 12 years and older. In certain variations, the pediatric subject has an initial BMI at the 95thpercentile or greater for age and sex (obesity).

[0048] In another aspect of the disclosure, a subject will be provided a regimen of incretin-based therapy for a period of time until the patient demonstrates a particular weight loss (e.g., a desirable amount of weight loss) and then the incretin-based therapy will be stopped and monotherapy of the compound of formula (I), or a pharmaceutically acceptable salt thereof will be initiated. In some such embodiments, following cessation of the incretinbased therapy, the subject will be administered a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that will maintain the weight of the subject without further weight loss or with minimal weigh loss. For instance, in certain embodiments, following cessation of the incretin-based therapy to a human subject, a sodium salt of the compound of formula (I) can be administered to the human subject at a dose of from about13MF-364661167Attorney Docket No.: 28650-20018.40100 mg to about 600 mg, or from about 200 mg to about 400 mg, or from about 400 mg to about 1500 mg, or from about 400 mg to about 1200 mg. In other such embodiments, following cessation of the incretin-based therapy, the subject will be administered a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that will continue to experience weight loss even after the incretin-based therapy is terminated. For instance, in certain embodiments, following cessation of the incretin-based therapy to a human subject, a sodium salt of the compound of formula (I) can be administered to the human subject at a dose of from about 600 mg to about 1,000 mg, or a dose of 700 mg to 900 mg, or a dose of 400 mg to 1500 mg, or a dose of 600 mg to 1500 mg, or a dose of 800 mg to 1200 mg. In any of the foregoing embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered as a tablet to a human subject. In some variations of the foregoing, the dose is administered once daily. In other variations of the foregoing, the dose is administered twice or three times daily.

[0049] In some embodiments, following cessation of the incretin-based therapy to a human subject, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to the human subject at a total daily dose of from about 100 mg to about 600 mg, or from about 200 mg to about 400 mg, or from about 400 mg to about 800 mg, or from about 400 mg to about 1000 mg, or from about 400 mg to about 1200 mg, or from about 400 mg to about 1500 mg. In other such embodiments, following cessation of the incretin-based therapy, the subject will be administered a total daily dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that will continue to experience weight loss even after the incretin-based therapy is terminated. For instance, in certain embodiments, following cessation of the incretin-based therapy to a human subject, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to the human subject at a total daily dose of from about 400 mg to about 1000 mg, or from about 600 mg to about 1,000 mg, or a dose of 700 mg to 900 mg, or a dose of 400 mg to 1500 mg, or a dose of 600 mg to 1500 mg, or a dose of 800 mg to 1200 mg. In any of the foregoing embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered as a tablet to a human subject. In some variations of the foregoing, the dose is administered once daily. In other variations of the foregoing, the dose is administered twice or three times daily.AMPK Activator Compound14MF-364661167Attorney Docket No.: 28650-20018.40

[0050] Tthe AMPK activator is a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0051] In some embodiments, the compound is 4-chloro-N-[2-[(4-chlorophenyl)methyl]- 3-oxo-l,2,4-thiadiazol-5-yl]benzamide, or a salt, solvate or a prodrug thereof.

[0052] In certain embodiments, the compound is an alkali metal salt of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide. “Alkali metals” are metals found, along with hydrogen, in group I of the periodic table. The alkali metals are lithium, sodium, potassium, rubidium, cesium, and francium. It will therefore be understood that an “alkali metal salt” is a chemical compound consisting of an assembly of cations of one or more alkali metals and associated anions. Accordingly, the term “an alkali metal salt of 4- chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide” refers to a compound comprising alkali metal cations (e.g., lithium, rubidium, cesium, sodium, and potassium) and anions of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5- yl]benzamide. For example, alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-l,2,4-thiadiazol-5-yl]benzamide are as depicted below:wherein X+represents the alkali metal (e.g. lithium, rubidium, cesium, sodium, or potassium) cation.

[0053] In one embodiment, the compound is a sodium salt of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide. The term “a sodium salt of 4- chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide” refers to a15MF-364661167Attorney Docket No.: 28650-20018.40 compound comprising sodium cations and anions of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide. For example:wherein Na+represents the sodium cation. In another embodiment, the compound is a potassium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5- yl] benzamide.

[0054] The skilled person will recognize that, when dissolved in a suitable solvent (e.g., water), the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide may dissociate into its anionic and cationic components.

[0055] Throughout this specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails.Where it is possible for the compound to exist as a tautomer (e.g., in an alternative resonance form), the depicted structure represents one of the possible tautomeric forms, wherein the actual tautomeric form(s) observed may vary depending on environmental factors such as solvent, temperature, or pH. All tautomeric (and resonance) forms and mixtures thereof are included within the scope of the Invention. For example, the following tautomers are included within the scope of the invention:

[0056] For the avoidance of doubt, alkali metal salts of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide are solid under ambient conditions, and thus the scope of the invention includes all amorphous, crystalline, and part crystalline forms thereof.16MF-364661167Attorney Docket No.: 28650-20018.40

[0057] Alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-l,2,4-thiadiazol-5-yl]benzamide may be reacted with the appropriate alkali metal hydroxide, or an alternative alkali metal base compound. Salt switching techniques may also be used to convert one salt into another salt.

[0058] Sodium salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5- yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide may be reacted with sodium hydroxide, or an alternative sodium base compound. Salt switching techniques may also be used to convert one salt into another salt.

[0059] Where the salt is prepared from 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo- l,2,4-thiadiazol-5-yl]benzamide, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-l,2,4-thiadiazol-5-yl]benzamide may be made in accordance with the techniques described in international patent application WO 2011 / 004162.

[0060] Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0061] In some embodiments, the AMPK activator used in the methods provided herein is a compound of formula (II):or a salt thereof, wherein R1is selected from the group consisting of -C(O)-C2H4-CO2H and - PO3H2, or a salt or solvate thereof. In some embodiments, this compound is able to metabolise in vivo to form 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-17MF-364661167Attorney Docket No.: 28650-20018.40 yl] benzamide. In certain embodiments, this compound is a salt. For example, salts of this compound include:wherein X+represents an alkali metal, alkaline earth metal or quaternary ammonium (e.g. lithium, magnesium, calcium, ammonium, tetramethylammonium and, particularly, sodium and potassium) cation, with appropriate stoichiometric adjustments being made in view of charges of the ions. In certain embodiments, X+represents an alkali metal (e.g. lithium, rubidium, cesium or, particularly, sodium or potassium) cation.Pharmaceutical Dosage Forms of the AMPK Activator Compound

[0062] The compound that is an AMPK activator is administered to a human subject in need thereof in the form of a pharmaceutical formulation, which is also referred to herein as a pharmaceutical dosage form.

[0063] In one embodiment, the AMPK activator compound is the sole active pharmaceutical ingredient present in the dosage form. In a further embodiment, AMPK activator compound is present in the dosage form alongside one or more other active pharmaceutical ingredients, or may be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0064] In particular embodiments, the AMPK activator compound is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 pm (e.g.18MF-364661167Attorney Docket No.: 28650-20018.40 as measured using laser diffraction). In one embodiment, the particles containing the AMPK activator compound may have a particle size distribution defined by a D90 of less than about 10 pm (e.g. from about 5 pm to about 10 pm) (e.g. as measured using laser diffraction). The particle size distribution may alternatively be defined by a D90 of less than about 8 pm (e.g. from about 5 pm to about 8 pm). In a further embodiment, the particles consisting of the AMPK activator compound may have a particle size distribution defined by a D50 of less than about 6 pm (e.g. from about 0.5 pm to about 6 pm). In a yet further embodiment, the particle size distribution of the particles consisting of the AMPK activator compound may further be a defined by a DIO of less than about 2 pm (e.g. from about 0.2 pm to about 2 pm). The particle size distribution parameters mentioned above may be applicable, individually or in combination. For example, in particular embodiments, the dosage form comprises particles containing the AMPK activator compound, said particles having a particle size distribution defined by a D90 of less than about 10 pm and a D50 of less than about 6 pm. Still further, said particles may have a particle size distribution defined by a D90 of less than 9 pm; a D50 of less than 6 pm or less than 5 pm; and a D10 of less than 2 pm or less than 1.5 pm. The particle size distribution of particles containing the AMPK activator compound may be measured by laser diffraction, using, for example a commercially available particle size analyzer.Oral Dosage Forms of the AMPK Activator Compound

[0065] In some variations, the AMPK activator compound may be provided in the form of a tablet or a capsule. For example, capsules such as soft gelatin capsules may be prepared containing the AMPK activator compound alone, or together with a suitable vehicle, e.g. vegetable oil, fat, etc. Similarly, hard gelatin capsules may contain the AMPK activator compound alone, or in combination with solid powdered ingredients such as a disaccharide (e.g. lactose or saccharose), an alcohol sugar (e.g. sorbitol or mannitol), a vegetable starch (e.g. potato starch or corn starch), a polysaccharide (e.g. amylopectin or cellulose derivatives), or gelling agent (e.g. gelatin).

