GLP-1 receptor agonist compositions and methods of use thereof

Abstract

The present disclosure relates to use of GLP-1 receptor agonist in certain dosage regimes for inducing or maintaining weight loss or managing body weight.

Description

Atty Ref. METS-022 / 03WO 350242-2228GLP-1 RECEPTOR AGONIST COMPOSITIONS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application 63 / 697,341, filed September 20, 2024; U.S. Provisional Application 63 / 744,026, filed January 10, 2025; U.S. Provisional Application 63 / 803,315, filed May 9, 2025, the contents each of which are incorporated herein by reference in their entireties.REFERENCE TO THE ELECTRONIC SEQUENCE FILE

[0002] The contents of the electronic sequence listing (METS_022_03WO_SeqList_ST26.xml; Size: 4,481 bytes; and Date of Creation: September 11, 2025) are herein incorporated by reference in their entirety.BACKGROUND

[0003] According to the National Health and Nutrition Examination Survey (NHANES, 2009-2010), 33.0% of adults in the United States aged 20 and over are overweight, 35.7% are obese, and 6.3% are extremely obese. In addition, a large percentage of children in the United States are overweight or obese.

[0004] The cause of obesity is complex and multi-factorial. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk.

[0005] There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type-2 diabetes disease risk, increases independently with increased body mass index (BMI). Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for females, and a seven percent increase in the risk of cardiac disease for males, for each point of a BMI greater thanAtty Ref. METS-022 / 03WO 350242-222824.9 (see Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002).

[0006] Diabetes is a chronic syndrome of impaired carbohydrate, protein, and fat metabolism owing to insufficient secretion of insulin or to target tissue insulin resistance. It occurs in two major forms: insulin-dependent diabetes mellitus (type 1 diabetes) and noninsulin dependent diabetes mellitus (type 2 diabetes). Diabetes type 1, or insulin dependent diabetes mellitus (IDDM) is caused by the destruction of P cells, which results in insufficient levels of endogenous insulin. Diabetes type 2, or non-insulin dependent diabetes, results from a defect in both the body’s sensitivity to insulin, and a relative deficiency in insulin production. According to the National Diabetes Statistics Report, 2014 around 28.9 million adults in the United States aged 20 and over have diabetes (2009-2012 National Health and Nutrition Examination Survey estimates applied to 2012 U.S. Census data). In adults 90 to 95% of the diabetes is type 2 diabetes.

[0007] There is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. It has been shown that considerable weight loss can effectively cure type 2 diabetes (Lim et al., Diabetologia June 2011).

[0008] Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, many of these drugs have serious adverse side effects. When less invasive methods have failed, and the patient is at high risk for obesity related morbidity or mortality, weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and suitable for use in only a limited number of patients. It is not only obese subjects who wish to lose weight. People with weight within the recommended range, for example, in the upper part of the recommended range, may wish to reduce their weight, to bring it closer to the ideal weight. Thus, a need remains for agents that can be used to affect weight loss in overweight and obese subjects as well as in subjects who are of normal weight.Atty Ref. METS-022 / 03WO 350242-2228

[0009] A number of approaches to the development of agents useful in effecting weight loss have involved gastrointestinal peptide hormones and their analogues. For example, derivatives of peptides deriving from the preproglucagon molecule have been proposed for use in treatment of obesity and / or diabetes. Preproglucagon is a precursor peptide of glucagon-like peptide 1 (GLP-1), as well as other hormones including glucagon GLP-1 is produced in vivo in the intestinal L cell in response to the presence of nutrients in the lumen of the gut. GLP-1 possesses a number of physiological functions including increasing insulin secretion from the pancreas in a glucose-dependent manner, decreasing glucagon secretion from the pancreas, inhibiting gastric emptying and decreasing food intake by increasing satiety. Increased insulin secretion leads to a decrease in circulating glucose concentration.

[0010] Examples of research into analogues of such peptides are described in, for example, WO20 13 / 004983 which describes peptide molecules containing sequence from both the GLP- 1 and glucagon peptides. WO2015 / 132599 also discloses peptide hormone analogues, which are derivable from preproglucagon and which are useful in the therapy of disorders such as obesity and diabetes. WO2017 / 178829 discloses compounds that are analogues of exendin-4, GLP-1 and oxyntomodulin which have a modified ligand bias and therapeutically useful characteristics. Another example is the peptide liraglutide, a GLP-1 agonist which has the sequence of GLP-l(7-37) with an arginine residue substituted for the native lysine at position 34, and with the sidechain of the lysine residue at position 26 being acylated by a hexadecanoyl group(palmitic acid) attached to the lysine though a glutamic acid spacer. Liraglutide has been developed for use as a once daily injectable drug for the treatment of type II diabetes. The same active ingredient as in liraglutide is marketed as Saxenda for the treatment of obesity (once daily injection). Semaglutide, sold as a once weekly injectable analogue of GLP-1 marketed as Wegovy, has two amino acid substitutions compared to human GLP-1 (AIB8, Arg34) and is derivatized at lysine 26 with a linker and a Cl 8 diacid fatty acid.

[0011] GLP-1 receptor agonists are widely used for treatment of chronic disease. Currently available GLP-1 receptor agonist medicaments require administration via frequent injections. A treatment regimen with longer dosing intervals may lead to improved patient convenience and improved patient compliance. Therefore, there remains a need for readily administrable dosage form of GLP-1 receptor agonists suitable for less frequent dosing.Atty Ref. METS-022 / 03WO 350242-2228SUMMARY

[0012] In some aspects, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

[0013] In some aspects, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1. In some embodiments, about 0.4 mg to about 1.2 mg of the GLP-1 receptor agonist or a salt thereof is administered once weekly for about 28 weeks to about 36 weeks. In some embodiments, after administering the GLP-1 receptor agonist once weekly for about 28 weeks to about 36 weeks, about 2 mg to about 5 mg (e.g., about 2.4 mg, about 3.2 mg, about 4.8 mg) of the GLP-1 receptor agonist or a salt thereof is administered once monthly.

[0014] In some aspects, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject who has received a prior GLP- 1 receptor agonist administered on a daily or weekly basis, the method comprising (a) discontinuing the administration of the prior GLP-1 receptor agonist; and (b) thereafter, initiating the subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

[0015] In some aspects, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to aboutAtty Ref. METS-022 / 03WO 350242-222836 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1. In some embodiments, about 0.2 mg to about 0.6 mg (e.g., 0.4 mg) of the GLP-1 receptor agonist or a salt thereof is administered once weekly for about 28 weeks. In some embodiments, on about weeks 28 of treatment, about 0.6 mg to about 1.0 mg (e.g., about 0.8 mg) of the GLP-1 receptor agonist or a salt thereof is administered once weekly for about 8 weeks. In some embodiments, after administering the GLP-1 receptor agonist once weekly for about 36 weeks, about 1.4 mg to about 1.8 mg (e.g., about 1.6 mg) of the GLP-1 receptor agonist or a salt thereof is administered once biweekly.

[0016] In some aspects, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 2 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 10.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.4 mg to about 10.0 mg, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

[0017] In some embodiments, the C-terminal Lys of the peptide is linked to a group of formula I:wherein R is a C16-C18 alkylene or alkenylene group; andR1is CO2H.

[0018] In some embodiments, the composition comprises the GLP-1 receptor agonistAtty Ref. METS-022 / 03WO 350242-2228(Compound A).

[0019] In some embodiments, the subject has obesity or is overweight. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2. In some embodiments, the subject further has a weight-related comorbid condition. In some embodiments, the weight-related comorbid condition is T2DM.

[0020] Other aspects and embodiments will be apparent to one skilled in the art in light of the detailed description and Examples that follow.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1A and FIG. IB show the effects of native GLP-1, Semaglutide and Compound A on cAMP (FIG. 1A) and B-arrestin (FIG. IB) signaling in human cell lines overexpressing GLP-1 receptors.

[0022] FIG. 2 shows the mean percent change from baseline weight ±SE by visit for each treatment in SAD cohorts.

[0023] FIG. 3 shows concentration profiles following single doses of Compound A over time.

[0024] FIG. 4 shows the weekly mean percent body weight change from baseline in MAD cohorts of Phase 1 / 2 clinical trial.

[0025] FIG. 5 A and FIG. 5B show projected mean plasma concentrations of Compound A in MAD cohorts of Phase 1 / 2 clinical trial.

[0026] FIG. 6A and FIG. 6B show weekly mean percent body weight change from baseline (FIG. 6A) and least sequres (LS) mean difference in percent change at Day 85 from baseline weight (FIG. 6B) in Part C cohorts of the Phase 1 / 2 clinical trial.

[0027] FIG. 7A and FIG. 7B show the results of % weight for 4 x dose escalation group. FIG. 7A shows the percent change from baseline (%CFB) in body weight and FIG. 7B showsAtty Ref. METS-022 / 03WO 350242-2228 the arithmetic mean difference (±95% CI) from placebo in %CFB body weight at Day 115. N and n indicate the number of randomized participants at baseline and Day 115, respectively. Arithmetic means are shown regardless of adherence. *For the 1.2 mg group, the placebo- corrected weight change in the adherence to treatment subgroup was -14.2%.

[0028] FIG. 8 shows the distribution of preliminary dose normalized Compound A Cmax by cohort.

[0029] FIG. 9 shows the distribution of preliminary dose normalized Compound A AUCo- 168 by cohort. AUCo-i68=area under the curve evaluated until 168 hours post-dose.

[0030] FIG. 10 shows the predicted pharmacokinetic profile of Compound A in a weekly to monthly dosing regimen.

[0031] FIG. 11 shows the study design of the Part-1 clinical study.

[0032] FIG. 12 shows the study design of the Part-2 clinical study.

[0033] FIG. 13 shows the study design of the Part-3 clinical study.

[0034] FIG. 14 shows the study design of the Phase 2b Part A and Part B studies.SEQUENCES

[0035] The amino acid sequences herein are shown with the N-terminus to the left, and where sequences are set out across multiple lines, the N-terminus is to the top left. Unless indicated otherwise, the amino acid residues in the sequences are L-amino acids.

[0036] The amino acid sequences listed in the application are shown using standard letter abbreviations for amino acids. The unnatural amino acid 2-aminoisobutyric acid has its usual abbreviation ‘AIB’.DETAILED DESCRIPTIONDefinitions

[0037] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0038] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “aboutAtty Ref. METS-022 / 03WO 350242-222825,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5.

[0039] The terms “administer,” “administering” or “administration” as used herein refer to administering a compound or salt of the compound or a composition or formulation comprising the compound or salt of the compound to a subject.

[0040] The term “subject” as used interchangeably herein, refers to a human or other vertebrates, including but not limited to, other primates; farm animals for example swine, cattle and poultry; sport animals for example horses; or companion animals for example dogs and cats.

[0041] The terms “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0042] The term “pharmaceutically acceptable” as used herein, refers to those compounds, salts, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0043] The term “salts” as used herein embraces salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. Salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloropprocaine,, diethanolamine,, p procaiine,, N- b enzy Iphenethy 1 amine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium,Atty Ref. METS-022 / 03WO 350242-2228 tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. When the GLP-1 receptor agonists of the disclosure are formulated as a salt for human or animal administration, the salts are pharmaceutically acceptable salts.

[0044] The term “carrier” or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature.

[0045] The term “effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” as used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or composition containing the compound or salt) that, when administered to a patient, or self-administered by a patient, is capable of performing the intended result.

[0046] The term “animal” as used herein refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and veterinary subjects. In preferred embodiments of the disclosure, the subject is a human subject.

[0047] The term “appetite” as used herein refers to a natural desire, or longing for food. In one embodiment, appetite is measured by a survey to assess the desire for food. Increased appetite generally leads to increased feeding behaviour.Atty Ref. METS-022 / 03WO 350242-2228

[0048] The term “Appetite Suppressants” as used herein refer to compounds that decrease the desire for food. Commercially available appetite suppressants include, but are not limited to, amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine fenfluramine, dexfenfluramine, and fluoxetine.

[0049] The term “Body Mass Index (BMI)” as used herein refers to a mathematical formula for measuring body mass, also sometimes called Quetelet' s Index. BMI is calculated by dividing weight (in kg) by height2 (in metres2). The current standards for both men and women accepted as "normal" are a BMI of 20-24.9 kg / m2. In one embodiment, a BMI of greater than 25 kg / m2can be used to identify an obese subject. Grade I obesity (which is sometimes referred to as being “overweight” rather than obesity) corresponds to a BMI of 25- 29.9 kg / m2. Grade II obesity corresponds to a BMI of 30-40 kg / m2; and Grade III obesity corresponds to a BMI greater than 40 kg / m2(Jequier, Am. J Clin. Nutr. 45: 1035-47, 1987). Ideal body weight will vary among species and individuals based on height, body build, bone structure, and sex.

[0050] The term “diabetes” as used herein refers to a failure of cells to transport endogenous glucose across their membranes either because of an endogenous deficiency of insulin and / or a defect in insulin sensitivity. Diabetes is a chronic syndrome of impaired carbohydrate, protein, and fat metabolism owing to insufficient secretion of insulin or to target tissue insulin resistance. It occurs in two major forms: insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin dependent diabetes mellitus (NIDDM, type II) which differ in etiology, pathology, genetics, age of onset, and treatment. The two major forms of diabetes are both characterized by an inability to deliver insulin in an amount and with the precise timing that is needed for control of glucose homeostasis. Diabetes type I, or insulin dependent diabetes mellitus (IDDM) is caused by the destruction of P cells, which results in insufficient levels of endogenous insulin. Diabetes type II, or non-insulin dependent diabetes, results from a defect in both the body’s sensitivity to insulin, and a relative deficiency in insulin production.

[0051] The term “energy metabolism” as used herein refers to that the body has to expend a certain amount of energy to maintain normal metabolism. In civilized man this is often set at about 2,800 Calories daily. If food consumption does not provide this, weight loss results. However, energy metabolism is also regulated, and, for example, administration of glucagon is thought to increase the metabolic rate so that a greater food intake is required to achieveAtty Ref. METS-022 / 03WO 350242-2228 energy balance and maintain weight. Thus, if food intake is maintained at the usual level, but energy metabolism is increased, weight loss will result.

[0052] The term “food intake” as used herein refers to the amount of food consumed by an individual. Food intake can be measured by volume or by weight. For example, food intake may be the total amount of food consumed by an individual. In a feeding experiment, ‘Food Intake’ is the weight of a standardized chow consumed by an animal in a 24 hour period. Or, food intake may be the amount of proteins, fat, carbohydrates, cholesterol, vitamins, minerals, or any other food component, of the individual. “Protein intake” refers to the amount of protein consumed by an individual. Similarly, “fat intake,” “carbohydrate intake,” “cholesterol intake,” “vitamin intake,” and “mineral intake” refer to the amount of proteins, fat, carbohydrates, cholesterol, vitamins, or minerals consumed by an individual.

[0053] The term “glucagon-like peptide 1 (GLP-1)” is derived from the transcription product of the proglucagon gene. The biologically active forms of GLP-1 are truncated forms known as GLP-l(7-37) and GLP-1 (7-36)-NH2 (the designation -NH2 designates an amino acid sequence in which the C-terminal amino acid has a -C(O)NH2 group in place of a carboxylic acid group). The sequence of human GLP-l(7-37) is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp- Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg- Gly (SEQ ID NO: 2). The sequence of human GLP-1 (7-36)-NH2 is His-Ala-Glu-Gly-Thr-Phe- Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val- Lys-Gly-Arg— CONH2 (SEQ ID NO: 3).

[0054] The terms “GLP-1 receptor agonist,” “GLP-1 analog,” “GLP-1 agonist” are used interchangeably herein and refer to a class of anorectic drugs that reduce blood sugar and energy intake, as well as induce other biological responses, by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating. The term as used herein can also refer to multi-agonist drugs that activate the GLP- 1 receptor together with one or more other receptors, including the gastric inhibitory polypeptide (GIP) receptor, glucagon receptor, amylin receptor, calcitonin receptor, and other receptors.

[0055] The term “normal Daily Diet” as used herein refers to the average food intake for an individual of a given species. A normal daily diet can be expressed in terms of caloric intake, protein intake, carbohydrate intake, and / or fat intake. A normal daily diet in humans generally comprises the following: about 2,000, about 2,400, or about 2,800 to significantlyAtty Ref. METS-022 / 03WO 350242-2228 more calories. In addition, a normal daily diet in humans generally includes about 12 g to about 45 g of protein, about 120 g to about 610 g of carbohydrate, and about 11 g to about 90 g of fat. A low calorie diet would be no more than about 85%, and preferably no more than about 70%, of the normal caloric intake of a human individual. In animals, the caloric and nutrient requirements vary depending on the species and size of the animal. For example, in cats, the total caloric intake per pound, as well as the percent distribution of protein, carbohydrate and fat varies with the age of the cat and the reproductive state. A general guideline for cats, however, is 40 cal / lb / day (18.2 cal / kg / day). About 30% to about 40% should be protein, about 7% to about 10% should be from carbohydrate, and about 50% to about 62.5% should be derived from fat intake. One of skill in the art can readily identify the normal daily diet of an individual of any species.

[0056] The term “obesity” as used herein refers to a condition in which excess body fat may put a person at health risk (see Barlow and Dietz, Pediatrics 102:E29, 1998; National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Obes. Res. 6 (suppl. 2):51S-209S, 1998). Excess body fat is a result of an imbalance of energy intake and energy expenditure. For example, the Body Mass Index (BMI) may be used to assess obesity. In one commonly used convention, a BMI of 25.0 kg / m2to 29.9 kg / m2is overweight, while a BMI of 30 kg / m2or greater is obese. In another convention, waist circumference is used to assess obesity. In this convention, in men a waist circumference of 102 cm or more is considered obese, while in women a waist circumference of 89 cm or more is considered obese. Strong evidence shows that obesity affects both the morbidity and mortality of individuals. For example, an obese individual is at increased risk for heart disease, non-insulin dependent (type 2) diabetes, hypertension, stroke, cancer (e.g. endometrial, breast, prostate, and colon cancer), dyslipidemia, gall bladder disease, sleep apnea, reduced fertility, and osteoarthritis, amongst others (see Lyznicki et al., Am. Fam. Phys. 63:2185, 2001).

[0057] The term “overweight” as used herein refers to an individual who weighs more than their ideal body weight. An overweight individual can be obese but is not necessarily obese. For example, an overweight individual is any individual who desires to decrease their weight. In one convention, an overweight individual is an individual with a BMI of 25.0 kg / m2 to 29.9 kg / m2.

[0058] The term “pl” is an abbreviation for isoelectric point. An alternative abbreviation sometimes used is IEP. It is the pH at which a particular molecule carries no net electric charge.Atty Ref. METS-022 / 03WO 350242-2228At a pH below its pl a protein or peptide carries a net positive charge. At a pH above its pl a protein or peptide carries a net negative charge. Proteins and peptides can be separated according to their isoelectric points using a technique called isoelectric focusing which is an electrophoretic method that utilizes a pH gradient contained within a polyacrylamide gel.

[0059] The term “peripheral administration” as used herein refers to administration outside of the central nervous system. Peripheral administration does not include direct administration to the brain. Peripheral administration includes, but is not limited to intravascular, intramuscular, subcutaneous, inhalation, rectal, transdermal or intra-nasal administration.

[0060] The term “polypeptide” as used herein refers to a polymer in which the monomers are amino acid residues which are joined together through amide bonds. Unless dictated otherwise by context, the terms “polypeptide”, “peptide”, or “protein” as used herein encompass any amino acid sequence and include modified sequences such as glycoproteins. The term “polypeptide” covers naturally occurring proteins, as well as those which are recombinantly or synthetically produced, and may include chemical modifications. The term “polypeptide fragment” refers to a portion of a polypeptide, for example a fragment which exhibits at least one useful sequence in binding a receptor. The term “functional fragments of a polypeptide” refers to all fragments of a polypeptide that retain an activity of the polypeptide. Biologically functional peptides can also include fusion proteins, in which the peptide of interest has been fused to another peptide that does not decrease its desired activity.

[0061] The term “subcutaneous administration” as used herein refers to administration of a substance to the subcutaneous layer of fat which is found between the dermis of the skin and the underlying tissue. Subcutaneous administration may be by an injection using a hypodermic needle fitted, for example, to a syringe or a “pen” type injection device. Other administration methods may be used for example microneedles. Injection with a hypodermic needle typically involves a degree of pain on behalf of the recipient. Such pain may be masked by use of a local anesthetic or analgesic. However, the usual method used to reduce the perceived pain of injections is to merely distract the subject immediately prior to and during the injection. Pain may be minimized by using a relatively small gauge hypodermic needle, by injecting a relatively small volume of substance and by avoiding excessively acidic or alkali compositions which may cause the subject to experience a “stinging” sensation at the injection site. Compositions having a pH of pH 4 and pH 10 are usually regarded as tolerably comfortable.Atty Ref. METS-022 / 03WO 350242-2228

[0062] The term “biweekly” as used herein refers to administering a compound every two weeks (e.g., once every fourteen days ± 2 days).Compositions

[0063] In some aspects, the compositions of the present disclosure comprise a GLP-1 receptor agonist comprising a peptide having the amino acid sequence of Phe-AIB-Glu-Gly- Thr-Phe-Thr-Ser-Asp-Val-Ser-Lys-Gln-Leu-Glu-Glu-Lys-Arg-Val-Arg-Glu-Phe-Ile-Glu- Trp-Leu-Lys-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Lys-Pro-Pro-Pro-Gly-Lys-Lys (SEQ ID NO: 1) or a salt thereof.

[0064] In some embodiment, the C-terminal Lys of the peptide is linked to a group of formula I:wherein R is a C16-C18 alkylene or alkenylene group; andR1is CO2H.

[0065] In some embodiments, the s-amino group on the C-terminal Lys is attached to the group of formula I, such that the bond is an amide bond.

[0066] In some embodiments, the present disclosure provides compositions comprising the GLP-1 receptor agonist(or “Compound A”) or a salt thereof. Compound A comprises the amino acid sequence of SEQID NO: 1. The GLP-1 receptor agonists of the present disclosure (e.g., Compound A) areAtty Ref. METS-022 / 03WO 350242-2228 disclosed in PCT Publication No. WO 2022 / 123271, which is hereby incorporated by reference in its entirety for all purposes.

[0067] In some embodiments, the GLP-1 receptor agonist described herein is used in the free base form or as a salt, or as any mixture thereof. In some embodiments, the GLP-1 receptor agonist is in the free base form. It is understood that “free base form” refers to the case where the GLP-1 receptor agonist is not in the form of a salt. In some embodiments, Compound A is provided in free base form, in salt form, or as a mixture thereof. In some embodiments, Compound A is in the free base form. In some embodiments, Compound A is in the salt form. In some embodiments, Compound A is in the form of an acetate salt. Unless otherwise provided herein, an active pharmaceutical ingredient (API) (e.g., Compound A) weight provided herein is for the free base form. Similarly, the stated dose amounts of the GLP-1 receptor agonist (e.g., Compound A) is expressed as the free base form. When a salt form is administered, the salt form is administered at a dose that provides the molar equivalent of the free base.

[0068] In some embodiments, the compositions of the present disclosure comprise the GLP-1 receptor agonist described herein in an amount from about 0.1 to about 20 mg, or about 0.1 mg to about 10 mg. In some embodiments, the compositions of the disclosure comprise the GLP-1 receptor agonist or a salt thereof, in an amount from about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg, about 10.5 mg, , about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg,Atty Ref. METS-022 / 03WO 350242-2228 about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.5 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, or about 20.0 mg of the GLP-1 receptor agonist or a salt thereof.

[0069] In some embodiments, the GLP-1 receptor agonist is in the form of a salt. Salts of the GLP-1 receptor agonist of the disclosure include those which are pharmaceutically acceptable, i.e. which are suitable for use in medicine. However, salts having non- pharmaceutically acceptable counterions are also within the scope of the present disclosure, for example, for use as intermediates in the preparation of the compounds.

[0070] Suitable salts according to the disclosure include those formed with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, benzenesulfonic, and isethionic acids. Other acids such as oxalic acid may be useful as intermediates in obtaining the compositions of the disclosure in final form. In some embodiments, the GLP-1 receptor agonist is in the form of chloride salt. In some embodiments, the GLP-1 receptor agonist is in the form of acetate salt.

[0071] In some embodiments, salts with bases include ammonium salts, alkali metal salts, for example potassium and sodium salts, alkaline earth metal salts, for example calcium and magnesium salts, and salts with organic bases, for example dicyclohexylamine and N-methyl- D-glucomine.

[0072] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. In some embodiments, the compositions of the present disclosure comprise solvates of the GLP-1 receptor agonist described herein.

[0073] Those skilled in the art of organic and / or medicinal chemistry will also appreciate than many organic compounds can exist in different forms, including as amorphous material and / or in one or more crystalline forms. Different physical forms of organic compounds are known as polymorphs. The disclosure also encompasses all such different physical forms ofAtty Ref. METS-022 / 03WO 350242-2228 the GLP-1 receptor agonists described herein, as well as different physical forms of its derivatives and salts.

[0074] The GLP-1 receptor agonist of the present disclosure (e.g., Compound A) is a potent GLP-1 receptor agonist. In vitro studies assessing cyclic adenosine monophosphate (cAMP) accumulation responses in human GLP-1 receptor-overexpressing Chinese hamster ovary cells indicate that Compound A has over 2-fold greater potency as a GLP-1 receptor agonist compared to semaglutide. Semaglutide has an 8.3-fold lower potency than the reference hGLP- 1 (Ozempic (semaglutide) Nonclinical Review, FDA, 2017), Compound A’s potency is only 3.7-fold lower than the reference hGLP-1 (GLP-1 EC50 of 5.77 nM versus Compound AEC50 of 21.5 nM).

[0075] The GLP-1 receptor agonist of the present disclosure (e.g., Compound A) is a Gs protein-biased GLP-1 receptor agonist which preferentially recruits the Gs protein over betaarrestin-2 (PArr2), contrasting native human GLP-1 (hGLP-1) and semaglutide, which are comparatively balanced, recruiting both effectors maximally. This biased agonism has been correlated with prolonged residence of the GLP-1 receptor at the cell surface following Compound A stimulation when compared with hGLP-1 and semaglutide. The prolonged halflife in vivo of the GLP-1 receptor agonists (as assessed in humans or an animal model) permits injections no more frequently than daily and preferably no more than twice, or more preferably no more than once a week, whilst still producing acceptable therapeutic or cosmetic benefits.

[0076] The GLP-1 receptor agonist of the present disclosure (e.g., Compound A) has high solubility (20 mg / mL) across a pH range from 3 to 9 and an extended half-life in preclinical species. High solubility in aqueous solution at pH 4.5 to allow an effective dose to be administered in a low volume inj ection (thereby resulting in lower pain of inj ection). Solubility may be easily assessed by in vitro tests known to those skilled in the art.

[0077] In some embodiments, the composition of the present disclosure is in the form of an injectable aqueous solution. Injectable aqueous solutions may be prepared using methods known to those skilled in the art. In some embodiments, the injectable aqueous solution is prepared by reconstituting Compound A lyophilized powder using saline (0.9% w / v).

[0078] The GLP-1 receptor agonist of the present disclosure (e.g., Compound A) has good storage stability, with no significant degradation seen on storage in solution for 4 weeks at 4°C.

[0079] In some embodiments, the compositions of the present disclosure exhibit potent and prolonged duration of action in vivo following subcutaneous administration. The half-life ofAtty Ref. METS-022 / 03WO 350242-2228 compositions of the present disclosure was assessed in a pig PK model and humans. The compositions of the present disclosure were found to have a half-life significantly longer than semaglutide. In some embodiments, the composition of the present disclosure has half-life (T1 / 2) of at least about 300 hours following administration. In some embodiments, the composition of the present disclosure has T1 / 2 of about 300 hours to about 500 hours following administration. In some embodiments, the composition of the present disclosure has T1 / 2 of about 300 hours, about 320 hours, about 340 hours, about 360 hours, about 380 hours, about 400 hours, about 420 hours, about 440 hours, about 460 hours, about 480 hours, or about 500 hours.

[0080] In some embodiments, the compositions of the present disclosure further comprise a carrier.

[0081] In some embodiments, the compositions of the present disclosure are in the form of an injectable aqueous solution. In some embodiments, the compositions are present in a syringe or other administration device for subcutaneous administration.

[0082] In some embodiments, the compositions have a pH of less than about 5. In some embodiments, the compositions have a pH of about 4 to about 5. In some embodiments, the compositions have a pH of about 4.5. In some embodiments, the compositions have a pH of about 3 to about 10.

[0083] In some embodiments, the compositions according to the disclosure include those suitable for parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intra-articular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators), rectal and topical (including dermal, transdermal, transmucosal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

[0084] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.Atty Ref. METS-022 / 03WO 350242-2228

[0085] The compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-inj ection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor. An aqueous carrier may be, for example, an isotonic buffer solution at a pH of from about 3.0 to about 8.0, preferably at a pH of from about 3.5 to about 7.4, for example from 3.5 to 6.0, for example from 3.5 to about 5.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid, and sodium acetate / acetic acid buffers. The composition preferably does not include any compounds known to be deleterious to peptide compounds.

[0086] Preferred unit dosage compositions are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

[0087] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present disclosure may include other agents conventional in the art having regard to the type of formulation in question.

[0088] The compositions of the present disclosure may also be suitably administered as sustained-release systems. Suitable examples of sustained-release systems of the disclosure include suitable polymeric materials, for example semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules; suitable hydrophobic materials, for example as an emulsion in an acceptable oil; or ion exchange resins; sparingly soluble derivatives of the compound of the disclosure, for example, a sparingly soluble salt; hydrogels; and microspheres. Sustained-release systems may be administered rectally; parenterally;Atty Ref. METS-022 / 03WO 350242-2228 intracisternally; intravaginally; intraperitoneally; topically, for example as a powder, ointment, gel, drop or transdermal patch; bucally.