[0066] The pharmaceutical dosage forms described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice. The pharmaceutical dosage forms will generally be provided as a mixture comprising the AMPK activator compound and one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may be selected with due regard to the intended route of administration19MF-364661167Attorney Docket No.: 28650-20018.40 in accordance with standard pharmaceutical practice. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and are preferably have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of methods of drug delivery may also be found in, e.g., Langer, Science 249, 1527 (1990).

[0067] The skilled person will understand that the pharmaceutical dosage forms described herein may act systemically, and may therefore be administered accordingly using suitable techniques known to those skilled in the art. The pharmaceutical dosage form as described herein will normally be administered orally, e.g., as an oral pharmaceutical dosage form. Thus, in some variations, provided is an oral pharmaceutical dosage form comprising from about 100 to about 1000 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one variation, provided is an oral pharmaceutical dosage form comprising from about 200 to about 1000 mg of a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide.

[0068] Dosage forms intended for oral administration may further comprise an enteric coating in order to prevent or minimize dissolution or disintegration in the gastric environment. As such, oral preparations (e.g., capsules or tablets) coated by an enteric coating may provide targeted release of the AMPK activator compound in the small intestine. For example, the enteric coating may be present on surface of the formulation (e.g., on the surface of a tablet or a capsule), or each of the particles containing the AMPK activator compound may be coated with the enteric coating. Thus, in particular embodiments, the pharmaceutical dosage form used in the method of the invention further comprises an enteric coating.

[0069] In certain embodiments, the enteric coating is present on the pharmaceutical dosage form, and in some variations, said coating may be provided as an outer layer on the pharmaceutical dosage form.

[0070] Alternatively, particles containing the AMPK activator compound may be individually coated with the enteric coating, and said coated particles may be prepared into the pharmaceutical dosage form. Thus, in particular embodiments, the pharmaceutical20MF-364661167Attorney Docket No.: 28650-20018.40 dosage form contains particles comprising the AMPK activator compound and each particle is coated with the enteric coating.

[0071] The term “enteric coating” refers to a substance (e.g., a polymer) that is incorporated into an oral medication (e.g., applied onto the surface of a tablet, a capsule, particles or pellets) and that inhibits dissolution or disintegration of the medication in the gastric environment. Enteric coatings are typically stable at the highly acidic pH found in the stomach, but break down rapidly in the relatively basic pH of the small intestine. Therefore, enteric coatings prevent release of the active ingredient in the medication until it reaches the small intestine.

[0072] Any enteric coating known to the skilled person may be used in the present invention. Particular enteric coating materials that may be mentioned include those which comprise beeswax, shellac, an alkylcellulose polymer resin (e.g. ethylcellulose polymers, carboxymethylethylcellulose, or hydroxypropyl methylcellulose phthalate) or an acrylic polymer resin (e.g. acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate) copolymer, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers), cellulose acetate phthalate and polyvinyl acetate phthalate.

[0073] In some variations, the pharmaceutical compositions comprise the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutically acceptable excipient. In particular, the at least one pharmaceutically acceptable excipient may be a lubricant, a binder, a filler, a surfactant, a diluent, an antiadherent, a coating, a flavoring, a colorant, a glidant, a preservative, a sweetener, a disintegrant, an adsorbent, a buffering agent, an antioxidant, a chelating agent, a dissolution enhancer, a dissolution retardant, or a wetting agent.

[0074] Particular pharmaceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, saccharose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients, as well as disintegrating agents21MF-364661167Attorney Docket No.: 28650-20018.40 and lubricating agents such as sodium lauryl sulfate, Na-docusate, magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. In the preparation of a pharmaceutical dosage form of the AMPK activator compound for oral administration, particles containing the AMPK activator compound (preferably milled) may be mixed, either together or separately, with mannitol, PVP (polyvinylpyrrolidone) K30 and sodium lauryl sulfate.

[0075] In the preparation of a pharmaceutical dosage form, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be mixed, either together or separately, with one or more of the pharmaceutical excipients (including basic excipients) listed above.

[0076] Mixtures of the AMPK activator compound and one or more pharmaceutically acceptable excipients may be processed into pellets or granules, or compressed into tablets. Thus, pharmaceutical dosage form of the method of the inventions may be a tablet, minitablets, blocks, pellets, particles, granules, or a powder for oral administration.

[0077] Pharmaceutical formulations that may be mentioned include those in which the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is present in a total amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight of the formulation. That is, the weight ratio of the AMPK activator compound to the totality of the components (i.e., the AMPK activator compound and all pharmaceutical excipients, e.g. adjuvants, diluents and carriers) of the pharmaceutical formulation is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50).Dosage Amounts on Oral Dosage Forms of the AMPK Activator Compound

[0078] A “therapeutically effective amount”, an “effective amount” or a “dosage” as used herein refers to an amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, that is sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect. The effective amount or dosage 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.22MF-364661167Attorney Docket No.: 28650-20018.40

[0079] The term “about,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.

[0080] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally to a subject in need thereof (e.g., patient) at a dose of from about 100 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally at dose of from about 200 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally at dose of from about 300 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally at dose of from about 400 mg to about 800 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally at dose of from about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally at dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 500 mg. In some variations of the foregoing, the dose is administered once daily.

[0081] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally to a subject in need thereof (e.g., patient), wherein the administration results in a steady state blood plasma concentration of the compound of formula (I) of from about 40 pg / mL to about 400 pg / mL, or from about 40 pg / mL to about 300 pg / mL, or from about 50 pg / mL to about 300 pg / mL, or from about 50 pg / mL to about 280 pg / mL, or from about 75 pg / mL to about 400 pg / mL, or from about 75 pg / mL to about 300 pg / mL, or from about 75 pg / mL to about 280 pg / mL, or from about 100 pg / mL to about 280 pg / mL, or from about 70 pg / mL to about 120 pg / mL, or from about 90 pg / mL to about 160 pg / mL, or from about 100 pg / mL to about 150 pg / mL, or from about 120 pg / mL to about 140 pg / mL. In some variations of the23MF-364661167Attorney Docket No.: 28650-20018.40 foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally at a dose that results in steady state blood plasma concentration of from about 50 pg / mL to about 280 pg / mL while a full dose of the incretinbased therapy is administered. In other variations of the foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered daily at a dose that results in steady state blood plasma concentration of from about 100 pg / mL to about 280 pg / mL during the maintenance stage in which the incretin-based therapy is stopped. In some variations of the foregoing, the dose is administered once daily.

[0082] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally to a subject in need thereof (e.g., patient), wherein the administration results in a Cmax of the compound of formula (I) of from about 40 pg / mL to about 400 pg / mL, or from about 40 pg / mL to about 300 pg / mL, or from about 50 pg / mL to about 300 pg / mL, or from about 50 pg / mL to about 280 pg / mL, or from about 75 pg / mL to about 400 pg / mL, or from about 75 pg / mL to about 300 pg / mL, or from about 75 pg / mL to about 280 pg / mL, or from about 100 pg / mL to about 280 pg / mL, or from about 70 pg / mL to about 120 pg / mL, or from about 90 pg / mL to about 160 pg / mL, or from about 100 pg / mL to about 150 pg / mL, or from about 120 pg / mL to about 140 pg / mL. In some variations of the foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally at a dose that results in Cmax of 50 pg / mL to about 280 pg / mL while a full dose of the incretinbased therapy is administered. In other variations of the foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally at a dose that results in the Cmax of the compound of formula (I) from about 100 pg / mL to about 280 pg / mL during the maintenance phase in which the incretin-based therapy is stopped. In some variations of the foregoing, the dose is administered once daily.