[0089] Preparations for administration can be suitably formulated to give controlled release of the GLP-1 receptor agonsit of the disclosure. For example, the compositions may be in the form of particles comprising one or more of biodegradable polymers, polysaccharide jellifying and / or bioadhesive polymers, amphiphilic polymers, hydrogels, microspheres, agents capable of modifying the interface properties of particles of the compounds of the disclosure. These compositions exhibit certain biocompatibility features which allow a controlled release of the active substance, see U.S. Patent No. 5,700,486, the contents of which are incorporated by reference.

[0090] In some embodiments, the compoisitons of the dislcosure may be delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med. 321 :574, 1989) or by a continuous subcutaneous infusion, for example, using a mini-pump. An intravenous bag solution may also be employed. Other controlled release systems are discussed in the review by Langer (Science 249: 1527-1533, 1990) which is incorporated herein by reference. In some embodiments, the compositions of the disclosure are delivered by way of an implanted pump, described, for example, in U.S. Patent No. 6,436,091; U.S. Patent No. 5,939,380; U.S. Patent No. 5,993,414, the contents of which are incorporated herein by reference.

[0091] Implantable drug infusion devices are used to provide patients with a constant and long-term dosage or infusion of a drug or any other therapeutic agent. Essentially such device may be categorized as either active or passive. In some embodiments, the compositon of the present disclosure is formulated as a depot preparation. Such a long acting depot formulation can be administered by implantation, for example subcutaneously or intramuscularly; or by intramuscular injection. Thus, for example, the active ingredient can be formulated with suitable polymeric or hydrophobic materials, for example as an emulsion in an acceptable oil; or ion exchange resins; or as a sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0092] In some embodiments, the compositions of the disclosure are administered as a single pulse dose, as a bolus dose, or as pulse doses administered over time. In some embodiments, in pulse doses, a bolus administration of the active agent is provided, followed by a time period wherein no active agent is administered to the subject, followed by a secondAtty Ref. METS-022 / 03WO 350242-2228 bolus administration. In some embodiments, pulse doses are administered during the course of a day, during the course of a week, or during the course of a month.Dosing Regimens

[0093] In some embodiments, a dose of the compositions described herein is about 0.1 mg to about 20 mg, or about 0.1 mg to about 10 mg of the GLP-1 receptor agonist described herein (e.g., Compound A) or a salt thereof. In some embodiments, a dose of the compositions described herein is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg, about 10.5 mg, , about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.5 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, or about 20.0 mg of the GLP-1 receptor agonist described herein or a salt thereof. The effective amounts may be provided as a single dose or on regular schedule, i.e., on a weekly, biweekly, monthly, or yearly basis or an irregular schedule with varying administration days, weeks, months, etc. In some embodiments, a dose is administered about once weekly, about once biweekly, about once every three weeks, about once monthly, about once bimonthly, about once every three months, or any combination thereof.

[0094] In some embodiments, a dose of the GLP-1 receptor agonist may be administered weekly, biweekly, or monthly, or any combination thereof. In some embodiments, a dose ofAtty Ref. METS-022 / 03WO 350242-2228 the GLP-1 receptor agonist is administered weekly. In some embodiments, a dose of the GLP- 1 receptor agonist is administered biweekly. In some embodiments, a dose of the GLP-1 receptor agonist is administered monthly.

[0095] In some embodiments, the methods comprise administering the GLP-1 receptor agonist during a first period of treatment, and then administering the GLP-1 receptor agonist during a second period of treatment, wherein the doses and / or dosing frequency of the GLP-1 receptor agonist in the first period and the second period are the same or different, and may be any dose or frequency disclosed herein. In some embodiments, the methods comprise administering the GLP-1 receptor agonist weekly during a first period of treatment, and then administering the GLP-1 receptor agonist biweekly or monthly during a second period of treatment. In some embodiments, the dose administered in the second period is greater than the dose administered first period.

[0096] In some embodiments, the methods comprise administering the GLP-1 receptor agonist during an initiation phase. In some embodiments, the methods comprise administering the GLP-1 receptor agonist during a maintenance phase. In some embodiments, the doses and / or dosing frequency of the GLP-1 receptor agonist in the initiation phase and maintenance phase are the same. In some embodiments, the doses and / or dosing frequency of the GLP-1 receptor agonist in the initiation phase and maintenance phase are different, and may be any dose or frequency disclosed herein.

[0097] In some embodiments, the methods comprise administering the GLP-1 receptor agonist, weekly, at a starting dose during the initiation phase. In some embodiments, the methods comprise administering the GLP-1 receptor agonist, at a maintenance dose during the maintenance phase. In some embodiments, the maintenance dose is greater than the starting dose (e.g., the first dose is titrated to the second dose). In some embodiments, the maintenance dose is administered at a different dosing frequency compared to the starting dose. In some embodiments, the maintenance dose is administered at a different dosing frequency compared to the starting dose. In some embodiments, the maintenance dose is administered biweekly or monthly.

[0098] In some embodiments, the initiation phase may comprise one or more dose increases (titrations). For example, in some embodiments, a starting dose may be increased to by any increment described herein (e.g., by about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg,Atty Ref. METS-022 / 03WO 350242-2228 about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, or about 4.0 mg) to an increased dose. The dose increase may occur after 3, 4, 5, 6, 7, 8, 9, or 10 months.

[0099] In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once weekly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once biweekly (i.e. about once every two weeks). In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once monthly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once every 4 weeks.

[0100] In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.2, about 0.4, about 0.6, about 0.8, about 0.9, about 1.0, about 1.2, about 1.6, or about 2.4 mg is administered about once weekly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.4, about 0.6, about 0.8, about 0.9, about 1.0, about 1.2, about 1.6, about 1.8, about 2.0, about 2.4, about 3.2, or about4.8 mg is administered about once biweekly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.4, about 0.8, about 1.2, about 1.6, about 1.8, about 2.0, about 2.4, about 3.2, about 3.6, about 4.0, about 4.8, about 6.4, or about 9.6 mg is administered about once monthly.

[0101] In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.2 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.6 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.9 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.0 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once weekly. In some embodiments, Compound A or a salt thereof isAtty Ref. METS-022 / 03WO 350242-2228 administered at a dose of about 1.6 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once weekly.

[0102] In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.6 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.9 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.0 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.6 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.8 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.0 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 3.2 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.8 mg once biweekly.

[0103] In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.6 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.8 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.0 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 3.2 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 3.6 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.0 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.8 mg once monthly. In some embodiments, Compound A or a salt thereof isAtty Ref. METS-022 / 03WO 350242-2228 administered at a dose of about 6.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 9.6 mg once monthly.

[0104] In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg is administered about once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg once biweekly or monthly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof at a dose of or about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg is administered about once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg about once every 2 or 4 weeks. In some embodiments, Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg about once biweekly or monthly. In some embodiments, Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg is administered about once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg about once every 2 or 4 weeks. In some embodiments, the weekly dose is administered for about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or more, and thereafter a once biweekly or monthly dose is administered. In some embodiments, the weekly dose is administered for about 4 weeks. In some embodiments, the weekly dose is administered for about 8 weeks. In some embodiments, the weekly dose is administered for about 12 weeks. In some embodiments, the weekly dose is administered for about 28 weeks. In some embodiments, the weekly dose is administered for about 36 weeks. In some embodiments, the weekly dose is administered for about 52 weeks. In some embodiments, the monthly dose is administered for about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months,Atty Ref. METS-022 / 03WO 350242-2228 about 10 months, about 11 months, about 12 months, or more. In some embodiments, the biweekly or monthly dose is from about 1.1 -fold to about 10-fold of the amount of an immediately preceding weekly dose. In some embodiments, the amount of the biweekly or monthly dose is from about 2-fold to about 4-fold of the amount of an immediately preceding weekly dose. In some embodiments, the amount of the biweekly or monthly dose is about 2- fold or about 4-fold of the amount of an immediately preceding weekly dose. In some embodiments, the amount of the biweekly or monthly dose is increased by about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg compared to the amount of an immediately preceding weekly dose. In some embodiments, the weekly dose is about 0.4 mg to about 1.2 mg, and thereafter the biweekly or monthly dose is about 0.8 mg to about 4.8 mg. In some embodiments, the weekly dose is about 0.6 mg, and thereafter the biweekly or monthly dose is about 1.2 mg. In some embodiments, the weekly dose is about 0.6 mg, and thereafter the biweekly or monthly dose is about 2.4 mg. In some embodiments, the weekly dose is about 0.8 mg, and thereafter the biweekly or monthly dose is about 1.6 mg. In some embodiments, the weekly dose is about 0.8 mg, and thereafter the biweekly or monthly dose is about 3.2 mg. In some embodiments, the weekly dose is about 1.0 mg, and thereafter the biweekly or monthly dose is about 2.0 mg. In some embodiments, the weekly dose is about 1.0 mg, and thereafter the biweekly or monthly dose is about 4.0 mg. In some embodiments, the weekly dose is about 1.2 mg, and thereafter the biweekly or monthly dose is about 2.4 mg. In some embodiments, the weekly dose is about 1.2 mg, and thereafter the biweekly or monthly dose is about 4.8 mg. In some embodiments, the weekly dose is increased from about 0.4 mg to about 1.2 mg in about 12 weeks, and thereafter the biweekly or monthly dose is at about 2.4 mg. In some embodiments, the weekly dose is increased from about 0.4 mg to about 1.2 mg in about 12 weeks, and thereafter the biweekly or monthly dose is at about 4.8 mg. In some embodiments, the weekly dose of about 0.4 mg is administered for about 3 weeks, thereafter the weekly dose of about 0.8 mg is administered for about 3 weeks, and thereafter the biweekly or monthly dose of about 1.2 mg is administered for about 3 weeks. In some embodiments, the weekly dose of about 1.0 mg is administered to the subject for about 12 weeks, and thereafter the biweekly or monthly dose of about 2.0 mg or about 4.0 mg is administered to the subject. In some embodiments, the weekly dose of about 0.8 mg is administered to the subject for about 12 weeks, and thereafter the biweekly or monthly dose of about 1.6 mg or about 3.2 mg is administered to the subject. In some embodiments, the weekly dose of about 0.6 mg isAtty Ref. METS-022 / 03WO 350242-2228 administered to the subject for about 12 weeks, and thereafter the biweekly or monthly dose of about 1.2 mg or about 2.4 mg is administered to the subject. In some embodiments, the weekly dose is about 0.4 mg for about 28 weeks followed by another weekly dose of about 0.8 mg for about 8 weeks, and thereafter the biweekly dose is about 1.6 mg. In some embodiments, the weekly dose is about 0.6 mg for about 36 weeks, and thereafter the monthly dose is about 2.4 mg. In some embodiments, the weekly dose is about 0.9 mg for about 36 weeks, and thereafter the monthly dose is about 3.2 mg. In some embodiments, the weekly dose is about 1.2 mg for about 36 weeks, and thereafter the monthly dose is about 4.8 mg.

[0105] In some embodiments, the weekly dose of a GLP-1 receptor agonist described herein or a salt thereof is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 1.1-fold to about 10-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is from about 2-fold to about 4-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 2-fold or about 4-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg higher than the immediately preceding weekly dose. In some embodiments, the weekly dose of Compound A or a salt thereof is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 1.1-fold to about 10-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is from about 2-fold to about 4-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 2-fold or about 4-fold of the immediately preceding weekly dose. In some embodiments, the weekly dose is increased through one or more titrations to a higher once weekly dose, wherein each higher once weekly dose is about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg higher than the immediately preceding weekly dose.Atty Ref. METS-022 / 03WO 350242-2228

[0106] In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, or about 0.1 mg to about 4.0 mg for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, or about 2 weeks to about 12 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, or about 0.2 mg to 8.0 mg for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, or about 2 to about 12 weeks, per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.1 mg to about 20.0 mg, about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg. In some embodiments, each titration period is for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, or about 0.1 mg to about 4.0 mg for about 2 weeks to about 52 week, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, or about 2 weeks to about 12 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, or about 0.2 mg to about 8.0 mg for a period of about 2 weeks to about 52 week, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, or about 2 to about 12 weeks per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.1 mg to about 20.0 mg, about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg. In some embodiments, a titrated dose is increased by about 1.5-fold to about 8-fold compared to an immediately preceding dose, for example, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold,Atty Ref. METS-022 / 03WO 350242-2228 about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose. In some embodiments, a titrated dose is increased by about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, or about 0.1 mg to about 5 mg compared to an immediately preceding dose, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10.0 mg, about 10.5 mg, , about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.5 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, or about 20.0 mg higher than an immediately preceding dose. In some embodiments, the weekly maintenance dose is administered for at least about 2 weeks, for example, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, or more. In some embodiments, the weekly maintenance dose is about 1.5-fold to about 8-fold, for example, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose,Atty Ref. METS-022 / 03WO 350242-2228 wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once weekly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter a once weekly dose of about 1.2 mg for about 20 weeks or more. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter a once weekly dose of about 1.6 mg for about 20 weeks or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter a once weekly maintenance dose of about 1.6 mg. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks and a once weekly dose of about 1.6 mg for about another 4 weeks, and thereafter a once weekly maintenance dose of about 2.4 mg. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter a once weekly maintenance dose of about 1.6 mg. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks and a once weekly dose of about 1.6 mg for about another 4 weeks, and thereafter a once weekly maintenance dose of about 2.4 mg.

[0107] In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg, or about 0.1 mg to about 4.0 mg for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks,Atty Ref. METS-022 / 03WO 350242-2228 followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, or about 0.2 mg to 8.0 mg for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, or about 2 to about 12 weeks, per titration step, and thereafter followed by administration of a once biweekly or monthly dose of about 0.1 mg to about 20.0 mg, about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, or about 0.2 mg to 8.0 mg for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, or about 2 to about 12 weeks, per titration step, and thereafter followed by administration of a once biweekly or monthly dose of about 0.1 mg to about 20.0 mg, about 0.1 mg to about 10.0 mg, or about 0.1 mg to about 8.0 mg. In some embodiments, a titrated dose is about 1.5-fold to about 8-fold of the amount of the immediately preceding dose, for example, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose. In some embodiments, a titrated dose is increased by about 0.1 to about 20 mg, about 0.1 to about 10 mg, or about 0.1 to about 5 mg compared to an immediately preceding dose, for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg,Atty Ref. METS-022 / 03WO 350242-2228 about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10.0 mg, about 10.5 mg, , about 11.0 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.5 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, or about 20.0 mg higher than an immediately preceding dose. In some embodiments, the biweekly or monthly dose is administered for at least about 4 weeks, for example, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 week, at least about 48 weeks, at least about 52 weeks, at least about 56 week, at least about 60 weeks, at least about 64 weeks, or more. In some embodiments, the biweekly or monthly dose is about 1.5-fold to about 8-fold, for example, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4- fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter a once biweekly or monthly dose of about 3.2 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.8 mg for about 12 weeks, and thereafter a once biweekly or monthly dose of about 3.2 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, then a once weekly dose of about 1.2 mg for about 4 weeks, and thereafter a once biweekly or monthly dose of about 4.8 mg for at least about 16 weeks to aboutAtty Ref. METS-022 / 03WO 350242-222852 weeks, or more. In some embodiments, a GLP-1 receptor agonist described herein or a salt thereof is administered at a once weekly dose of about 0.6 mg for about 4 weeks, followed by a once weekly dose of about 1.2 mg for about 8 weeks, and thereafter a once biweekly or monthly dose of about 4.8 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter a once biweekly or monthly dose of about 3.2 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.8 mg for about 12 weeks, and thereafter a once biweekly or monthly dose of about 3.2 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, then a once weekly dose of about 1.2 mg for about 4 weeks, and thereafter a once biweekly or monthly dose of about 4.8 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.6 mg for about 4 weeks, followed by a once weekly dose of about 1.2 mg for about 8 weeks, and thereafter a once biweekly or monthly dose of about 4.8 mg for at least about 16 weeks to about 52 weeks, or more. In some embodiments, Compound A or a salt thereof is administered at a once weekly dose of about 0.4 mg for about 28 weeks, followed by a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter a once biweekly or monthly dose of about 1.6 mg.

[0108] In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, or about 0.2 mg to about 0.6 mg, for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, or about 12 weeks to about 28 weeks, followed byAtty Ref. METS-022 / 03WO 350242-2228 one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to 8.0 mg, about 0.2 mg to about 4.0 mg, about 0.2 mg to about 2.0 mg, about 0.2 mg to about 1.0 mg, or about 0.6 mg to about 1.0 mg for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, or about 6 weeks to about 10 weeks, per titration step, and thereafter followed by administration of a once biweekly or monthly dose of about 0.1 mg to about 20.0 mg, about 1 mg to about 10.0 mg, about 1 mg to about 8.0 mg, about 1 mg to about 4.0 mg, about 1 mg to about 2.0 mg, about 1.4 mg to about 1.8 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.2 mg to about 0.6 mg (e.g., about 0.4 mg) for about 28 weeks. In some embodiments, on about weeks 28-36 of treatment, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.6 mg to about 1.0 mg (e.g., about 0.8 mg). In some embodiments, starting on week 36 of treatment, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof at a once biweekly dose of about 1.4 mg to about 1.8 mg (e.g., 1.6 mg). In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg for about 28 weeks, followed by a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter followed by administration of a once biweekly dose of about 1.6 mg.

[0109] In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, about 0.2 mg to about 1.0 mg, 0.6 mg to about 1.6 mg, or about 0.4 to about 0.8 mg, for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 12 weeks to about 28 weeks, or about 2 weeks to about 12 weeks, and thereafter followed by administration of a once biweekly or monthly dose of about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to about 8.0 mg, about 2.0 mg to about 8.0 mg, about 4.0 mg to about 6.0 mg, about 4.6 mg to about 5.0 mg (e.g., about 4.8 mg), about 2.0 mg to about 6.0 mg, about 2.0 mg to about 5.0 mg, about 2.5 mg to about 4 mg, about 3.0 mg to about 3.4 mg (e.g., about 3.2Atty Ref. METS-022 / 03WO 350242-2228 mg), about 0.2 mg to about 4.0 mg, about 0.2 mg to about 3.0 mg, about 1.0 mg to about 3.0 mg, about 2.0 mg to about 3.0 mg, or about 2.2 mg to about 2.6 mg (e.g., about 2.4 mg). In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg to about 0.8 mg (e.g., 0.6 mg) for about 36 weeks. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.6 mg for about 36 weeks. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.7 mg to about 1.1 mg (e.g., 0.9 mg) for about 36 weeks. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.9 mg for about 36 weeks. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.0 mg to about 1.4 mg (e.g., 1.2 mg) for about 36 weeks. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.2 mg for about 36 weeks. In some embodiments, starting on about week 36, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once biweekly or monthly dose of about 4.6 mg to about 5.0 mg (e.g., about 4.8 mg), about 3.0 mg to about 3.4 mg (e.g., about 3.2 mg), or about 2.2 mg to about 2.6 mg (e.g., about 2.4 mg). In some embodiments, the methods comprise administration of the GLP- 1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.6 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 2.4 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.9 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 3.2 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.2 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 4.8 mg.

[0110] In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of aboutAtty Ref. METS-022 / 03WO 350242-22280.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, or about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, or about 2 weeks to about 4 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to 8.0 mg, about 0.2 mg to about 4.0 mg, about 0.2 mg to about 2.0 mg, about 0.4 mg to about 2.0 mg, about 0.4 mg to about 1.0 mg (e.g., 0.8 mg), or about 1.4 mg to about 1.8 mg (e.g., 1.6 mg) for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, or about 2 weeks to about 4 weeks, per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.4 mg to about 20.0 mg, about 0.4 mg to about 10.0 mg, about 0.4 mg to about 8.0 mg, about 0.4 mg to about 4.0 mg, about 0.4 mg to about 3.0 mg, or about 1.0 mg to about 3.0 mg, or about 1.6 mg to about 2.4 mg (e.g., about 1.6 mg or about 2.4 mg). In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 4 weeks. In some embodiments, on the following 4 weeks, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.4 mg to about 1.8 mg (e.g., 1.6 mg). In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 8 weeks. In some embodiments, on the following 8 weeks, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.4 mg to about 1.8 mg (e.g., 1.6 mg). In some embodiments, for the remainder of treatment, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 1.6 mg to about 2.4 mg (e.g., about 1.6 mg or about 2.4 mg). In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg for about 8 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, theAtty Ref. METS-022 / 03WO 350242-2228 methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg for about 8 weeks, followed by a once weekly dose of about 1.6 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.8 mg for about 8 weeks, followed by a once weekly dose of about 1.6 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, the methods comprise administration of the GLP-1 receptor agonist or a salt thereof (e.g., Compound A or a salt thereof) at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a first hihger once weekly dose of about 0.8 mg for about 4 weeks and a second higher once weekly dose of about 1.6 mg for about another 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg.

[0111] In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, or about 0.2 mg to about 0.6 mg, for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, or about 12 weeks to about 28 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to 8.0 mg, about 0.2 mg to about 4.0 mg, about 0.2 mg to about 2.0 mg, about 0.2 mg to about 1.0 mg, or about 0.6 mg to about 1.0 mg for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, or about 6 weeks to about 10 weeks, per titration step, and thereafter followed by administration of a once biweekly or monthly dose of about 0.1 mg to about 20.0Atty Ref. METS-022 / 03WO 350242-2228 mg, about 1 mg to about 10.0 mg, about 1 mg to about 8.0 mg, about 1 mg to about 4.0 mg, about 1 mg to about 2.0 mg, about 1.4 mg to about 1.8 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.2 mg to about 0.6 mg (e.g., about 0.4 mg) for about 28 weeks. In some embodiments, on about weeks 28-36 of treatment, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.6 mg to about 1.0 mg (e.g., about 0.8 mg). In some embodiments, starting on week 36 of treatment, the methods comprise administration of Compound A or a salt thereof at a once biweekly dose of about 1.4 mg to about 1.8 mg (e.g.,1.6 mg). In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 28 weeks, followed by a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter followed by administration of a once biweekly dose of about 1.6 mg.

[0112] In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, about 0.2 mg to about 1.0 mg, 0.6 mg to about 1.6 mg, or about 0.4 to about 0.8 mg, for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 12 weeks to about 28 weeks, or about 2 weeks to about 12 weeks, and thereafter followed by administration of a once biweekly or monthly dose of about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to about 8.0 mg, about 2.0 mg to about 8.0 mg, about 4.0 mg to about 6.0 mg, about 4.6 mg to about 5.0 mg (e.g., about 4.8 mg), about 2.0 mg to about 6.0 mg, about 2.0 mg to about 5.0 mg, about 2.5 mg to about 4 mg, about 3.0 mg to about 3.4 mg (e.g., about 3.2 mg), about 0.2 mg to about 4.0 mg, about 0.2 mg to about 3.0 mg, about 1.0 mg to about 3.0 mg, about 2.0 mg to about 3.0 mg, or about 2.2 mg to about2.6 mg (e.g., about 2.4 mg). In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg to about 0.8 mg (e.g., 0.6 mg) for about 36 weeks. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.6 mg for about 36 weeks. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.7 mg to about 1.1 mg (e.g., 0.9 mg) for about 36 weeks. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.9 mg for about 36 weeks. In some embodiments, the methods compriseAtty Ref. METS-022 / 03WO 350242-2228 administration of Compound A or a salt thereof at a once weekly dose of about 1.0 mg to about 1.4 mg (e.g., 1.2 mg) for about 36 weeks. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 1.2 mg for about 36 weeks. In some embodiments, starting on week 36, the methods comprise administration of Compound A or a salt thereof at a once biweekly or monthly dose of about 4.6 mg to about 5.0 mg (e.g., about 4.8 mg), about 3.0 mg to about 3.4 mg (e.g., about 3.2 mg), or about 2.2 mg to about 2.6 mg (e.g., about 2.4 mg). In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.6 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 2.4 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.9 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 3.2 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 1.2 mg for about 36 weeks, and thereafter followed by administration of a once monthly dose of about 4.8 mg.

[0113] In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.1 mg to about 10.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.0 mg, or about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, or about 2 weeks to about 4 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose ranges about 0.2 mg to about 20.0 mg, about 0.2 mg to about 10.0 mg, about 0.2 mg to 8.0 mg, about 0.2 mg to about 4.0 mg, about 0.2 mg to about 2.0 mg, about 0.4 mg to about 2.0 mg, about 0.4 mg to about 1.0 mg (e.g., 0.8 mg), or about 1.4 mg to about 1.8 mg (e.g., 1.6 mg) for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, or about 2 weeks to about 4 weeks, per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.4 mg to about 20.0 mg, about 0.4 mg to about 10.0 mg, about 0.4 mg to about 8.0 mg, about 0.4 mg to about 4.0 mg, about 0.4 mg to about 3.0 mg, or about 1.0 mg to about 3.0 mg, or about 1.6 mg to about 2.4 mg (e.g., about 1.6 mg or about 2.4 mg). In some embodiments, the methods comprise administration of Compound A or a saltAtty Ref. METS-022 / 03WO 350242-2228 thereof at a once weekly dose of about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 4 weeks. In some embodiments, on the following 4 weeks, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 1.4 mg to about 1.8 mg (e.g., 1.6 mg). In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.2 mg to about 1.0 mg (e.g., about 0.4 mg or about 0.8 mg) for about 8 weeks. In some embodiments, on the following 8 weeks, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 1.4 mg to about 1.8 mg (e.g., 1.6 mg). In some embodiments, for the remainder of treatment, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 1.6 mg to about 2.4 mg (e.g., about 1.6 mg or about 2.4 mg). In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 8 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.8 mg for about 8 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 8 weeks, followed by a once weekly dose of about 1.6 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.8 mg for about 8 weeks, followed by a once weekly dose of about 1.6 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.8 mg for about 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 1.6 mg. In some embodiments, the methods comprise administration of Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a first hihger once weekly dose of about 0.8 mg for about 4 weeks and a second higher once weekly dose of about 1.6 mg for about another 4 weeks, and thereafter followed by administration of a once weekly maintenance dose of about 2.4 mg.

[0114] In some embodiments, the disclosure provides compositions and dosage regimens that provide an effective serum or plasma concentration of the active agent in the subject. AsAtty Ref. METS-022 / 03WO 350242-2228 used herein, an “effective concentration” is characterized by the concentration of API (e.g., Compound A) in the plasma or serum that is effective to exert a desired or intended physiological response.

[0115] In some embodiments, the administration of the compositions of the present disclosure is subcutaneous.

[0116] In some embodiments, the subcutaneous administration of the compositions of the present disclosure provides a T1 / 2 of at least about 300 hours following administration. In some embodiments, the subcutaneous administration of the compositions of the present disclosure provides a T1 / 2 of about 300 hours to about 500 hours following administration. In some embodiments, the subcutaneous administration of the compositions of the present disclosure provides a T1 / 2 of about 300 hours, about 320 hours, about 340 hours, about 360 hours, about 380 hours, about 400 hours, about 420 hours, about 440 hours, about 460 hours, about 480 hours, or about 500 hours, including any values or ranges therebetween following administration.

[0117] In some embodiments, the subcutaneous administration of the compositions of the present disclosure provide a Tmax of at least about 40 hours following administration. In some embodiments, the subcutaneous administration of the compositions of the present disclosure provides a Tmax of about 40 hours to about 80 hours following administration. In some embodiments, the subcutaneous administration of the compositions of the present disclosure provides a Tmax of about 40 hours, about 45 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 70 hours, about 75 hours, or about 80 hours, including any values or ranges therebetween following administration.

[0118] In some embodiments, the subcutaneous administration of the compositions of the present disclosure provide a Cmax of about 10 ng / mL to about 2500 ng / mL, for example, about 10 ng / mL, about 50 ng / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, about 1000 ng / mL, about 1050 ng / mL, about 1100 ng / mL, about 1150 ng / mL, about 1200 ng / mL, about 1250 ng / mL, about 1300 ng / mL, about 1350 ng / mL, about 1400 ng / mL, about 1450 ng / mL, about 1500 ng / mL, about 1550 ng / mL, about 1600 ng / mL, about 1650 ng / mL, about 1700 ng / mL, about 1750 ng / mL, about 1800 ng / mL, about 1850 ng / mL, about 1900 ng / mL, aboutAtty Ref. METS-022 / 03WO 350242-22281950 ng / mL, about 2000 ng / mL, about 2050 ng / mL, about 2100 ng / mL, about 2150 ng / mL, about 2200 ng / mL, about 2250 ng / mL, about 2300 ng / mL, about 2350 ng / mL, about 2400 ng / mL, about 2450 ng / mL, or about 2500 ng / mL, including any values or ranges therebetween, following administration of the composition.