[0083] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally to a subject in need thereof (e.g., patient), wherein the administration results in a steady state AUCo-24 of the compound of formula (I) of from about 1,000 h*pg / mL to about 4,000 h*pg / mL, or from about 1,000 h*pg / mL to about 2,000 h*pg / mL, or from about 1,500 h*pg / mL to about 4,000 h*pg / mL, or from about 1,800 h*pg / mL to about 3,100 h*pg / mL, or from about 1,500 h*pg / mL to about 2,000 h*pg / mL, or from about 2,500 h*pg / mL to about24MF-364661167Attorney Docket No.: 28650-20018.404,000 h*pg / mL, or from about 3,000 h*pg / mL to about 3,500 h*pg / mL. In some variations of the foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally at a dose that results in a steady state AUC0-24 of from about 3,000 h*pg / mL to about 3,500 h*pg / mL, while a full dose of the incretin-based therapy is administered. In other variations of the foregoing, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally at a dose that results in a steady state AUC0-24 from about 1,000 h*pg / mL to about 3,500 h*pg / mL during the maintenance phase in which the incretin-based therapy is stopped. In some variations of the foregoing, the dose is administered once daily.

[0084] In some embodiments, the compound of formula (I) is provided in a tablet with the components shown in Table 1.Table 1. Exemplary composition of tablet comprising Na salt tablet of formula (I)^Corresponds to 400 mg of free form of the compound of formula (I)Incretin-Based Therapies

[0085] In some embodiments, the incretin-based therapy comprises an agent effective against the GLP-1 receptor. In certain embodiments, the incretin-based therapy may act by mimicking the GLP-1 hormone that is released in the gastrointestinal tract in response to eating. GLP-1 helps to prompt the body to produce more insulin, which reduces blood glucose (sugar). GLP-1 in higher amounts also may also interact with the parts of the brain that help to reduce appetite and signal a feeling of fullness.25MF-364661167Attorney Docket No.: 28650-20018.40

[0086] In certain embodiments, the incretin-based therapy activates at least a GLP-1 receptor or causes GLP-1 agonism. In certain embodiments, the incretin-based therapy improves the efficiency of incretin function by activating at least a GLP- 1 receptor or causing GPL-1 agonism. In some variations, the incretin-based therapy targets one or more additional receptors, in addition to targeting GLP-1.

[0087] In one embodiment, the incretin-based therapy targets GLP-1 sufficient to reduce food intake and body weight.

[0088] In some variations, the incretin-based therapy comprises a GLP-1 receptor agonist. In certain variations, suitable examples may include Semaglutide, Exenatide, Liraglutide, Ecnoglutide, Danuglipron, Lotigliprion, RGT-075, GSBR-1290, ECC5004, CT- 996, XW014, MDR-001, NLY12, TERN-601, MET-097, and MET-224. In some variations, the incretin-based therapy comprises a GLP-l / GIP dual receptor agonist or antagonist. In certain variations, suitable examples may include Tirzepatide, AMG-133, VK2735, CT-388, SCO-094, VK2735, and GPCR. In some variations, the incretin-based therapy comprises a GLP-l / GIP / glucagon triple receptor agonist. In certain variations, suitable examples may include Retatrutide, and DD03. In some variations, the incretin-based therapy comprises a GLP-l / glucagon dual receptor agonist. In certain variations, suitable examples may include Pemvidutide, BI456906, DD01, and Mazdutide. In some variations, the incretin-based therapy comprises a GLP-l / amylin dual receptor agonist. In certain variations, suitable examples may include Amecrytin. In some variations, the incretin-based therapy comprises a GLP-1 receptor agonist / amylin analog. In certain variations, suitable examples may include CagriSema. In other variations, the incretin-based therapy comprises other GLP-1 receptor agonist combinations. In certain variations, suitable examples may include Dapiglutide, CIN209, and CIN210. In yet other variations, the incretin-based therapy comprises an agent that increases circulating incretins, such as DPP4 inhibitors. In certain variations, suitable examples may include Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, and Vildagliptin.

[0089] In some variations, the incretin-based therapy comprises Semaglutide, Liraglutide, Orfoglipron, Ecnoglutide, Danuglipron, GSBR 1290, AZD5004, RG6652 (CT996), TERN- 601, XW014, Hyglutide, Efpeglenatide, GZR 18, Noiiglutide, RGT-075, HSR-7535, DD02S, MDR 001, Visepegenatide, Utreglutide, Tirzepatide, Survodutide, Retatrutide, Maridebart cafraglutide, Mazdutide, NN9541 / NN9542, RG6641 (CT388), Pemvidutide, VK2735, Dapiglutide, NN9487, CagriSema, HRS9531, HS 20094, PB-718, DD01, UBT251,26MF-364661167Attorney Docket No.: 28650-20018.40GMA106, HEC88473, HDM1002, DA 1726, PG 102, SCO-094, or DR10624. In certain variations, the incretin-based therapy comprises Semaglutide, Liraglutide, Orfoglipron, Ecnoglutide, Danuglipron, GSBR 1290, AZD5004, RG6652 (CT996), TERN-601, XW014, Hyglutide, Efpeglenatide, GZR 18, Noiiglutide, RGT-075, HSR-7535, DD02S, MDR 001, Visepegenatide or Utreglutide. In certain variations, the incretin-based therapy comprises Semaglutide, Liraglutide, Orfoglipron, Ecnoglutide, Danuglipron, GSBR 1290, AZD5004, RG6652 (CT996), TERN-601, XW014, or Hyglutide.

[0090] In other variations, the incretin-based therapy comprises Orforglipron, Lotiglipron, Danuglipron, GSBR-1290, AZD5004, RG6652 / CT996, TERN-601, XW014, RGT-075, HRS-7535 / KAI-7535, MDR-001, HS-10535, or HDM1002.

[0091] In some variations of the foregoing, the incretin-based therapy leads to clinically significant weight loss. In certain variations, the incretin-based therapy leads to weight loss reduction at levels that also cause significant lean mass (or muscle mass) loss in the subject. In certain variations of the foregoing, the incretin-based therapy leads to at least 5% reduction, or between 5% and 30% reduction, or between 5% and 15% reduction in bodyweight in the subject. In certain variations of the foregoing, the subject further experiences a decrease in lean mass (or muscle mass). In certain variations, at least 25%, or between 25% and 40% of the weight loss from the incretin-based therapy is fat free mass.

[0092] In some variations, the subject is obese and suffers from sarcopenia or frailty.

[0093] In some variations, the incretin-based therapy is administered subcutaneously, e.g., via injection. In certain variations, the incretin-based therapy is administered via a single-patient-use pen. In certain variations, the incretin-based therapy is administered at a therapeutically effective dose. In one variation, the incretin-based therapy is administered at a therapeutically effective dose once daily, or once weekly.

[0094] In one embodiment, the incretin-based therapy used in the methods described herein is semaglutide. In some variations, semaglutide is subcutaneously administered (e.g., via injection) to the human subject once weekly at a therapeutically effective dose. In some variations, semaglutide is administered at 2 mg / 3 mL (0.68 mg / mL) via an injection device (e.g., a single-patient-use pen) that delivers 0.25 mg or 0.5 mg per injection. In other variations, semaglutide is administered at 4 mg / 3 mL (1.34 mg / mL) via an injection device (e.g., a single-patient-use pen) that delivers 1 mg per injection. In other variations,27MF-364661167Attorney Docket No.: 28650-20018.40 semaglutide is administered at 8 mg / 3 mL (2.68 mg / mL) via an injection device (e.g., a single-patient-use pen) that delivers 2 mg per injection. In certain embodiments of the foregoing, semaglutide is administered once weekly at any time of day, with or without meals.

[0095] In other variations, semaglutide is subcutaneously administered (e.g., via injection) to the human subject in the abdomen, thigh or upper arm. In certain variations, semaglutide is administered at an initial dose of 0.25 mg once weekly for 4 weeks; then in 4 week intervals, the dose administered is increased until a dose of 2.4 mg is reached. In certain variations, the maintenance dose of semaglutide is 2.4 mg or 1.7 mg once weekly in adult human subjects; and the maintenance dose in pediatric patients aged 12 years and older is 2.4 mg weekly. In certain variations, semaglutide is delivered via injection (e.g., a prefilled, single dose pen) at doses of between 0.25 mg and 7.5 mg. In certain variations, semaglutide is delivered via injection (e.g., a pre-filled, single dose pen) at doses of between 0.25 mg and 2.5 mg. In certain variations, semaglutide is delivered via injection (e.g., a prefilled, single dose pen) at doses of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg. In certain variations, semaglutide is delivered via injection (e.g., a pre-filled, single dose pen) at doses of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg, or 7.2 mg.

[0096] In other variations, semaglutide is orally administered to the human subject. In certain variations of the foregoing, semaglutide is administered once daily. In some embodiments, semaglutide is administered at a once-daily dose of 25 mg or 50 mg. In certain variations, semaglutide is administered at a once-daily dose of 25 mg. In certain variations, semaglutide is administered at a once-daily dose of 50 mg.