[0119] In some embodiments, the subcutaneous administration of the compositions of the present disclosure provide a AUCinf of about 10,000 ng h / mL to about 1,000,000 ng h / mL, for example, about 10,000 ng h / mL, about 20,000 ng h / mL, about 30,000 ng h / mL, about 40,000 ng h / mL, about 50,000 ng h / mL, 60,000 ng h / mL, about 70,000 ng h / mL, about 80,000 ng h / mL, about 90,000 ng h / mL, about 100,000 ng h / mL, about 200,000 ng h / mL, about 300,000 ng h / mL, about 400,000 ng h / mL, about 500,000 ng h / mL, 600,000 ng h / mL, about 700,000 ng h / mL, about 800,000 ng h / mL, about 900,000 ng h / mL, or about 1000,000 ng h / mL, including any values or ranges therebetween, following administration of the composition.Methods of Use

[0120] In some aspects, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, wherein the method comprises subcutaneous administration of a composition of the present disclosure. In some embodiments, the subject is obese, overweight or normal weight. Some embodiments provide a method of inducing or maintaining weight loss or managing body weight in a subject, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of inducing or maintaining weight loss or managing body weight in a subject with obesity or overweight, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of inducing or maintaining weight loss or managing body weight in a subject with obesity or with overweight and at least one weight-related comorbidity, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. In some embodiments, the weight-related comorbidity includes hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the comorbid condition is type 2 diabetes. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and one or more weight-related comorbid conditions. InAtty Ref. METS-022 / 03WO 350242-2228 some embodiments, the comorbid condition is type 2 diabetes. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and hypertension. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and dyslipidemia. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and low HDL-C. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and T2DM.

[0121] Some embodiments provide a method of treating type 2 diabetes mellitus, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of improving glycemic control, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of reducing the risk of a major cardiovascular event, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of reducing the risk of eGFR decline or end-stage kidney disease, wherein the method comprises subcutaneous administration of Compound A or a salt thereof. Some embodiments provide a method of treating obstructive sleep apnea, wherein the method comprises subcutaneous administration of Compound A or a salt thereof.

[0122] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.2 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.6 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.9 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.0 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.6 mg once weekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once weekly.Atty Ref. METS-022 / 03WO 350242-2228

[0123] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.6 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.9 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.0 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.6 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.8 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.0 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 3.2 mg once biweekly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.8 mg once biweekly.

[0124] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 0.8 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.2 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.6 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 1.8 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.0 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 2.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 3.2 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose ofAtty Ref. METS-022 / 03WO 350242-2228 about 3.6 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.0 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 4.8 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 6.4 mg once monthly. In some embodiments, Compound A or a salt thereof is administered at a dose of about 9.6 mg once monthly.

[0125] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of of about 0.1 mg to about 10.0 mg once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 0.6 mg for about 36 weeks, and thereafter a once monthly dose of about 2.4 mg. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 0.9 mg for about 36 weeks, and thereafter a once monthly dose of about 3.2 mg. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 1.2 mg for about 36 weeks, and thereafter a monthly dose of about 4.8 mg.

[0126] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 28 weeks followed by a higher once weekly dose of about 0.8 mg for about 8 weeks, and thereafter a biweekly dose of about 1.6 mg.

[0127] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprisingAtty Ref. METS-022 / 03WO 350242-2228 subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 10.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.1 mg to about 10.0 mg. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a higher once weekly dose of about 0.8 mg for about 4 weeks, and thereafter a weekly maintenance dose of about 1.6 mg. In some embodiments, the method comprises subcutaneous administration of a composition comprising Compound A or a salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a higher once weekly dose of about 0.8 mg for about 4 weeks and another higher once weekly dose of about 1.6 mg for about 4 weeks, and thereafter a weekly maintenance dose of about 2.4 mg.

[0128] In some embodiments, the present disclosure provide methods of inducing or maintaining weight loss or managing body weight in a subject who has received a prior GLP- 1 receptor agonist administered on a daily or weekly basis, the method comprising (a) discontinuing the administration of the prior GLP-1 receptor agonist; and (b) thereafter, initiating the subcutaneous administration of a composition comprising Compound A or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly.

[0129] In some embodiments, the methods of the present disclosure induce weight loss in the subject by at least about 5%, about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80% or more, compared to baseline prior to administration.

[0130] In some embodiments, the methods provided herein may be used as next-step treatment following a prior GLP-1 receptor agonist that the subject has received. In some embodiments, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject who has received a prior GLP-1 receptor agonist administered on a daily or weekly basis, comprising a) discontinuing the administration of the prior GLP-1 receptor agonist; and b) thereafter, initiating the subcutaneous administration of the composition described herein at a dose of about 0.1 mg to about 10.0 mg, or about 0.1 mgAtty Ref. METS-022 / 03WO 350242-2228 to about 8.0 mg once monthly. Examples of prior GLP-1 receptor agonists that the subject may have received include, but are not limited to, Semaglutide, liraglutide, Cagrisema, tirzepatide, amycretin, dulaglutide, retatrutide, mazdutide, exenatide, cotadutide, AZD9550, AMG-133, survodutide, efinopegdutide, pemvidutide, VK-2735, CT-868, CT-388, utreglutide, dapiglutide, NYL-01, DD-01, vurolenatide, OPK88003, ecnoglutide, GMA102, GMA105, GMA106, efpeglenatide, HM-15211, HM-15275, noiiglutide, HRS-17031, HRS-9531, DR- 10624, SCO-094, HS-20094, AP-026, BI-3006337, supaglutide, HS-20094, GX-G6, GZR-18, BGM-0504, HEC-88473, ZT-002.

[0131] In some embodiments, the present disclosure provides methods of treating or preventing a disease or disorder or other non-desired physiological state in a subject comprising administration of a therapeutically effective dose of a composition described herein. In some embodiments, the composition described herein is administered subcutaneously.

[0132] In some embodiments, the disease or disorder or other non-desired physiological state is diabetes or obesity, and particularly diabetes (e.g. type II diabetes).

[0133] In some embodiments, the disease or disorder or other non-desired physiological state may be the physiological state of being overweight.

[0134] In some embodiments, the disease or disorder or other non-desired physiological state may be diabetic, for example insulin resistance or glucose intolerance, or both; diabetes mellitus, for example, Type II diabetes.

[0135] In some embodiments, the disease or disorder or other non-desired physiological state may be a disorder in which obesity or being overweight is a risk factor. Such disorders include, but are not limited to, heart disease, cardiovascular disease, for example hypertension, atherosclerosis, congestive heart failure, and dyslipidemia; stroke; gallbladder disease; osteoarthritis; sleep apnea; reproductive disorders for example, polycystic ovarian syndrome; cancers, for example breast, prostate, colon, endometrial, kidney, and esophagus cancer; varicose veins; acanthosis nigricans; eczema; exercise intolerance; insulin resistance; hypertension hypercholesterolemia; cholithiasis; osteoarthritis; orthopedic injury; insulin resistance, for example, type 2 diabetes and syndrome X; and thromboembolic disease (see Kopelman, Nature 404:635-43, 2000; Rissanen et al., British Med. J. 301, 835, 1990).

[0136] Other disorders associated with obesity include depression, anxiety, panic attacks, migraine headaches, PMS, chronic pain states, fibromyalgia, insomnia, impulsivity, obsessive compulsive disorder, and myoclonus. Certain neurological disorders and certain firms ofAtty Ref. METS-022 / 03WO 350242-2228 neurological degeneration are also associated with obesity. Furthermore, obesity is a recognized risk factor for increased incidence of complications of general anesthesia (see e. g., Kopelman, Nature 404:635-43, 2000). In general, obesity reduces life span and carries a serious risk of co-morbidities such as those listed above.

[0137] Other diseases or disorders associated with obesity are birth defects, maternal obesity being associated with increased incidence of neural tube defects, carpal tunnel syndrome (CTS); chronic venous insufficiency (CVI); daytime sleepiness; deep vein thrombosis (DVT); end stage renal disease (ESRD); gout; heat disorders; impaired immune response; impaired respiratory function; infertility; liver disease; lower back pain; obstetric and gynecologic complications; pancreatitis; as well as abdominal hernias; acanthosis nigricans; endocrine abnormalities; chronic hypoxia and hypercapnia; dermatological effects; elephantitis; gastroesophageal reflux; heel spurs; lower extremity edema; mammegaly which causes considerable problems such as bra strap pain, skin damage, cervical pain, chronic odours and infections in the skin folds under the breasts, etc.; large anterior abdominal wall masses, for example abdominal panniculitis with frequent panniculitis, impeding walking, causing frequent infections, odours, clothing difficulties, low back pain; musculoskeletal disease; pseudotumor cerebri (or benign intracranial hypertension), and sliding hiatal hernia.

[0138] According to certain embodiments, the disease or disorder or other non-desired physiological state may be non-alcoholic fatty liver disease.

[0139] According to certain embodiments, the disease or disorder or other non-desired physiological state may be being of a non-desired weight despite not being obese or overweight. The subject may be of normal weight (this includes but is not limited to subjects who were previously overweight or obese and who wish to prevent a return to an unhealthy weight). A subject may be a subject who desires weight loss, for example female and / or male subjects who desire a change in their appearance. In some cases where the subject is of a normal weight, aspects of the disclosure may relate to cosmetic treatment rather than to therapeutic treatment.

[0140] In some embodiments, the present disclosure provides a method of reducing appetite in a subject, reducing food intake in a subject, reducing calorie intake in a subject, improving insulin release in a subject, improving carbohydrate metabolism in a subject, and / or improving carbohydrate tolerance in a subject, comprising administration of a therapeuticallyAtty Ref. METS-022 / 03WO 350242-2228 effective dose of a composition described herein. Such methods may relate to treating subjects having a pre-diabetic state such as insulin insensitivity or pre-diabetes.

[0141] In some embodiments, the present disclosure provides a method for improving a lipid profile in a subject comprising administration of a therapeutically effective amount of a compound, derivative, salt or composition of the disclosure. In some embodiments, the disclosure provides a method for alleviating a condition or disorder that can be alleviated by reducing nutrient availability comprising administration of a therapeutically effective dose of a composition described herein.

[0142] The compositions described herein may be used for weight control and treatment, for example reduction or prevention of obesity, in particular any one or more of the following: preventing and reducing weight gain; inducing and promoting weight loss; and reducing obesity as measured by the Body Mass Index. The compositions described herein may be used in maintaining any one or more of a desired body weight, a desired Body Mass Index, a desired appearance and good health.

[0143] The compositions of the present disclosure may also be used in treating, prevention, ameliorating or alleviating conditions or disorders caused by, complicated by, or aggravated by a relatively high nutrient availability. The term “condition or disorder which can be alleviated by reducing caloric (or nutrient) availability” is used herein to denote any condition or disorder in a subject that is either caused by, complicated by, or aggravated by a relatively high nutrient availability, or that can be alleviated by reducing nutrient availability, for example by decreasing food intake. Subjects who are insulin resistant, glucose intolerant, or have any form of diabetes mellitus, for example, type 1, 2 or gestational diabetes, can also benefit from methods in accordance with the present disclosure.

[0144] Conditions or disorders associated with increased caloric intake include, but are not limited to, insulin resistance, glucose intolerance, obesity, diabetes, including type 2 diabetes, eating disorders, insulin-resistance syndromes, and Alzheimer’s disease.

[0145] In some embodiments, the present disclosure provides a method of providing cytoprotection in a subject, such as providing cardiac protection, providing neuroprotection and / or treating or preventing neurodegeneration, comprising administration of a therapeutically effective dose of a composition described herein.

[0146] In some embodiments, the disease or disorder or other non-desired physiological state which the composition of the disclosure may be used to treat or prevent isAtty Ref. METS-022 / 03WO 350242-2228 neurodegeneration. Such neurodegeneration may be caused by apoptosis, necrosis or loss of function of neuronal cells, preferably in the CNS. Neurodegeneration treated or prevented may be that following a brain injury (for example following physical trauma or following a non- traumatic injury such a stroke, tumor, hypoxia, poisoning, infection, ischemia, encephalopathy or substance abuse). Alternatively or additionally, neurodegeneration may be prevented or treated in a subject having (or diagnosed as having a predisposition to) a neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, Gehrig’s disease (Amyotrophic Lateral Sclerosis), Huntington’s disease, Multiple Sclerosis, other demyelination related disorders, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette’s syndrome, Guillain Barre Syndrome, Wilson’s disease, Pick’s disease, neuroinflammatory disorders, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich’s ataxia, ataxia teangi ectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies, neuronal ceroid lipofuscinosis. Preferably, the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Gehrig’s disease (Amyotrophic Lateral Sclerosis) and Huntington’s disease. In such circumstances the treatment would be regarded as neuroprotective. According to certain preferred embodiments, the treatment is neuroprotective following cerebral ischemia or neuroprotective in a subject having a neurodegenerative disease or diagnosed as having a predisposition to a neurodegenerative disease.

[0147] According to other embodiments, the disease or disorder or other non-desired physiological state is cardiac degeneration (in particular myocardial degeneration by apoptosis, necrosis or loss of function of myocardial cells), in which case the composition of the disclosure provides cardiac protection. According to certain preferred embodiments the composition of the disclosure is protective of myocardial function following myocardiac infarction.

[0148] The compositions described herein are preferably used in the treatment of a human subject. However, while the compositions described herein will typically be used to treat human subjects, they may also be used to treat similar or identical conditions in otherAtty Ref. METS-022 / 03WO 350242-2228 vertebrates for example other primates; farm animals for example swine, cattle and poultry; sport animals for example horses; or companion animals for example dogs and cats.NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0149] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.1. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.2. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.3. A method of inducing or maintaining weight loss or managing body weight in a subj ect who has received a prior GLP-1 receptor agonist administered on a daily or weekly basis, the method comprising(a) discontinuing the administration of the prior GLP-1 receptor agonist; and(a) thereafter, initiating the subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.4. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0Atty Ref. METS-022 / 03WO 350242-2228 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.5. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 2 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 10.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.4 mg to about 10.0 mg, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.6. The method of any one of embodiments 1-5, wherein the C-terminal Lys of the peptide is linked to a group of formula I:wherein R is a C16-C18 alkylene or alkenylene group; andR1is CO2H.7. The method of embodiment 6, wherein the composition comprises the GLP-1 receptor agonistAtty Ref. METS-022 / 03WO 350242-2228(Compound A).8. The method of embodiment 7, wherein the composition comprises the acetate salt of Compound A.9. The method of embodiment 7, wherein the composition comprises the chloride salt of Compound A.10. The method of any one of embodiments 1-9, wherein the composition is in the form of an injectable aqueous solution.11. The method of any one of embodiments 1-9, wherein the composition is present in a syringe or other administration devices for subcutaneous administration.12. The method of any one of embodiments 1-11, wherein the weekly, biweekly, or monthly dose is about 0.16 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.2 mg, about 1.5 mg, about 1.6 mg, about 2.0 mg, about 2.4 mg, about 2.5 mg, about 3.2 mg, about 3.6 mg, about 4.0 mg, about 4.8 mg, about 6.0 mg, about 6.4 mg, about 8.0 mg, or about 9.6 mg.13. The method of any one of embodiments 2-12, wherein the weekly dose is administered for about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks,Atty Ref. METS-022 / 03WO 350242-2228 about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, or more, and thereafter a monthly dose is administered.14. The method of embodiment 13, wherein the weekly dose is administered for about 4 weeks.15. The method of embodiment 13, wherein the weekly dose is administered for about 8 weeks.16. The method of embodiment 13, wherein the weekly dose is administered for about 12 weeks.17. The method of embodiment 13, wherein the weekly dose is administered for about 28 weeks.18. The method of embodiment 13, wherein the weekly dose is administered for about 36 weeks.19. The method of any one of embodiments 2-5 and 13, wherein the amount of the biweekly or monthly dose is from about 2-fold to about 4-fold of the amount of the weekly dose.20. The method of any one of embodiments 2-5 and 13, wherein the weekly dose is about 0.4 mg to about 1.2 mg, and the biweekly or monthly dose is about 0.8 mg to about 4.8 mg.21. The method of any one of embodiments 2-5 and 13, wherein the weekly dose is about 0.4 mg followed by about 0.8 mg, and the biweekly dose is about 1.6 mg.22. The method of embodiment 2 or 13, wherein the weekly dose is about 0.6 mg, and the monthly dose is about 2.4 mg.23. The method of embodiment 2 or 13, wherein the weekly dose is about 0.6 mg administered for about 36 weeks, and the monthly dose is about 2.4 mg.Atty Ref. METS-022 / 03WO 350242-222824. The method of embodiment 2 or 13, wherein the weekly dose is about 0.9 mg, and the monthly dose is about 3.2 mg.25. The method of embodiment 2 or 13, wherein the weekly dose is about 0.9 mg administered for about 36 weeks, and the monthly dose is about 3.2 mg.26. The method of embodiment 2 or 13, wherein the weekly dose is about 1.2 mg, and the monthly dose is about 4.8 mg.27. The method of embodiment 2 or 13, wherein the weekly dose is about 1.2 mg administered for about 36 weeks, and the monthly dose is about 4.8 mg.28. The method of embodiment 4 or 5, wherein the each higher weekly dose is about 2-fold to about 4-fold of an immediately preceding weekly dose.29. The method of embodiment 4 or 5, wherein the each higher weekly dose is about 2-fold of an immediately preceding weekly dose.30. The method of embodiment 4 or 5, wherein the each higher weekly dose is about 4-fold of an immediately preceding weekly dose.31. The method of embodiment 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks.32. The method of embodiment 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks, and the biweekly dose is about 1.4 mg to about 2 mg.33. The method of embodiment 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks, and the monthly dose is about 2 mg to about 5 mg.Atty Ref. METS-022 / 03WO 350242-222834. The method of embodiment 4, wherein the weekly dose is about 0.4 mg administered for about 28 weeks, followed by the weekly dose of about 0.8 mg administered for about 8 weeks, and the biweekly dose is about 1.6 mg.35. The method of embodiment 5, wherein the weekly dose is about 0.4 mg to about 1.6 mg administered for about 2 weeks to about 36 weeks, and the weekly maintenance dose is about 1.6 mg to about 2.4 mg .36. The method of embodiment 5, wherein the weekly dose is about 0.4 mg administered for about 4 weeks followed by a higher weekly dose of about 0.8 mg administered for about 4 weeks, and the weekly maintenance dose is about 1.6 mg.37. The method of embodiment 5, wherein the weekly dose is about 0.4 mg administered for about 4 weeks followed by a first higher weekly dose of about 0.8 mg administered for about 4 weeks followed by a second higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.38. The method of embodiment 5, wherein the weekly dose is about 0.4 mg administered for about 8 weeks, and the weekly maintenance dose is about 1.6 mg.39. The method of embodiment 5, wherein the weekly dose is about 0.8 mg administered for about 8 weeks, and the weekly maintenance dose is about 1.6 mg.40. The method of embodiment 5, wherein the weekly dose is about 0.4 mg administered for about 8 weeks followed by a higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.41. The method of embodiment 5, wherein the weekly dose is about 0.8 mg administered for about 8 weeks followed by a higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.42. The method of any one of embodiments 1-41, wherein the subject has obesity or is overweight.Atty Ref. METS-022 / 03WO 350242-222843. The method of any one of embodiments 1-42, wherein the subject has a body mass index (BMI) of at least 27 kg / m244. The method of embodiment 42 or 43, wherein the subject has a weight-related comorbid condition.45. The method of embodiment 44, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).46. The method of embodiment 45, wherein the weight-related comorbid condition is T2DM.47. The method of embodiment 13, wherein the weekly dose is about 1.0 mg, and thereafter the monthly dose is about 4.0 mg.48. The method of embodiment 13, wherein the weekly dose is about 1.2 mg, and thereafter the monthly dose is about 2.4 mg.49. The method of embodiment 13, wherein the weekly dose is about 1.2 mg, and thereafter the monthly dose is about 4.8 mg.50. The method of embodiment 13, wherein the weekly dose is increased from about 0.4 mg to about 1.2 mg in about 12 weeks, and thereafter the monthly dose is at about 2.4 mg.51. The method of embodiment 13, wherein the weekly dose is increased from about 0.4 mg to about 1.2 mg in about 12 weeks, and thereafter the monthly dose is at about 4.8 mg.52. The method of embodiment 50 or 51, wherein the weekly dose of about 0.4 mg is administered for about 4 weeks, thereafter the weekly dose of about 0.8 mg is administered forAtty Ref. METS-022 / 03WO 350242-2228 about 4 weeks, and thereafter the weekly dose of about 1.2 mg is administered for about 4 weeks.53. The method of embodiment 13, wherein the weekly dose of about 1.0 mg is administered to the subject for about 12 weeks, and thereafter the monthly dose of about 2.0 mg or about 4.0 mg is administered to the subject.54. The method of embodiment 13, wherein the weekly dose of about 0.8 mg is administered to the subject for about 12 weeks, and thereafter the monthly dose of about 1.6 mg or about 3.2 mg is administered to the subject.55. The method of embodiment 13, wherein the weekly dose of about 0.6 mg is administered to the subject for about 12 weeks, and thereafter the monthly dose of about 1.2 mg or about 2.4 mg is administered to the subject.56. The method of embodiment 13, wherein the weekly dose of about 0.4 mg is administered to the subject for about 4 weeks, followed by the weekly dose of about 0.8 mg for about 8 weeks, and thereafter the monthly dose of about 3.2 mg is administered to the subject.57. The method of embodiment 13, wherein the weekly dose of about 0.8 mg is administered to the subject for about 12 weeks, and thereafter the monthly dose of about 3.2 mg is administered to the subject.58. The method of embodiment 13, wherein the weekly dose of about 0.4 mg is administered to the subject for about 4 weeks, followed by the weekly dose of about 0.8 mg for about 4 weeks and then the weekly dose of about 1.2 mg for about 4 weeks, and thereafter the monthly dose of about 4.8 mg is administered to the subject.59. The method of embodiment 13, wherein the weekly dose of about 0.6 mg is administered to the subject for about 4 weeks, followed by the weekly dose of about 1.2 mgAtty Ref. METS-022 / 03WO 350242-2228 for about 8 weeks, and thereafter the monthly dose of about 4.8 mg is administered to the subject.EXAMPLES

[0150] The following examples are provided to further illustrate the embodiments of the present disclosure but are not intended to limit the scope of the claims. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.Example 1. Preclinical Assessment of Compound A

[0151] The composition of the disclosure was prepared on the day of use by reconstituting lyophilized peptide to the required concentration using water for injection (WFI). To calculate WFI required, a correction factor was applied to the mass of peptide weighed, accounting for batch purity. When not in use, lyophilized Compound A was stored at -20°C in a desiccator.

[0152] The activity and selectivity of Compound A at the GLP-1 receptor were evaluated by measuring cAMP signaling and P-arrestin recruitment in human cell lines overexpressing GLP-1 receptors, with native GLP-1 and semaglutide as comparators. As shown in FIG. 1A and FIG. IB, unlike native GLP-1 and semaglutide, Compound A fully activated the cAMP pathway (FIG. 1A), but induced minimal to no recruitment of P-arrestin (FIG. IB), suggesting that Compound A is a potent and substantially biased GLP-1 RA.

[0153] To evaluate the PK profile of Compound A, the composition was administered to male white pigs via either a subcutaneous (SC) injection into the fat pads at the back of the neck or intravenously (IV) via a cannula into a marginal ear vein. Whole blood samples were collected in individual lithium heparin-treated containers with protease inhibitor, by direct puncture of a jugular vein pre dose and 6 hours post dose, then at days 2, 3, 4, 5, 6, 8, 9, and 10. Samples were placed immediately on ice and processed within 15 minutes of collection. Samples were centrifuged at 3,000 G for 10 minutes at 4°C; 150 pL supernatant plasma samples were stored at -80°C until use. Plasma peptide levels were quantified by liquid chromatography mass spectrometry (LC-MS / MS). Peptide was precipitated from the stabilized plasma samples using 100% acetonitrile, then separated on a reverse-phase Cl 8 column (Acquity UPLC CSH [C18, 1.7 pm, 50 mm x 2.1 mm, Waters]), ionized by positive electrospray ionization, andAtty Ref. METS-022 / 03WO 350242-2228 detected by MS / MS (Sciex Triple Quad 6500+). Pharmacokinetic parameters were determined using Phoenix WinNonlin (Version 8.3) and plotted using GraphPad Prism (Version 10.0).

[0154] After both IV and SC administration of the composition, pharmacokinetics were characterized by dose-dependent increases in exposure with monophasic elimination profiles (Table 1). After the 0.15 mg IV dose, mean (standard deviation [SD]) Cmax was 71.0 (20.0) ng / mL, AUCo-iastwas 6623 (1489) ng*hr / mL, and tl / 2 was 84.7 (21.8) hours. After the 0.2 mg IV dose, mean (SD) Cmax was 154 (34.9) ng / mL, AUCo-iast was 14,827 (5740) ng*hr / mL, and tl / 2 was 122 (44.0) hours. Across both 0.2 and 0.3 mg SC doses, individual tmax values ranged from 6.0 to 48.0 hours post dose, suggesting a relatively slow rate of absorption. After the 0.2 mg SC dose, mean (SD) Cmax was 72.6 (23.9) ng / mL, AUCo-iast was 9879 (2267) ng*hr / mL, and tl / 2 was 140 (47.9) hours. After the 0.3 mg SC dose, mean (SD) Cmax was 168 (112) ng / mL, AUCo-iast was 24,088 (15,316) ng*hr / mL, and ti / 2 was 254 (247) hours. By comparison of the AUCo-iast values after the 0.2 mg SC versus IV dose, the relative bioavailability was -66% (i.e., 9879 vs 14,827 ng*hr / mL), consistent with extensive absorption of the compound after SC administration.

[0155] It has been demonstrated that human subcutaneous PK of therapeutic proteins, such as GLP-1 analogue, liraglutide and insulin analogues could be reliably predicted from data obtained in an established pig model. See Pedersen K et al., Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir, Translational Research, Volume 239, 2022, Pages 71-84. Table 2 shows the projected PK values in humans based on the data from pigs. It is surprising that the projected human apparent clearance (50.4 mL / h) based on the pig model is more than 3-fold higher than the observed human apparent clearance (14.3 mL / h) from the clinical study asAtty Ref. METS-022 / 03WO 350242-2228 described in Example 2. These clinical findings suggest that Compound A has a much longer serum half-life in humans than would have been estimated based on the pig data.Example 2. Phase 1 / 2 Clinical Assessment of Compound A

[0156] A multi-arm, double-blind, placebo-controlled Phase 1 / 2 clinical trial was conducted in adult participants with an initial BMI of >30 kg / m2(obesity) or >27 kg / m2(overweight) in the presence of at least one weight-related related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, obstructive sleep apnea, cardiovascular disease, or dyslipidemia). There are three parts to this study. Part A consists of single ascending dose (SAD) cohorts of Compound A (or placebo), Part B is multiple-ascending dose (MAD) cohorts of Compound A (or placebo), and Part C consists of 13-week Dosing Cohorts of Compound A (or placebo).

[0157] The doses administered in SAD Cohorts A1-A7 are 0.16 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, and 1.6 mg Compound A.

[0158] The doses administered in MAD Cohorts B1-B5 are 5 once-weekly doses of 0.2 mg, 0.4 mg, 0.8 mg, 1.0 mg, and 1.2 mg Compound A over a 4-week period on study Days 1, 8, 15, 22, and 29. In Cohort B6, a dose of 0.8 mg was administered weekly for four weeks, followed by a 1.6 mg dose at week 5. The dosing regimen of B6 was designed to evaluate a potential regimen in inducing tolerance to gastrointestinal side effects with a well-tolerated weekly regimen before stepping up to a higher monthly maintenance dose.Atty Ref. METS-022 / 03WO 350242-2228

[0159] The Part C doses are chosen to evaluate the safety, tolerability, PK and PD of Compound A administered weekly in five additional cohorts for 13 weeks. Table 3 provides the dosing regimens for Part C. Cohorts 1 through 4 evaluated titration-free regimens of 12 weekly doses of Compound A (0.6 mg, 0.8 mg, 1.0 mg, and 1.2 mg) and Cohort 5 evaluated a dose-titration regimen with 0.4 mg with a single 2- or 4-fold dose increase over the weekly dose (ie, after steady state Compound A exposure) to assess the tolerability of switching to a pharmacologically matched, dose at monthly intervals. In Part C, participants have obesity and are overweight without Type 2 diabetes.Atty Ref. METS-022 / 03WO 350242-2228

[0160] The primary endpoints include safety assessment via evaluation of adverse events (AEs), vital signs (including temperature, heart rate and blood pressure), 12-lead electrocardiogram (ECG), corrected QT (QTc) analysis, laboratory evaluations, physical examination, glucose monitoring, and injection site reactions. Tolerability will be assessed via an assessment of treatment-emergent adverse events (TEAE).

[0161] The secondary endpoints include PK and PD measures. The PK parameters include maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration versus time curve during the dosing interval (AUC), minimum observed concentration (Cmin), elimination tl / 2, average concentration over the dosing interval (Cavg). The PD parameters include Percent change from baseline in weight at Week 12 (Day 85) and all other post-baseline pre-dose weekly measurements, occurrence of weight loss that is > 5%, > 10%, and > 15%, change from baseline (at all post-baseline measurements) in Body Mass Index (BMI), body weight (absolute and percent weight loss), waist circumference, change from baseline (at all post-baseline measurements) in glucose metabolism parameters (fasting insulin, hemoglobin Ale [HbAlc], fasting glucose and fasting glucagon), and change from baseline (at all post-baseline measurements) in lipid levels (triglycerides, high-density lipoprotein-cholesterol [HDL-C] and low-density lipoprotein-cholesterol [LDL-C]).

[0162] The inclusion criteria for participants include overweight / obese but otherwise healthy adult male or female with a BMI within 27.0 kg / m2 to 38.0 kg / m2, inclusively. The participants are at least 18 years of age but not older than 70 years of age. The participants have estimated glomerular filtration rate (eGFR) >90 mL / min at the screening visit.

[0163] Participants are randomized prior to their first dose within a cohort (Compound A or placebo) and to a 13th dose that is higher than the 12th dose.