[0097] In some variations of the foregoing, the methods herein comprise administering an AMPK activator compound as described herein (e.g., compound of formula (I)) to a human subject that has been taking or is currently taking semaglutide. In certain variations, the human subject starting on the AMPK activator compound has experienced weight loss and lean mass loss from taking semaglutide, and the administration of the AMPK activator compound (e.g., compound of formula (I)) further increases weight loss in the human subject and / or maintains weight loss, while reversing lean mass loss or preserving lean mass. In some variations, the dose of semaglutide administered is reduced or eliminated over time.28MF-364661167Attorney Docket No.: 28650-20018.40

[0098] In some embodiments of the foregoing, the methods herein are indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management. In some variations, the subject is an adult patient with an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus or dyslipidemia). In some variations, the subject is a pediatric patient aged 12 years and older with an initial BMI at the 95thpercentile of greater for age and sex (obesity).

[0099] In another embodiment, incretin-based therapy used in the methods described herein is liraglutide. In some variations, liraglutide is subcutaneously administered (e.g., via injection) to the human subject once weekly at a therapeutically effective dose. In some variations, liraglutide is administered (e.g., via injection) at a dose of a 6 mg / mL solution in an injection device (e.g., a pre-filled, multi-dose pen) that delivers doses of 0.6 mg, 1.2 mg or 1.8 mg.

[0100] In some variations of the foregoing, the methods herein comprise administering an AMPK activator compound as described herein (e.g., compound of formula (I)) to a human subject that has been taking or is currently taking liraglutide. In certain variations, the human subject starting on the AMPK activator compound has experienced weight loss and lean mass loss from taking liraglutide, and the administration of the AMPK activator compound (e.g., compound of formula (I)) further increases weight loss in the human subject and / or maintains weight loss, while reversing lean mass loss or preserving lean mass. In some variations, the dose of liraglutide administered is reduced or eliminated over time.

[0101] In some embodiments of the foregoing, the methods herein are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, and / or to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.

[0102] In other embodiments of the foregoing, the methods herein are indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management. In some variations, the subject is an adult patient with an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 229MF-364661167Attorney Docket No.: 28650-20018.40 diabetes mellitus or dyslipidemia). In some variations, the subject is a pediatric patient 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.

[0103] In some variations of the foregoing, liraglutide is subcutaneously administered (e.g., via injection) to the human subject in the abdomen, thigh or upper arm. In certain variations, liraglutide is administered once daily at any time of the day, without regard to the timing of meals. In one variation, liraglutide is administered at dose of 3 mg daily.

[0104] In another embodiment, incretin-based therapy used in the methods described herein is liraglutide. In some variations, liraglutide is subcutaneously administered (e.g., via injection) to the human subject once weekly at a therapeutically effective dose. In some variations, liraglutide is administered (e.g., via injection) at a dose of a 6 mg / mL solution in an injection device (e.g., a pre-filled, multi-dose pen) that delivers doses of 0.6 mg, 1.2 mg or 1.8 mg.

[0105] In another embodiment, incretin-based therapy used in the methods described herein is tirzepatide. In some variations, tirzepatide is subcutaneously administered (e.g., via injection) to the human subject once weekly at a therapeutically effective dose. In some variations, tirzepatide is administered (e.g., via injection) at a dose of 2.5 mg, 5 mg, 7.5 mg, lOmg, 12.5 mg, or 15 mg per 0.5 mL in a single dose (e.g., in a single-dose pen or a single dose vial).

[0106] In some variations of the foregoing, the methods herein comprise administering an AMPK activator compound as described herein (e.g., compound of formula (I)) to a human subject that has been taking or is currently taking tirzepatide. In certain variations, the human subject starting on the AMPK activator compound has experienced weight loss and lean mass loss from taking tirzepatide, and the administration of the AMPK activator compound (e.g., compound of formula (I)) further increases weight loss in the human subject and / or maintains weight loss, while reversing lean mass loss or preserving lean mass. In some variations, the dose of tirzepatide administered is reduced or eliminated over time.

[0107] In other embodiments of the foregoing, the methods herein are indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management. In some variations, the subject is an adult patient with an initial body mass index (BMI) of 30 kg / m2or greater (obesity) or 27 kg / m2or greater (overweight) in the30MF-364661167Attorney Docket No.: 28650-20018.40 presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

[0108] In some variations, tirzepatide is subcutaneously administered (e.g., via injection) to the human subject once weekly at a therapeutically effective dose. In some variations, tirzepatide is subcutaneously administered in the abdomen, thigh or upper arm. In certain embodiments of the foregoing, tirzepatide is administered once weekly at any time of day, with or without meals.ENUMERATED EMBODIMENTS