[0164] Blood samples are collected by direct venipuncture into a labeled tube containing the appropriate anticoagulant as specified by the bioanalytical facility. As an option for the participant or if judged necessary by the clinical staff, blood samples may be collected from aAtty Ref. METS-022 / 03WO 350242-2228 catheter placed in the participant’s vein. The complete blood sampling schedules are presented in Table 4.

[0165] The method for the determination of Compound A in human plasma using UHPLC with MS / MS detection has met acceptance criteria with respect to specificity, sensitivity, precision, accuracy, matrix effect, linearity, recovery and dilution integrity, spanning a theoretical concentration range of 5.00 ng / mL to 2000.00 ng / mL for Compound A. Carryover is present and is controlled throughout the validation. Stability evaluations in matrix and solutions have also met acceptance criteria, demonstrating insignificant degradation over the specified storage durations and conditions. The bioanalytical method is provided in Table 5.Atty Ref. METS-022 / 03WO 350242-2228

[0166] The recovery of Compound A was evaluated by extracting human plasma QC samples without IS. At the end of the extraction procedure, a pure solution containing the IS was added to the samples (i.e. a pure solution contained IS). Additionally, non-extracted samples were prepared by extracting blank human plasma and adding a pure solution containing Compound A and Compound A IS at the end of the extraction procedure, as above. Therefore, the IS acts as an external standard in this evaluation. The peak response ratios of the extracted human plasma QC samples were compared to the peak response ratios of the nonextracted samples, representing a 100% recovery. The evaluation was assessed for Compound A at low, medium and high QC concentrations. Results are presented in Table 6A and 6B.Atty Ref. METS-022 / 03WO 350242-2228

[0167] The recovery of Compound A IS was evaluated by extracting high human plasma QC samples with IS, as outlined in the bioanalytical method. The non-extracted samples consisted of high human plasma QC samples extracted without IS, where a pure solution containing the IS was added at the end of the extraction procedure (i.e. a pure solution contained IS). The inverse peak response ratios of these extracted QC samples were compared to the inverse peak response ratios of the non-extracted samples of IS, representing a 100% recovery. Samples were assessed at a single IS concentration. Results are presented in Table 7.Atty Ref. METS-022 / 03WO 350242-2228

[0168] Analyst, version 1.6.3, was used to acquire and review chromatograms. Regressions and final tables were generated using Watson LIMS™, version 7.6.1. Statistical calculations presented in this study were performed using displayed precision. Sample tracking was performed using Watson™, version 7.6.1. All computer applications used were validated.

[0169] Due to differences in rounding / software limitation, results may differ slightly when attempting to reproduce these calculations manually.

[0170] In the SAD cohorts, Compound A was found to be generality well-tolerated. Dosedependent mean body weight loss up to 4.4% (SD=2.2) was observed approximately one month after a single 1.6 mg dose, and body weight persisted through the end of follow-up. The greatest mean changes from baseline in weight, BMI, and waist circumference were seen on Day 57 in the 1.6 mg Compound A cohort with a mean percent change from baseline of -4.3% or -3.4 kg (FIG. 2) in weight, -4.34% or -1.29 kg / m2 in BMI, and -3.81% or -1.40 inches in waist circumference. All participants in the 1.6 mg cohort lost weight, with 2 participants losing >5% of body weight by Day 57.

[0171] FIG. 3 shows the concentration profiles followig a single dose of SC Compound A. The PK profile of Compound A showed linear PK with low variability and a half-life of approximately 380 hours, or 15 to 16 days.

[0172] Table 8 shows the PK profile from SAD cohort.Table 8. PK data from SAD cohortCohort / tmaxaCmax AUCinf tl / 2Dose Level (h) (ng / mL) (h*ng / mL) (h)Cohort Al 72.0 18.5 11,200 3980.16 mg SC (48.0-144); (6.07%); (14.5%); (14.8%),6 6 6 6Cohort A2 48 44.1 26,000 368Atty Ref. METS-022 / 03WO 350242-22280.4 mg SC (48.0-144); (15.0%); (12.8%); (26.3%);5 5 5 5Cohort A3 72 103 57,800 3480.8 mg SC (48.0-96.0); (15.8%); (14.5%); (14.4%);6 6 6 6Cohort A4 60 74.3 40,200 3460.6 mg SC (48.0-168); (18.2%); (22.8%); (37.8%);6 6 6 6Cohort A5 48 219 116,000 3391.6 mg SC (12.0-168); (24.3%); (1 1.6%); (11.6%);6 6 6 6Cohort A6 60 128 87,000 4771.2 mg SC (48.0-120); (8.99%); (33.7%); (64.0%);6 6 6 6Cohort A7 48 1231.0 mg SC (48.0-96.0); (19.4%);6 6

[0173] In the MAD cohorts, Compound A was shown to be generally well tolerated, with no moderate or severe treatment-related adverse events observed. Dose-dependent weight loss was observed after five doses across all cohorts, with a mean weight loss of 7.5% (SD=1.6) at day 36 (one week after the final dose) in the 1.2 mg dose-group. The mean weight loss in this 1.2 mg dose-group was persistent and increased to 8.1% (SD=2.2) at day 57, and was 7.5% (SD=2) at day 85 (eight weeks after the last dose), reflecting the long half-life of Compound A and supporting the potential for monthly dosing. Similarly, in the 0.8 mg cohort, mean body weight loss was 6.3% (SD=4) at day 36, 5.2% (SD=4.5) at day 57, and 5.8% (SD=4.2) at day 85. In the pooled placebo group, mean body weight loss at day 36 was 0.6% (SD=2.2), 0.6% (SD=1.6) at day 57, and 0.1% (SD=2.3) at day 85. FIG. 4 shows the weekly mean percent change from baseline observed through day 36 in the MAD cohorts. PK analyses from the MAD cohorts indicated predicted plasma accumulation of Compound A after multiple weekly doses of Compound A, with a maximum concentration (Cmax) after the fifth dose approximately three to four-fold higher than the Cmax after the first dose (FIG. 5A and FIG. 5B). Dose levels > 0.8 mg of Compound A saturated GLP-1 receptors within 4 to 5 weeks, exceeding the apparent EC90 (the effective drug concentration producing 90% of its maximum effect). PKAtty Ref. METS-022 / 03WO 350242-2228 modeling suggests an accumulation ratio of approximately four-fold upon continued weekly dosing, with steady state concentration reached by week 11, potentially enabling clinically meaningful weight loss without a need for dose titration. Additionally, accumulation leads to plasma exposure exceeding the apparent EC90 for weekly Compound A doses of 0.8 mg or higher, supporting that a higher, potential monthly dose can deliver continued weight loss or weight maintenance without producing substantial tolerability issues.

[0174] In the Part C cohorts, subcutaneous administration of Compound A after 12 titration-free weekly doses induced dose-dependent weight loss, with substantial reductions in mean body weight of 11.3% (SE=1.1) in the 1.2 mg dose cohort (p< 0.001 vs. placebo) at day 85 (one week after the 12thdose), with no plateau observed (FIG. 6A and FIG. 6B). Similarly, in the 0.6 mg cohort, mean placebo-adjusted body weight loss was 7.2% (SE=1.1) at day 85 (< 0.001 vs. placebo). All cohorts achieved clinically meaningful and statistically significant weight loss at Day 85. Compound A was generally well-tolerated across dose groups, with most of the adverse events (AEs) being gastrointestinal (GI) in nature and mild. There were no treatment-related serious AEs. Multiple titration-free dose cohorts demonstrated tolerability in line with approved agents. Exceptional tolerability was observed in the 0.4mg / 0.8mg / 1.2mg dose escalated cohort (C5 cohort), where GI AEs were notably sporadic and mild, with one case of nausea (5%) and two cases of vomiting (10%) observed over the initial 85-day follow up period. Competitive placebo-adjusted weight loss of 6.3% was observed at day 85 in this cohort. Escalation to a two-fold (2x) and four-fold (4x) higher, monthly dose at week 13 was well-tolerated on initial follow-up, reinforcing the viability of monthly dosing after weekly induction. FIG. 7A shows the weight loss trajectory continued from Day 85 to Day 115 following a single 4x QM dose. In the 2 x dose groups, body weight was maintained between Day 85 and Day 115, with a difference in mean placebo- subtracted %body weight of 1% or less. FIG. 7B shows the placebo-subtracted weight loss difference at Day 115 after a single 4x QM dose. Dose-linear pharmacokinetics and an approximately four-fold increase in exposure were confirmed after 12 weeks, attributed to the 380-hour half-life of Compound A, supporting the feasibility of titration-free dosing.

[0175] Table 9 shows the PK profile from the Part C cohorts.Atty Ref. METS-022 / 03WO 350242-2228Table 9. PK data from the Part C cohortsCohort / NCA tmax“ (h) Cmax AUCo-iesDose Level Visit (ng / mL) (h*ng / mL)Cohort Cl: 0.6 mg SC x Day 1 72.0 50.8 7,26012, then 1.2 / 2.4 mg (36.0-168); (22.5%); (23.7%);20 20 20Cohort C2: 0.8 mg SC x Day 1 72.0 75.2 10,80012, then 1.6 / 3.2 mg (36.0-96.0); (18.7%); (19.1%);20 20 20Cohort C3: 1.0 mg SC x Day 1 72.0 82.4 11,70012, then 2.0 / 4.0 mg (36.0-168); (26.5%); (24.4%);20 20 19Cohort C4: 1.2 mg SC x Day 1 48.0 132 19,10012, then 2.4 / 4.8 mg (36.0-168.0); (19.4%); (19.9%);19 19 18Cohort C5: 0.4 mg SC x 4, Day 1 60.0 33.7 4,560 then 0.8 mg x 4, then (16.0-96.0); (27.6%); (25.1%);1.2 mg x 4, then 20 20 202.4 / 4.8 mgCohort / NCA tmax“ Cmax AUCo-iesDose Level Visit (h) (ng / mL) (h*ng / mL)Cohort Cl: 0.6 mg SC x Day 85 NC NC NC12, then 1.2 mgCohort Cl: 0.6 mg SC x Day 85 NC NC NC12, then 2.4 mgCohort C2: 0.8 mg SC x Day 85 72.0 393 NC12, then 1.6 mg (72.0-72.0); (18.0%);2 2Cohort C2: 0.8 mg SC x Day 85 48.0 587 NC12, then 3.2 mg (4.00-72.0); (16.1%);7 7Cohort C3: 1.0 mg SC x 12, Day 85 NC NC NC then 2.0 mgCohort C3: 1.0 mg SC x 12, Day 85 NC NC NC then 4.0 mgCohort C4: 1.2 mg SC x 12, Day 85 60.0 554 NC then 2.4 mg(48.0-96.0); (17.1%);4 4Cohort C4: 1.2 mg SC x Day 85 24.0 1,110 NC12, then 4.8 mg (8.0-48.0); (18.6%);5 5Cohort C5: 0.4 mg SC x Day 85 NC NC NC4, then 0.8 mg x 4, then 1.2 mg x4, , then 2.4 mgCohort C5: 0.4 mg SC x Day 85 NC NC NC4, then 0.8 mg x 4, then 1.2 mg x4, , then 4.8 mgatmax presented as median (minimum, maximum)Atty Ref. METS-022 / 03WO 350242-2228bInsufficient data were available at the time of this preliminary PK update for complete characterization of the Day 85 PK parameters (i .e. tmax, Cmax, and AUCO-168) across all cohorts AUCo-i68=area under the curve evaluated until 168 hours post-dose; CV=coeffi cient of variation; Cmax=maximum concentration; NC=not calculated; NCA=noncompartmental analysis; PK=pharmacokinetic; SC=subcutaneous; Tmax=time to maximum concentration

[0176] Cumulative dose normalized Cmax and AUCo-168 data across Parts A, B, and C do not exhibit monotonic trending with dose, suggesting no apparent departures from doseproportionality. FIG. 8 and FIG. 9 show the distribution of preliminary dose normalized Compound A Cmax and AUCo-168, respectively, by cohort.Example 3. Dosing regimens based on human PK profile

[0177] The PK profile obtained from the clinical study as described in Example 2 is applied to determine the optimal dosing frequency for the Compound A dose levels to be used in further clinical studies.

[0178] The dosing frequency in clinical therapy using Compound A may depend on the plasma half-life T1 / 2 after subcutaneous administration. The clinical study in Example 2 estimates that subcutaneous administration of Compound A provides a prolonged T1 / 2 of about 300 hours to 500 hours. Long period of activity in vivo (as assessed in humans) permits administration no more frequently than daily and preferably no more than twice a week, whilst still producing acceptable therapeutic or cosmetic benefits.

[0179] A clinical study design in which dosing frequency is switched from once weekly to once monthly in healthy overweight or obese subjects is contemplated in the present disclosure. In this clinical study design, a subject will receive multiple (e.g. 12) once-weekly subcutaneous doses of Compound A to reach PK steady state followed by multiple once-monthly doses of Compound A. Additional once-monthly doses of Compound A may be administered in an extended period. Key assessements include body weight loss, tolerability and pharmacokinetics. FIG. 10 shows the predicted pharmacokinetic profile of Compound A in a weekly to monthly dosing regimen. The objective of this regimen is to induce tolerance through weekly doses and maintain exposure through matched monthly doses.

[0180] Two additional clinical study designs are contemplated in the present disclosure. In option 1, a subject will receive once-weekly subcutaneous doses of Compound A (e.g. 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg or 1.6mg) for about 1 month to about 5 months, or until beneficialAtty Ref. METS-022 / 03WO 350242-2228 effects (e.g., body weight loss) are observed, followed by fixed once-monthly maintenance doses which amount is 2-fold or 4-fold of the weekly dose. In option 2, a subject will receive once-weekly subcutaneous doses of Compound A (e.g. 0.6 mg, 0.8 mg or 1.0 mg) for about 1 month to about 3 months, or until beneficial effects are observed, followed by a flexible chronic dosing schedule, such as continued weekly administration at any dose, continued with reduced frequency (e.g. once monthly) at any dose, or a pulse therapy as described herein. Key assessements include body weight loss.Example 4. Clinical Study of Compound A

[0181] A clinical study of Compound A, including Part-1, Part-2 and Part-3, is conducted on participants with obesity or overweight.

[0182] The Part-1 study is a 28-week, double-blind, placebo-controlled clinical trial of Compound A assessing body weight changes at different titration-free weekly doses in participants with obesity or overweight without type 2 diabetes (T2DM). These participants receive one of four dose levels of Compound A (0.4 mg, 0.6 mg, 0.9 mg, or 1.2 mg) or placebo weekly for 28 weeks (FIG. 11). The primary efficacy endpoint is the percent change in body weight from baseline at week 28. The study is designed without titration to expediate the assessment of dose separation.

[0183] The Part-2 study is a 28-week, double-blind, placebo-controlled clinical trial of Compound A assessing body weight changes at different weekly doses in participants with obesity or overweight with T2DM. These participants receive one of 4 dose levels (0.4 mg, 0.8 mg, 1.2 mg, or 1.6 mg) or placebo for 28 weeks. The higher two dose cohorts receive two titration steps (4 weeks at each dose level) before arriving at the higher dose levels (FIG. 12). The primary efficacy endpoint is the percent change in body weight from baseline at week 28.

[0184] The Part-3 study is a double-blind, placebo-controlled clinical trial of Compound A assessing body weight changes in participants with obesity or overweight without T2DM. These participants are randomized to one of four arms (0.8 mg weekly with or without a single 4-week titration step, and 1.2 mg weekly with one or two 4-week titration steps) or placebo for 12 weeks, followed by multiple monthly doses that are 4-fold higher than the weekly doses (FIG. 13). The primary efficacy endpoint is the percent change in body weight from baseline at week 28 (after 4 monthly doses). The participants continue to receive monthly Compound A after that.Atty Ref. METS-022 / 03WO 350242-2228Example 5. Phase 2b Clinical Study of Compound A

[0185] This study is a 28-week Phase 2b study designed to examine the safety and efficacy of four weekly Compound A dose levels (vs placebo) administered subcutaneously for 28 weeks in participants with obesity or overweight. The primary objective will be the effect of Compound A on percent change in body weight at Week 28. This data will support the dose selection for the Phase 3 clinical studies and allow for sufficient time to observe maximal, or near maximal, weight loss effects at each dose level.

[0186] The ultra long-half life and the biased pharmacology of Compound A at the GLP-1 receptor have the potential to provide patients with multiple flexible dosing options (e.g., titration or titration-free once weekly (QW) dosing, intermittent (e.g., once biweekly (Q2W)) dosing, or once-monthly (QM) dosing. Therefore, the study extension aims to investigate the safety, tolerability and efficacy of switching to corresponding biweekly (Q2W) or once- monthly (QM) dose. Preliminary findings from Study Phase 1 / 2 Part C suggest that switching from a QW dose to up to a 4x multiple of the QW dose (QM dose) of Compound A is safe, well-tolerated, and merits further investigation.

[0187] The study includes Part A and Part B. Part A is a multi-center, randomized, doubleblind, placebo-controlled study to investigate the efficacy and safety of four different dose levels of Compound A vs. placebo for body weight loss in adult participants (aged 18 to 70) with obesity or overweight (body mass index [BMI] 27 to 50 kg / m2,) after 28 weeks of once- weekly dosing. Approximately 225 participants will be randomized in a 1 : 1 : 1 : 1 : 1 ratio to one of 5 treatment arms (n=45 per treatment arm) as shown in Table 10 and FIG. 14. Part A participants will receive 28 doses of Compound A once weekly from Week 0 (Day 1) through Week 27 (Day 190). The final Week 28 (Day 197) assessments will occur 1 week after the last dose of Compound A.

[0188] Part B is optional and available only to participants who have completed Week 28 (Day 197) assessments and procedures for the primary reporting milestone, shown good compliance throughout Part A, do not meet any study discontinuation criteria and sign an informed consent. For participants who elect to continue to Part B, additional double-blind visits will occur in Part B to maintain the double-blind in Part A. Investigators, participants, and Sponsor personnel directly involved in the conduct of the study will remain blinded to participant-level treatment allocation in Part B from the dosing at Week 28 (Day 197) until the first participant reaches Week 40 (Day 281). Part B participants will receive an additional 8Atty Ref. METS-022 / 03WO 350242-2228 weeks of QW Compound A treatment followed by 24 weeks of either a QW, Q2W, or QM dose regimen as described in Table 10. All participants will be followed for an additional 12 weeks (covering >5 half-lives of Compound A) after administration of the last dose of study medication for safety and efficacy assessments for a total duration of up to 75 weeks (including up to a 4-week Screening Period).

[0189] The target population are all overweight and obese adults aged 18 to 70 years, with a BMI of 27 to 50 kg / m2.Endpoints for Part A:

[0190] The primary efficacy endpoint of the study is percentage change from baseline in body weight at Week 28 (Day 197).

[0191] The secondary efficacy endpoints include (1) percent change from baseline in body weight at all weekly post-baseline weight measurements prior to Week 28 (Day 197); (2) occurrence of body weight reduction (weight loss) from baseline at Week 28 (Day 197) that is: > 5%, > 10%, or > 15%; (3) change from baseline (at all protocol-specified weekly postbaseline measurements in Part A) in body weight (kg), Body Mass Index (BMI) (kg / m2), and waist circumference (cm).Atty Ref. METS-022 / 03WO 350242-2228

[0192] The safety and tolerability endpoints include: (1) occurrence, severity and relatedness of treatment emergent adverse events (TEAEs) AEs of clinical interest: gastrointestinal adverse events (AEs) of Nausea, Vomiting and Diarrhea; (2) occurrence, severity, and relatedness of other TEAEs; (3) occurrence of abnormal clinically significant physical examination; (4) 12-lead electrocardiogram (ECG) measurements; (5) Laboratory measurements; (6) Columbia-Suicide Severity Rating Scale (C-SSRS); (7) Patient Health Questionnaire (PHQ-9); and (8) occurrence of anti -drug antibodies (AD As).

[0193] The pharmacokinetic (PK) endpoint for the duration of the weekly dosing in Part A for all participants include Minimum observed concentration (Cmin). The following endpoints measured for the duration of the weekly dosing in Part A for subset of 10 participants of each arm: (1) Area under the concentration versus time curve during the dosing interval (AUC(0- t)); (2) maximum observed concentration (Cmax); (3) time to maximum concentration (Tmax); (4) other PK parameters; and (5) Compound A concentrations.

[0194] The exploratory endpoints include change from baseline (at all protocol-specified post-baseline measurements in Part A) in the foilwing glucose metabolism paramters: fasting insulin, glycated hemoglobin A1C [14b Ale], fasting glucose and fasting glucagon; and (2) change from baseline (at all protocol-specified post-baseline measurements in Part A) in lipid levels (triglycerides, high-density lipoprotein-cholesterol [HDL-C] and low-density lipoprotein-cholesterol [LDL-C]).Endpoints for Part B:

[0195] The exploratory efficacy endpoints include: (1) percent change from baseline in body weight at all Part B protocol-specified post-baseline measurements; (2) occurrence of body weight reduction (weight loss) at all Part B protocol- specified measurements that is: >5%, >10%, >15%, >20%; (3) Change from baseline (at all Part B protocol-specified measurements) in: body weight (kg), Body Mass Index (BMI) (kg / m2), and waist circumference (cm).

[0196] The exploratory safety and tolerability endpoints include: (1) occurrence and severity of treatment-emergent adverse events (TEAEs): (2) occurrence of abnormal clinically significant physical examination; (3) occurrence of abnormal clinically significant 12-lead electrocardiogram (ECG) measurements; (4) occurrence of abnormal clinically significant clinical laboratory measurements; (5) Columbia-Suicide Severity Rating Scale (C-SSRS); (6) Patient Health Questionnaire (PHQ-9); (7) occurrence of anti-drug antibodies (AD As).Atty Ref. METS-022 / 03WO 350242-2228

[0197] The exploratory pharmacokinetic (PK) endpoints include Minimum observed concentration (Cmin); (2) other PK parameters; and (3) Compound A concentrations.Inclusion Criteria

[0198] Participants include male and female adults aged 18 to 70 years. Eligible participants must have a BMI between 30.0 and 50.0 kg / m2at Screening (with or without weight-related comorbidities). Participants with a BMI of 27.0 to <30.0 kg / m2are eligible only if they have at least one of the following weight-related comorbidities: (1) Hypertension, defined as being on blood pressure-lowering medication or having systolic BP >130 mmHg or diastolic BP >80 mmHg at Screening; (2) Dyslipidemia, defined as being on lipid-lowering medication or having LDL-C >160 mg / dL (4.1 mmol / L) or triglycerides >150 mg / dL (1.7 mmol / L); or (3) Low HDL-C, defined as <40 mg / dL (1.0 mmol / L) for men or <50 mg / dL (1.3 mmol / L) for women at Screening. Participants must also have stable body weight, defined as a self-reported change (gain or loss) of <5 kg within the 3 months prior to Screening.

Claims

Atty Ref. METS-022 / 03WO 350242-2228CLAIMS1. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

2. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once weekly for at least 3 weeks, followed by a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

3. A method of inducing or maintaining weight loss or managing body weight in a subj ect who has received a prior GLP-1 receptor agonist administered on a daily or weekly basis, the method comprising(a) discontinuing the administration of the prior GLP-1 receptor agonist; and(b) thereafter, initiating the subcutaneous administration of a composition comprising a glucagon-like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

4. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 3 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 6.0 mg for a period of about 2 weeks to about 36 weeks, and thereafter followed by a dose of about 0.4 mg to about 10.0 mg once biweekly or monthly, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.Atty Ref. METS-022 / 03WO 350242-22285. A method of inducing or maintaining weight loss or managing body weight in a subj ect, the method comprising subcutaneous administration of a composition comprising a glucagon- like peptide-1 (GLP-1) receptor agonist or a salt thereof at a dose of about 0.1 mg to about 4.0 mg once weekly for at least 2 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher once weekly dose ranges about 0.2 mg to about 10.0 mg for a period of about 2 weeks to about 36 weeks per titration step, and thereafter followed by administration of a once weekly maintenance dose of about 0.4 mg to about 10.0 mg, wherein the GLP-1 receptor agonist comprises a peptide having the amino acid sequence of SEQ ID NO: 1.

6. The method of any one of claims 1-5, wherein the C-terminal Lys of the peptide is linked to a group of formula I:wherein R is a C16-C18 alkylene or alkenylene group; andR1is CO2H.

7. The method of claim 6, wherein the composition comprises the GLP-1 receptor agonist(Compound A).Atty Ref. METS-022 / 03WO 350242-22288. The method of claim 7, wherein the composition comprises the acetate salt of Compound A.

9. The method of claim 7, wherein the composition comprises the chloride salt of Compound A.

10. The method of any one of claims 1-9, wherein the composition is in the form of an injectable aqueous solution.

11. The method of any one of claims 1-9, wherein the composition is present in a syringe or other administration devices for subcutaneous administration.

12. The method of any one of claims 1-11, wherein the weekly, biweekly, or monthly dose is about 0.16 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.2 mg, about 1.5 mg, about 1.6 mg, about 2.0 mg, about 2.4 mg, about 2.5 mg, about 3.2 mg, about 3.6 mg, about 4.0 mg, about 4.8 mg, about 6.0 mg, about 6.4 mg, about 8.0 mg, or about 9.6 mg.

13. The method of any one of claims 2-12, wherein the weekly dose is administered for about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, or more, and thereafter a monthly dose is administered.

14. The method of claim 13, wherein the weekly dose is administered for about 4 weeks.

15. The method of claim 13, wherein the weekly dose is administered for about 8 weeks.

16. The method of claim 13, wherein the weekly dose is administered for about 12 weeks.

17. The method of claim 13, wherein the weekly dose is administered for about 28 weeks.Atty Ref. METS-022 / 03WO 350242-222818. The method of claim 13, wherein the weekly dose is administered for about 36 weeks.

19. The method of any one of claims 2-5 and 13, wherein the amount of the biweekly or monthly dose is from about 2-fold to about 4-fold of the amount of the weekly dose.

20. The method of any one of claims 2-5 and 13, wherein the weekly dose is about 0.4 mg to about 1.2 mg, and the biweekly or monthly dose is about 0.8 mg to about 4.8 mg.

21. The method of any one of claims 2-5 and 13, wherein the weekly dose is about 0.4 mg followed by about 0.8 mg, and the biweekly dose is about 1.6 mg.

22. The method of claim 2 or 13, wherein the weekly dose is about 0.6 mg, and the monthly dose is about 2.4 mg.

23. The method of claim 2 or 13, wherein the weekly dose is about 0.6 mg administered for about 36 weeks, and the monthly dose is about 2.4 mg.

24. The method of claim 2 or 13, wherein the weekly dose is about 0.9 mg, and the monthly dose is about 3.2 mg.

25. The method of claim 2 or 13, wherein the weekly dose is about 0.9 mg administered for about 36 weeks, and the monthly dose is about 3.2 mg.

26. The method of claim 2 or 13, wherein the weekly dose is about 1.2 mg, and the monthly dose is about 4.8 mg.

27. The method of claim 2 or 13, wherein the weekly dose is about 1.2 mg administered for about 36 weeks, and the monthly dose is about 4.8 mg.

28. The method of claim 4 or 5, wherein the each higher weekly dose is about 2-fold to about 4-fold of an immediately preceding weekly dose.Atty Ref. METS-022 / 03WO 350242-222829. The method of claim 4 or 5, wherein the each higher weekly dose is about 2-fold of an immediately preceding weekly dose.

30. The method of claim 4 or 5, wherein the each higher weekly dose is about 4-fold of an immediately preceding weekly dose.

31. The method of claim 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks.

32. The method of claim 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks, and the biweekly dose is about 1.4 mg to about 2 mg.

33. The method of claim 4, wherein the weekly dose is about 0.4 mg to about 1.2 mg administered for about 28 weeks to about 36 weeks, and the monthly dose is about 2 mg to about 5 mg.

34. The method of claim 4, wherein the weekly dose is about 0.4 mg administered for about 28 weeks, followed by the weekly dose of about 0.8 mg administered for about 8 weeks, and the biweekly dose is about 1.6 mg.

35. The method of claim 5, wherein the weekly dose is about 0.4 mg to about 1.6 mg administered for about 2 weeks to about 36 weeks, and the weekly maintenance dose is about 1.6 mg to about 2.4 mg .

36. The method of claim 5, wherein the weekly dose is about 0.4 mg administered for about 4 weeks followed by a higher weekly dose of about 0.8 mg administered for about 4 weeks, and the weekly maintenance dose is about 1.6 mg.

37. The method of claim 5, wherein the weekly dose is about 0.4 mg administered for about 4 weeks followed by a first higher weekly dose of about 0.8 mg administered for about 4 weeksAtty Ref. METS-022 / 03WO 350242-2228 followed by a second higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.

38. The method of claim 5, wherein the weekly dose is about 0.4 mg administered for about 8 weeks, and the weekly maintenance dose is about 1.6 mg.

39. The method of claim 5, wherein the weekly dose is about 0.8 mg administered for about 8 weeks, and the weekly maintenance dose is about 1.6 mg.

40. The method of claim 5, wherein the weekly dose is about 0.4 mg administered for about 8 weeks followed by a higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.

41. The method of claim 5, wherein the weekly dose is about 0.8 mg administered for about 8 weeks followed by a higher weekly dose of about 1.6 mg administered for about 4 weeks, and the weekly maintenance dose is about 2.4 mg.

42. The method of any one of claims 1-41, wherein the subj ect has obesity or is overweight.

43. The method of any one of claims 1-42, wherein the subject has a body mass index (BMI) of at least 27 kg / m2.

44. The method of claim 42 or 43, wherein the subject has a weight-related comorbid condition.

45. The method of claim 44, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

46. The method of claim 45, wherein the weight-related comorbid condition is T2DM.

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