[0109] The following enumerated embodiments are representative of some aspects of the invention.Embodiment Al. A method of reversing muscle loss or preserving muscle mass in a subject taking an incretin-based therapy, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.Embodiment A2. The method of embodiment Al, wherein the subject was previously administered an incretin-based therapy.Embodiment A3. The method of embodiment Al, wherein the subject is administered the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, concurrently with the incretin-based therapy.Embodiment A4. A method of managing body weight in a subject in need thereof, comprising: administering (1) a compound of formula (I) having the structure:31MF-364661167Attorney Docket No.: 28650-20018.40or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a therapeutically effective dose, in combination with (2) an incretin-based therapy.Embodiment A5. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises at least one agent effective against a glucagon-like peptide- 1 (GLP-1) receptor.Embodiment A6. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises a GLP- 1 receptor agonist.Embodiment A7. The method of any one of the preceding embodiments, wherein the incretin-based therapy causes GLP- 1 receptor agonism.Embodiment A8. The method of any one of the preceding embodiments, wherein the incretin-based therapy leads to at least 5% reduction in body weight in the subject.Embodiment A9. The method of embodiment A8, wherein at least 25% of the weight loss from the incretin-based therapy is fat free mass.Embodiment A 10. The method of any one of the preceding embodiments, wherein the combination of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the incretin-based therapy is administered as an adjunct to a reduced calorie diet and increased physical activity for weight management.Embodiment Al l. The method of any one of the preceding embodiments, wherein the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide.Embodiment A 12. The method of embodiment Al l, wherein the alkali metal salt is a sodium salt.Embodiment A13. The method of any one of embodiments Al to A12, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the32MF-364661167Attorney Docket No.: 28650-20018.40 subject at a dose that results in a Cmaxof the compound of formula (I) of from about 50 pg / mL to about 280 pg / mLEmbodiment A 14. The method of any one of embodiments Al to A 13, wherein the subject is a human.Embodiment A15. The method of embodiment A14, wherein the subject is an adult human.Embodiment A16. The method of embodiment A15, 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.Embodiment A17. The method of embodiment A14, wherein the subject is a pediatric human.Embodiment A 18. The method of embodiment A 17, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).Embodiment A19. The method of claim A17, 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.Embodiment A20. The method of any one of the preceding embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered.Embodiment A21. The method of embodiment A20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 400 mg and 1000 mg.Embodiment A22. The method of embodiment A20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose of 400 mg or 800 mg.Embodiment A23. The method of any one of the preceding embodiments, wherein the incretin-based therapy is subcutaneously administered via injection.33MF-364661167Attorney Docket No.: 28650-20018.40Embodiment A24. The method of any one of embodiments Al to A23, wherein the incretin-based therapy comprises semaglutide.Embodiment A25. The method of embodiment A24, wherein semaglutide is administered once weekly.Embodiment A26. The method of embodiment A24 or A25, wherein semaglutide is administered at a dose between 0.25 mg and 2.4 mg.Embodiment A27. The method of any one of embodiments A24 to A26, wherein semaglutide is administered at a once- weekly dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg.Embodiment A28. The method of any one of embodiments Al to A23, wherein the incretin-based therapy comprises liraglutide.Embodiment A29. The method of embodiment A28, wherein liraglutide is administered once daily.Embodiment A30. The method of embodiment A28 or A29, wherein liraglutide is administered at a dose between 0.6 mg and 3 mg.Embodiment A31. The method of any one of embodiments A28 to A30, wherein liraglutide is administered at a once-daily dose of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg.Embodiment A32. The method of any one of embodiments Al, A4 to A31, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure.Embodiment A33. The method of any one of embodiments Al, A4 to A31, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or eliminated and the compound of formula (I), or a pharmaceutically acceptable salt, solvate,34MF-364661167Attorney Docket No.: 28650-20018.40 or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure.Embodiment A34. The method of embodiment A33, wherein the dose of the incretinbased therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy.Embodiment A35. The method of any one of embodiments Al to A34, wherein reduction in bodyweight of the subject is predominantly attributable to a decrease in fat mass.Embodiment A36. The method of embodiment A35, wherein the method does not reduce lean body mass in the subject.Embodiment A37. The method of embodiment A35, wherein the method increases relative lean body mass in the subject.Embodiment A38. The method of any one of embodiments Al to A37, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases the portion of weight loss that is independent of a food intake reduction in the subject.Embodiment A39. The method of any one of embodiments Al to A38, wherein the subject is obese and suffers from sarcopenia or frailty.Embodiment Bl. A method of reversing muscle loss or preserving muscle mass in a subject taking an incretin-based therapy, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.35MF-364661167Attorney Docket No.: 28650-20018.40Embodiment B2. The method of embodiment Bl, wherein the subject was previously administered an incretin-based therapy.Embodiment B3. The method of embodiment Bl, wherein the subject is administered the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, concurrently with the incretin-based therapy.Embodiment B4. A method of managing body weight in a subject in need thereof, comprising: administering (1) a compound of formula (I) having the structure:(I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a therapeutically effective dose, in combination with (2) an incretin-based therapy.Embodiment B5. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises at least one agent effective against a glucagon-like peptide- 1 (GLP-1) receptor.Embodiment B6. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises a GLP- 1 receptor agonist.Embodiment B7. The method of any one of the preceding embodiments, wherein the incretin-based therapy causes GLP- 1 receptor agonism.Embodiment B8. The method of any one of the preceding embodiments, wherein the incretin-based therapy leads to at least 5% reduction in body weight in the subject.Embodiment B9. The method of embodiment B8, wherein at least 25% of the weight loss from the incretin-based therapy is fat free mass.Embodiment BIO. The method of any one of the preceding embodiments, wherein the combination of the compound of formula (I), or a pharmaceutically acceptable salt, solvate,36MF-364661167Attorney Docket No.: 28650-20018.40 or prodrug thereof, and the incretin-based therapy is administered as an adjunct to a reduced calorie diet and increased physical activity for weight management.Embodiment Bl 1. The method of any one of the preceding embodiments, wherein the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide.Embodiment B 12. The method of embodiment B 11 , wherein the alkali metal salt is a sodium salt.Embodiment B13. The method of any one of embodiments Bl to B12, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose that results in a Cmaxof the compound of formula (I) of from about 50 pg / mL to about 280 pg / mLEmbodiment B14. The method of any one of embodiments Bl to Bl 3, wherein the subject is a human.Embodiment B 15. The method of embodiment B 14, wherein the subject is an adult human.Embodiment B 16. The method of embodiment B 15, 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.Embodiment B 17. The method of embodiment B 14, wherein the subject is a pediatric human.Embodiment B 18. The method of embodiment B 17, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).Embodiment B 19. The method of embodiment B 17, 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.Embodiment B20. The method of any one of the preceding embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered.37MF-364661167Attorney Docket No.: 28650-20018.40Embodiment B21. The method of embodiment B20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 400 mg and 1000 mg.Embodiment B22. The method of embodiment B20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose of 400 mg or 800 mg.Embodiment B23. The method of any one of the preceding embodiments, wherein the incretin-based therapy is subcutaneously administered via injection.Embodiment B24. The method of any one of embodiments Bl to B23, wherein the incretin-based therapy comprises semaglutide.Embodiment B25. The method of embodiment B24, wherein semaglutide is administered once weekly.Embodiment B26. The method of embodiment B24 or B25, wherein semaglutide is administered at a dose between 0.25 mg and 2.4 mg.Embodiment B27. The method of any one of embodiments B24 to B26, wherein semaglutide is administered at a once- weekly dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg.Embodiment B28. The method of any one of embodiments Bl to B23, wherein the incretin-based therapy comprises liraglutide.Embodiment B29. The method of embodiment B28, wherein liraglutide is administered once daily.Embodiment B30. The method of embodiment B28 or B29, wherein liraglutide is administered at a dose between 0.6 mg and 3 mg.Embodiment B31. The method of any one of embodiments B28 to B30, wherein liraglutide is administered at a once-daily dose of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg.Embodiment B32. The method of any one of embodiments Bl, B4 to B31, wherein the incretin-based therapy is first administered to the subject for an initial period of time to38MF-364661167Attorney Docket No.: 28650-20018.40 induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure.Embodiment B33. The method of any one of embodiments Bl, B4 to B31, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or stopped and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure.Embodiment B34. The method of embodiment B33, wherein the dose of the incretinbased therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy.Embodiment B35. The method of embodiment B33, wherein the incretin-based therapy is stopped after initial weight loss in the subject is observed.Embodiment B36. The method of embodiment B35, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an effective dose sufficient to decrease the rate of weight regain in the subject as compared to administration of the incretin-based therapy alone.Embodiment B37. The method of embodiment B35, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an effective dose sufficient to maintain the weight loss and / or continue weight loss in the subject.Embodiment B38. The method of any one of embodiments Bl, B4 to B31, wherein the incretin-based therapy and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are co-administered to the subject to induce weight loss in the subject and / or maintain weight loss.39MF-364661167Attorney Docket No.: 28650-20018.40Embodiment B39. The method of any one of embodiments Bl to B38, wherein reduction in bodyweight of the subject is predominantly attributable to a decrease in fat mass.Embodiment B40. The method of embodiment B39, wherein the method does not reduce lean body mass in the subject.Embodiment B41. The method of embodiment B39, wherein the method increases relative lean body mass in the subject.Embodiment B42. The method of any one of embodiments Bl to B41, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases the portion of weight loss that is independent of a food intake reduction in the subject.Embodiment B43. The method of any one of embodiments Bl to B42, wherein the subject is obese and suffers from sarcopenia or frailty.Embodiment Cl. A method of reversing muscle loss or preserving muscle mass in a subject taking an incretin-based therapy, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.Embodiment C2. The method of embodiment Cl, wherein the subject was previously administered an incretin-based therapy.Embodiment C3. The method of embodiment Cl, wherein the subject is administered the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, concurrently with the incretin-based therapy.Embodiment C4. A method of managing body weight in a subject in need thereof, comprising:40MF-364661167Attorney Docket No.: 28650-20018.40 administering (1) a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a therapeutically effective dose, in combination with (2) an incretin-based therapy.Embodiment C5. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises at least one agent effective against a glucagon-like peptide- 1 (GLP-1) receptor.Embodiment C6. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises a GLP- 1 receptor agonist.Embodiment C7. The method of any one of the preceding embodiments, wherein the incretin-based therapy causes GLP- 1 receptor agonism.Embodiment C8. The method of any one of the preceding embodiments, wherein the incretin-based therapy leads to at least 5% reduction in body weight in the subject.Embodiment C9. The method of embodiment C8, wherein at least 25% of the weight loss from the incretin-based therapy is fat free mass.Embodiment CIO. The method of any one of the preceding embodiments, wherein the combination of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the incretin-based therapy is administered as an adjunct to a reduced calorie diet and increased physical activity for weight management.Embodiment Cl 1. The method of any one of the preceding embodiments, wherein the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide.Embodiment Cl 2. The method of embodiment Cl 1, wherein the alkali metal salt is a sodium salt.41MF-364661167Attorney Docket No.: 28650-20018.40Embodiment C13. The method of any one of embodiments Cl to C12, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose that results in a Cmaxof the compound of formula (I) of from about 50 pg / mL to about 280 pg / mLEmbodiment C14. The method of any one of embodiments Cl to Cl 3, wherein the subject is a human.Embodiment C15. The method of embodiment Cl 4, wherein the subject is an adult human.Embodiment C16. The method of embodiment Cl 5, 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.Embodiment C 17. The method of embodiment C 14, wherein the subject is a pediatric human.Embodiment Cl 8. The method of embodiment C 17, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).Embodiment C19. The method of embodiment C 17, 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.Embodiment C20. The method of any one of the preceding embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered.Embodiment C21. The method of embodiment C20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 400 mg and 1000 mg.Embodiment C22. The method of embodiment C20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose of 400 mg or 800 mg.42MF-364661167Attorney Docket No.: 28650-20018.40Embodiment C23. The method of any one of the preceding embodiments, wherein the incretin-based therapy is subcutaneously administered via injection.Embodiment C24. The method of any one of embodiments Cl to C23, wherein the incretin-based therapy comprises semaglutide.Embodiment C25. The method of embodiment C24, wherein semaglutide is administered once weekly.Embodiment C26. The method of embodiment C24 or C25, wherein semaglutide is administered at a dose between 0.25 mg and 2.4 mg.Embodiment C27. The method of any one of embodiments C24 to C26, wherein semaglutide is administered at a once- weekly dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg.Embodiment C28. The method of any one of embodiments Cl, C4 to C27, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure.Embodiment C29. The method of any one of embodiments Cl, C4 to C27, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or eliminated and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure.Embodiment C30. The method of embodiment C29, wherein the dose of the incretinbased therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy.Embodiment C31. The method of any one of embodiments Cl to C30, wherein reduction in bodyweight of the subject is predominantly attributable to a decrease in fat mass.43MF-364661167Attorney Docket No.: 28650-20018.40Embodiment C32. The method of embodiment C31, wherein the method does not reduce lean body mass in the subject.Embodiment C33. The method of embodiment C31, wherein the method increases relative lean body mass in the subject.Embodiment C34. The method of any one of embodiments Cl to C33, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases the portion of weight loss that is independent of a food intake reduction in the subject.Embodiment C35. The method of any one of embodiments Cl to C34, wherein the subject is obese and suffers from sarcopenia or frailty.Embodiment DI. A method of reversing muscle loss or preserving muscle mass in a subject taking an incretin-based therapy, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.Embodiment D2. The method of embodiment 1, wherein the subject was previously administered an incretin-based therapy.Embodiment D3. The method of embodiment DI, wherein the subject is administered the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, concurrently with the incretin-based therapy.Embodiment D4. A method of managing body weight in a subject in need thereof, comprising: administering (1) a compound of formula (I) having the structure:44MF-364661167Attorney Docket No.: 28650-20018.40or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a therapeutically effective dose, in combination with (2) an incretin-based therapy.Embodiment D5. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises at least one agent effective against a glucagon-like peptide- 1 (GLP-1) receptor.Embodiment D6. The method of any one of the preceding embodiments, wherein the incretin-based therapy comprises a GLP- 1 receptor agonist.Embodiment D7. The method of any one of the preceding embodiments, wherein the incretin-based therapy causes GLP- 1 receptor agonism.Embodiment D8. The method of any one of the preceding embodiments, wherein the incretin-based therapy leads to at least 5% reduction in body weight in the subject.Embodiment D9. The method of embodiment D8, wherein at least 25% of the weight loss from the incretin-based therapy is fat free mass.Embodiment DIO. The method of any one of the preceding embodiments, wherein the combination of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the incretin-based therapy is administered as an adjunct to a reduced calorie diet and increased physical activity for weight management.Embodiment Dl l. The method of any one of the preceding embodiments, wherein the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4- thiadiazol-5-yl]benzamide.Embodiment DI 2. The method of embodiment Dl l, wherein the alkali metal salt is a sodium salt.Embodiment D13. The method of any one of embodiments DI to D12, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the45MF-364661167Attorney Docket No.: 28650-20018.40 subject at a dose that results in a Cmaxof the compound of formula (I) of from about 50 pg / mL to about 280 pg / mLEmbodiment D14. The method of any one of embodiments DI to DI 3, wherein the subject is a human.Embodiment D15. The method of embodiment D14, wherein the subject is an adult human.Embodiment D16. The method of embodiment D15, 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.Embodiment D17. The method of embodiment D14, wherein the subject is a pediatric human.Embodiment DI 8. The method of embodiment D17, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).Embodiment D19. The method of embodiment D17, 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.Embodiment D20. The method of any one of the preceding embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered.Embodiment D21. The method of embodiment D20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 400 mg and 1000 mg.Embodiment D22. The method of embodiment D20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose of 400 mg or 800 mg.Embodiment D23. The method of any one of the preceding embodiments, wherein the incretin-based therapy is subcutaneously administered via injection.46MF-364661167Attorney Docket No.: 28650-20018.40Embodiment D24. The method of any one of embodiments DI to D23, wherein the incretin-based therapy comprises semaglutide.Embodiment D25. The method of embodiment D24, wherein semaglutide is administered once weekly.Embodiment D26. The method of embodiment D24 or D25, wherein semaglutide is administered at a dose between 0.25 mg and 2.4 mg.Embodiment D27. The method of any one of embodiments D24 to D26, wherein semaglutide is administered at a once- weekly dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg.Embodiment D28. The method of any one of embodiments DI, D4 to D27, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure.Embodiment D29. The method of any one of embodiments DI, D4 to D27, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or stopped and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure.Embodiment D30. The method of embodiment D29, wherein the dose of the incretinbased therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy.Embodiment D31. The method of embodiment D29, wherein the incretin-based therapy is stopped after initial weight loss in the subject is observed.Embodiment D32. The method of embodiment D31, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an47MF-364661167Attorney Docket No.: 28650-20018.40 effective dose sufficient to decrease the rate of weight regain in the subject as compared to administration of the incretin-based therapy alone.Embodiment D33. The method of embodiment D31, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an effective dose sufficient to maintain the weight loss and / or continue weight loss in the subject.Embodiment D34. The method of any one of embodiments DI, D4 to D27, wherein the incretin-based therapy and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are co-administered to the subject to induce weight loss in the subject and / or maintain weight loss.Embodiment D35. The method of any one of embodiments DI to D34, wherein reduction in bodyweight of the subject is predominantly attributable to a decrease in fat mass.Embodiment D36. The method of embodiment D35, wherein the method does not reduce lean body mass in the subject.Embodiment D37. The method of embodiment D36, wherein the method increases relative lean body mass in the subject.Embodiment D38. The method of any one of embodiments DI to D37, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases the portion of weight loss that is independent of a food intake reduction in the subject.Embodiment D39. The method of any one of embodiments DI to D38, wherein the subject is obese and suffers from sarcopenia or frailty.EXAMPLES

[0110] 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.48MF-364661167Attorney Docket No.: 28650-20018.40Example 1: Mice Study with Combination of Compound A and Semaglutide

[0111] This study explores the effect on body weight and fat tissue mass in obese mice when administered a combination of Compound A and semaglutide. As noted above, Compound A refers to the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo- l,2,4-thiadiazol-5-yl]benzamide, and is also referred to herein as “Cpmd A”.

[0112] Forty-five male C57BL / 6JRj mice were fed a high-fat diet (60% HFD, DI 2492 Research Diets) for 17 weeks before the start of the study. In week -1, the mice were randomized into eight groups (n=8 per group) based on body weight and fat tissue mass.

[0113] Group 1 -6 received daily subcutaneous (SubQ) injections with semaglutide (group 3 and 5, 1 nmol / kg; group 4 and 6, 3 nmol / kg) or vehicle SC (group 1 and 2). On study day 4, the diet was changed in group 2, 5, and 6 from HFD to Compound A HFD, where Compound A was formulated in food (0.5 mg Compound A / g food). On study day 15, due to faster and greater than expected weight loss in combination groups, the semaglutide dose concentration was reduced from 1 to 0.1 nmol / kg for group 3 and 5 and from 3 to 0.3 nmol / kg for group 4 and 6. On study day 23, the semaglutide dose concentration was further reduced to 0.1 nmol / kg in group 4 and 6 (not shown on graph below). Food intake was measured daily throughout the study. Fat and lean tissue mass were measured on Day 1 and Day 32.

[0114] The resulting groups as labeled here:1. Group 1: Vehicle Control2. Group 2: Compound A (0.5 mg / g food) plus subcutaneous control, Compound A dosing begins on Day 43. Group 3: Semaglutide (1 nmol / kg QD subcutaneous)4. Group 4: Semaglutide (3 nmol / kg QD subcutaneous)5. Group 5: Semaglutide (1 nmol / kg QD subcutaneous -> 0.1 nmol / kg on Day 15) + Compound A (0.5 mg / g food), Compound A dosing begins on Day 46. Group 6: Semaglutide (3 nmol / kg QD subcutaneous -> 0.3 nmol on Day 15 and then 0.1 nmol / kg on Day 23) + Compound A (0.5 mg / g food), Compound A dosing begins on Day 4Results49MF-364661167Attorney Docket No.: 28650-20018.40

[0115] Monotherapy treatment with Compound A, administered by diet, reduced body weight (absolute and relative). Weight loss was associated with a significant decrease in absolute and relative fat tissue mass. Compound A HFD further increased relative lean tissue mass.

[0116] In combination with semaglutide, Compound A HFD reduced body weight, reduced fat tissue mass and increased lean tissue mass. The effects of Compound A on body weight were not dependent on food intake.

[0117] The addition of Compound A to semaglutide resulted in faster and greater absolute weight loss during the first 15-days of treatment. A body weight plateau was not reached by Day 15, when the administered dose of semaglutide was reduced. Compound A prevented weight regain after a mandatory 90%+ reduction in the administered semaglutide dose (Day 15 - Day 32). See FIG. 1.

[0118] Statistical significance assessed on Day 32. Statistical significance (Dunnett’s test one factor linear model) was achieved in Groups 2, 5, 6, vs. vehicle control, P < 0.001.

[0119] The addition of Compound A to semaglutide did not materially alter the food intake response in mice treated with semaglutide, as seen in FIG. 2.

[0120] Compound A was also observed to increase the portion of weight loss that was independent of a food intake reduction. See Table 2 below.Table 2.50MF-364661167Attorney Docket No.: 28650-20018.40

[0121] Compound A was also found to reduce fat mass and preserve lean mass when added to semaglutide (measured on Day 1 and Day 32). See FIG 3. At the higher dose of semaglutide (0.3 nmol / kg) administered in combination with Compound A, further reduction in fat mass was observed, but no further reduction in lean mass was observed relative to Compound A alone and relative to the combination of Compound A and semaglutide at the lower dose (0.1 nmol / kg).

[0122] Statistical significance was assessed on Day 32. Statistical significance (Dunnett’s test one factor linear model) was achieved in Groups 2, 5, 6, vs. vehicle control, P < 0.001, for absolute change in fat mass. No difference in lean mass vs. vehicle control.

[0123] Compound A was observed to increase the proportion of lean tissue mass when added to semaglutide (measured on Day 1 and Day 32). See FIG. 4.

[0124] Overall, the results from this example show that when Compound A and semaglutide are co-administered as compared to Compound A alone and semaglutide alone, we see further decrease in fat mass, but preservation in lean mass.Example 2: Weight maintenance effect of Compound A on metabolic parameters after Semaglutide induction weight loss in male diet induced obese (DIO) mice51MF-364661167Attorney Docket No.: 28650-20018.40

[0125] A total of 40 male C57BL / 6JRj DIO mice (fed 60% high fat diet (HFD) for 16+ weeks) will be initiated. On week -2 animals are single-housed and before study start, animals are randomized into 5 groups (n=8) based on body weight and fat mass.

[0126] Groups:SubQ ControlVehicle HFD1. Semaglutide monotherapy (4 weeks) Vehicle HFD (2 weeks)2. Semaglutide monotherapy (4 weeks) Compound A in HFD low dose (2 weeks)3. Semaglutide monotherapy (4 weeks) Compound A in HFD med dose (2 weeks)4. Semaglutide monotherapy (4 weeks) Compound A in HFD high dose (2 weeks)

[0127] A total of 4 weeks treatment with Semaglutide SubQ followed by cessation of Semaglutide SC and initiation of 2 weeks of treatment with Compound A in the diet. Body weight and food intake were recorded daily for the entire study period. Baseline, week 4 and preterminal EchoMRI (lean and fat mass) were recorded. Muscle biopsy was performed at end of study for analysis.

[0128] The introduction of Compound A after semaglutide did not materially alter the food intake response in mice treated with semaglutide, as seen in FIG. 5. Semaglutide is also denoted as “sema” in this example.

[0129] As shown in FIG. 6, when the mice were taken off semaglutide, body weight increased (i.e., a ‘snapback’ was observed). However, when Compound A at the medium dose was introduced after stopping semaglutide, the snapback effect was lessened. Further, when Compound A at the high dose was introduced, weight loss was further observed.

[0130] FIG. 7 shows that administration of Compound A after stopping semaglutide had a dose-dependent effect on weight regain. Specifically, Compound A at the highest dose led to full maintenance of weight loss, while Compound A at the medium dose slowed down weight regain.Comparison of Examples 1 and 252MF-364661167Attorney Docket No.: 28650-20018.40

[0131] As described above, the effect of coadministration during and after treatment with semaglutide (sema) was investigated across two protocols in a mouse DIO model, with C57Bl / 6JRj mice on high fat diet (HFD) for 16-18 weeks.

[0132] In Example 1, a coadministration protocol was adopted. DIO mice (N=8 / group) were treated subcutaneously (sc) with 2 different doses of sema for 3 days or sc vehicle. Starting on Day 4, animals were treated with oral Compound A formulated in HFD, Compound A in combination with sema, sema alone, or control HFD. After 2 weeks, sema doses had to be reduced by 90% due to weight loss in combination arms. Compound A treatment alone or in combination was continued for an additional 17 days.

[0133] In Example 2, a sequential protocol was adopted. DIO mice (N=8 / group) were treated with sema sc or vehicle for 4 weeks. Sema was discontinued, and animals were treated with 3 different oral doses of Compound A in HFD, or HFD alone, for 2 weeks. Body weight, food intake, and body composition by EchoMRI were determined at various time points in both experiments.

[0134] The results of Example 1 showed that after 14 days, Compound A resulted in greater weight loss in combination with sema compared to sema or Compound A alone. After sema dose reduction on Day 15, sema controls became hyperphagic and rapidly regained weight over the following 2 weeks. Compound A maintained weight loss observed prior to sema dose reduction despite hyperphagia. Weight loss after 4 weeks of oral Compound A was comparable to higher dose of sema before dose reduction. Echo MRI at 4 weeks revealed similar fat and lean mass in sema alone compared to control, while weight loss in both Compound A and Compound A + sema groups was solely attributable to fat mass reduction with no reduction in lean mass. See FIG. 8.

[0135] With reference again to FIG. 8, the results of Example 2 showed that animals dosed with sema for 28 days showed a reduction in both fat and lean mass as expected. After sema withdrawal, Compound A demonstrated a dose-dependent prevention of weight regain, with the highest dose maintaining weight loss observed after 4 weeks of sema, despite hyperphagia following sema withdrawal. No further loss of lean mass was observed after 2 weeks of sequential Compound A treatment.

[0136] These results suggest that Compound A is suitable for use as a weight loss agent with complementary effects to incretins, with potential preservation of lean mass. Compound53MF-364661167Attorney Docket No.: 28650-20018.40A may be useful as monotherapy, in co-administration, or as weight maintenance therapy in subjects discontinuing incretins.Example 3: Effect of Compound A on calorimetry and metabolic parameters in combination with multiple doses of Semaglutide

[0137] A total of 48 male C57BL / 6JRj DIO mice (fed 60% HFD diet for 16+ weeks) will be initiated. On week -2 animals are single-housed and before study start, animals are randomized into 5 groups (n=8) based on body weight and fat mass.

[0138] Groups:1. Vehicle Control2. Compound A low dose in HFD + SubQ Control (Compound A dosing to begin on Day 4)3. Compound A low dose in HFD + Semaglutide 0.3 nmol / kg (low dose) (Compound A dosing to begin on Day 4)4. Compound A low dose in HFD + Semaglutide 1.0 nmol / kg (medium dose) (Compound A dosing to begin on Day 4)5. Semaglutide 0.3 nmol / kg + HFD6. Semaglutide 1.0 nmol / kg + HFD

[0139] A total of 4 weeks treatment with Compound A in the diet in combination with SubQ control or two different doses of semaglutide. Body weight and food intake are recorded daily for the entire study period. Metabolic cage parameters (including indirect calorimetry) are collected over a 3-day period at the beginning and end of study. Baseline and preterminal EchoMRI (lean and fat mass) are recorded.Example 4: Mice Study with Combination of Compound A and Orforglipron

[0140] This study explores the effect on body weight and fat tissue mass in obese mice when administered a combination of Compound A and Orforglipron. As noted above, Compound A refers to the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo- l,2,4-thiadiazol-5-yl]benzamide, and is also referred to herein as “Cpmd A”.54MF-364661167Attorney Docket No.: 28650-20018.40

[0141] Forty-eight male C57BL / 6JRj mice are fed a high-fat diet (60% HFD, D12492 Research Diets) for 17 weeks before the start of the study. In week -1, the mice are randomized into six groups (n=8 per group) based on body weight and fat tissue mass.

[0142] Group 1 receives high-fat diet and vehicle control. Group 2 starts on high-fat diet and vehicle control. On study day 4, the diet is changed from HFD to Compound A HFD. Groups 3-6 receive daily orforglipron administered by oral gavage, with orforglipron in a 90% polyethylene glycol 400 / 10% solutol solution (group 3 and 5, 10 mg / kg; group 4 and 6, 30 mg / kg). On study day 4, the diet is changed in group 5 and 6 from HFD to Compound A HFD, where Compound A is formulated in food (0.5 mg Compound A / g food). Food intake is measured daily throughout the study. Fat and lean tissue mass via MRI are measured on Day 1 and Day 32.

[0143] The groups as labeled here:1. Group 1: Vehicle Control2. Group 2: Compound A (0.5 mg / g food) plus subcutaneous control, Compound A dosing begins on Day 43. Group 3: Orforglipron (10 mg / kg QD oral gavage)4. Group 4: Orforglipron (30 mg / kg QD oral gavage)5. Group 5: Orfirglipron (10 mg / kg QD oral gavage) + Compound A (0.5 mg / g food), Compound A dosing begins on Day 46. Group 6: Orforglipron (30 mg / kg QD oral gavage + Compound A (0.5 mg / g food), Compound A dosing begins on Day 44Example 5: Weight maintenance effect of Compound A on metabolic parameters after Orforglipron induction weight loss in male diet induced obese (DIO) mice

[0144] A total of 24 male C57BL / 6JRj DIO mice (fed 60% high fat diet (HFD) for 16+ weeks) is initiated. On week -2 animals are single-housed and before study start, animals are randomized into 3 groups (n=8) based on body weight and fat mass.

[0145] Groups:1. SubQ ControlVehicle HFD2. Orforglipron monotherapy at 30 mg / kg (4 weeks)Vehicle HFD (2 weeks)55MF-364661167Attorney Docket No.: 28650-20018.403. Orforglipron monotherapy (4 weeks) Compound A monotherapy after stopping semaglutide dosing, Compound A in HFD at 0.5 mg / g food (2 weeks)

[0146] The study involves a total of 4 weeks treatment with orforglipron followed by cessation of orforglipron and initiation of 2 weeks of treatment with Compound A in the diet. Body weight and food intake are recorded daily for the entire study period. Baseline, week 4 and preterminal EchoMRI (lean and fat mass) are recorded. Muscle biopsy is performed at end of study for analysis.Example 6: Mice Study with Combination of Compound A and Tirzepatide

[0147] Male C57BL / 6JRj mice are fed a high-fat diet (HFD) for 20 weeks prior to the start of the study. On day -3, the mice are randomized into six groups based on body weight and fat tissue mass.

[0148] Groups:1. Vehicle HFD / Vehicle, receives daily subcutaneous (SC) vehicle treatment.2. Compound A HFD low / Vehicle, receives daily subcutaneous (SC) vehicle treatment.3. Compound A HFD high / Vehicle, receives daily subcutaneous (SC) vehicle treatment.4. Vehicle HFD / Tirzepatide, receives daily Tirzepatide treatment (2 nmol / kg, SC) for 31 days.5. Compound A HFD low / Tirzepatide, receives daily Tirzepatide treatment (2 nmol / kg, SC) for 31 days.6. Compound A HFD high / Tirzepatide, receives daily Tirzepatide treatment (2 nmol / kg, SC) for 31 days.

[0149] On study day 4, the diet for Groups 2 and 5 is switched to HFD with 0.25 mg / g Compound A, and the diet for Groups 3 and 6 is switched to a HFD with 0.5 mg / g Compound A. Groups 1 and 4 remain on Vehicle HFD.

[0150] Body weight is measured daily from study day -3 to day 32, and food intake is recorded daily from study day -1 to day 32. Fat and lean tissue mass are assessed at baseline (day -3), at week 3 (day 19), and at week 4 (day 29) using EchoMRI. On study day 32, animals are terminated, and plasma, liver and quad-riceps muscle samples are collected.56MF-364661167

Claims

Attorney Docket No.: 28650-20018.40CLAIMSWhat is claimed is:

1. A method of preserving muscle mass in a subject taking an incretin-based therapy, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. The method of claim 1, wherein the subject was previously administered an incretinbased therapy.

3. The method of claim 1, wherein the subject is administered the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, concurrently with the incretin-based therapy.

4. A method of managing body weight in a subject in need thereof, comprising: administering (1) a compound of formula (I) having the structure:or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a therapeutically effective dose, in combination with (2) an incretin-based therapy.

5. The method of any one of the preceding claims, wherein the incretin-based therapy comprises at least one agent effective against a glucagon-like peptide- 1 (GLP-1) receptor.57MF-364661167Attorney Docket No.: 28650-20018.

406. The method of any one of the preceding claims, wherein the incretin-based therapy comprises a GLP-1 receptor agonist.

7. The method of any one of the preceding claims, wherein the incretin-based therapy causes GLP-1 receptor agonism.

8. The method of any one of the preceding claims, wherein the incretin-based therapy leads to at least 5% reduction in body weight in the subject.

9. The method of any one of the preceding claims, wherein the combination of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the incretin-based therapy is administered as an adjunct to a reduced calorie diet and increased physical activity for weight management.

10. The method of any one of the preceding claims, wherein the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-l,2,4-thiadiazol-5-yl]benzamide.

11. The method of claim 10, wherein the alkali metal salt is a sodium salt.

12. The method of any one of claims 1 to 11, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose that results in a Cmax of the compound of formula (I) of from about 50 pg / mL to about 280 pg / mL13. The method of any one of claims 1 to 12, wherein the subject is a human.

14. The method of claim 13, wherein the subject is an adult human.

15. The method of claim 14, 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.

16. The method of claim 13, wherein the subject is a pediatric human.

17. The method of claim 16, wherein the pediatric human has an initial BMI at the 95thpercentile or greater for age and sex (obesity).

18. The method of claim 16, 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.58MF-364661167Attorney Docket No.: 28650-20018.4019. The method of any one of the preceding claims, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered.

20. The method of claim 19, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 200 mg and 1000 mg.

21. The method of claim 19 or 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose between 400 mg and 1000 mg.

22. The method of any one of claims 19 to 21, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered at a daily dose of 400 mg or 800 mg.

23. The method of any one of the preceding claims, wherein the incretin-based therapy is subcutaneously administered via injection.

24. The method of any one of claims 1 to 23, wherein the incretin-based therapy comprises semaglutide.

25. The method of claim 24, wherein semaglutide is administered once weekly.

26. The method of claim 24 or 25, wherein semaglutide is administered at a dose between 0.25 mg and 7.5 mg.

27. The method of any one of claims 24-26, wherein semaglutide is administered at a dose between 0.25 mg and 2.5 mg.

28. The method of any one of claims 24-27, wherein semaglutide is administered at a once- weekly dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg.

29. The method of any one of claims 1 to 23, wherein the incretin-based therapy comprises liraglutide.

30. The method of claim 29, wherein liraglutide is administered once daily.

31. The method of claim 29 or 30, wherein liraglutide is administered at a dose between 0.6 mg and 3 mg.59MF-364661167Attorney Docket No.: 28650-20018.4032. The method of any one of claims 29 to 31, wherein liraglutide is administered at a once-daily dose of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg.

33. The method of any one of claims 1 to 23, wherein the incretin-based therapy is administered orally.

34. The method of claim 33, wherein the incretin-based therapy comprises semaglutide.

35. The method of claim 34, wherein semaglutide is administered once daily.

36. The method of claim 34 or 35, wherein semaglutide is administered at a once-daily dose of 25 mg or 50 mg.

37. The method of any one of claims 1 and 4 to 36, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and administration of the incretin-based therapy is continued while the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is further administered to the subject to continue weight loss in the subject and / or maintain weight loss by increasing energy expenditure.

38. The method of any one of claims 1 and 4 to 36, wherein the incretin-based therapy is first administered to the subject for an initial period of time to induce initial weight loss in the subject; and the dose of the incretin-based therapy is reduced or stopped and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject to maintain weight loss by increasing energy expenditure.

39. The method of claim 38, wherein the dose of the incretin-based therapy is reduced by between 10% and 50%, and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, protects against bodyweight regain in the subject after reduction in the dose of the incretin-based therapy.

40. The method of claim 38, wherein the incretin-based therapy is stopped after initial weight loss in the subject is observed.

41. The method of claim 40, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an effective dose sufficient to60MF-364661167Attorney Docket No.: 28650-20018.40 decrease the rate of weight regain in the subject as compared to administration of the incretinbased therapy alone.

42. The method of claim 40, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered as an effective dose sufficient to maintain the weight loss and / or continue weight loss in the subject.

43. The method of any one of claims 1 and 4 to 42, wherein the incretin-based therapy and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are co-administered to the subject to induce weight loss in the subject and / or maintain weight loss.

44. The method of any one of claims 1 to 43, wherein reduction in body weight of the subject is predominantly attributable to a decrease in fat mass.

45. The method of claim 44, wherein the method does not reduce lean body mass in the subject.

46. The method of claim 44, wherein the method increases relative lean body mass in the subject.

47. The method of any one of claims 1 to 46, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases the portion of weight loss that is independent of a food intake reduction in the subject.

48. The method of any one of claims 1 to 47, wherein the subject is obese and suffers from sarcopenia or frailty.61MF-364661167

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