Combination dosage regimens of amylin receptor agonists and GLP-1 receptor agonists

Abstract

The present invention relates to a method of treating and / or preventing a disease or disorder in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an amylin receptor (AMYR) agonist and about 0.1 mg to about 10 mg of a GLP-1 receptor (GLP-1R) agonist (e.g. a GLP-1R / glucagon receptor dual agonist). Also provided are corresponding compositions and kits.

Description

[0001] POLYPEPTIDE COMBINATION DOSAGE REGIMENS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to dosage regimens for treating and / or preventing a disease or disorder in a subject by administering a combination of an amylin receptor agonist and a GLP-1 receptor agonist.

[0004] BACKGROUND

[0005] The incidence of obesity and diabetes have been rising in epidemic proportions.

[0006] Obesity is the result of complex relationships between genetic, socioeconomic, and cultural influences, and is defined as a BMI of > 30 kg / m2. It is a risk factor for the development of many comorbid conditions, including type 2 diabetes mellitus, CV disease, and chronic kidney disease, and it is estimated that obesity affects nearly a third of the world’s population (Chooi et al. 2019 Metabolism. 2019;92:6-10). Weight loss has been associated with improvements in comorbidities, however, achieving and maintaining weight loss through lifestyle interventions alone is difficult. Bariatric surgery is currently the most effective treatment for sustained body weight loss (O’Brien et al. 2019 Obes Surg. 2019;29(1 ):3-1 ); however, such surgical intervention is only appropriate for a minority of the patient population.

[0007] Diabetes is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Type 2 diabetes mellitus (T2DM) accounts for some 90 to 95 percent of all diagnosed cases of diabetes, and the risk of type 2 diabetes rises with increasing body weight. The prevalence of type 2 diabetes is three to seven times higher in those who are affected by obesity than in normal weight adults, and is 20 times more likely in those with a body mass index (BMI) greater than 35 kg / m2. However, weight-loss can improve control or cure type 2 diabetes.

[0008] Despite the development of several new treatments for overweight and obesity, concerns regarding tolerability, suboptimal response and the need for additional weight loss persist among a significant number of patients, highlighting an unmet need for additional treatment modalities. Glucagon and glucagon-like peptide-1 (GLP-1 ) derive from pre-proglucagon, a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1 ), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), that are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake. Glucagon is a 29- amino acid peptide that corresponds to amino acids 33 through 61 of proglucagon (53 to 81 of preproglucagon), while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of proglucagon (92 to 128 of preproglucagon). GLP-1 (7-36) amide or GLP-1 (7-37) acid are biologically active forms of GLP-1 , that demonstrate essentially equivalent activity at the GLP-1 receptor (GLP-1 R).

[0009] Glucagon is produced by the pancreas and interacts with the glucagon receptor ("GCGR"). Glucagon acts in the liver to raise blood glucose via gluconeogenesis and glycogenolysis. When blood glucose begins to fall, glucagon signals the liver to break down glycogen and release glucose, causing blood glucose levels to rise toward a normal level.

[0010] GLP-1 has different biological activities compared to glucagon. It is secreted from gut L- cells and binds to the GLP-1 R. Its activities include stimulation of insulin secretion, inhibition of glucagon secretion, and inhibition of food intake.

[0011] Both glucagon and GLP-1 , acting as agonists at their respective receptors, have been shown to be effective in weight loss. Certain GLP-1 analogues are being sold or are in development for treatment of obesity including, e.g., Liraglutide (Saxenda® from Novo Nordisk) and Semaglutide (Wegovy® from Novo Nordisk). Glucagon / GLP-1 dual agonist peptides such as cotadutide are also known and are in clinical development for treatment of diabetes, obesity, and metabolic dysfunction associated steatohepatitis (MASH).

[0012] Amylin analogues are also being considered for the treatment of obesity, excess food intake, and diabetes (see e.g., WO 2018 / 046719). Pramlintide, a synthetic analogue of human amylin, is clinically used in amylin replacement therapies and simulates the important glucoregulatory actions of amylin. These glucoregulatory actions complement those of insulin by regulating the rate of appearance of glucose in the circulation, and are achieved through three primary mechanisms: slowing the rate of gastric emptying, suppression of post-meal glucagon secretion and suppression of food intake (Roth JD et. al. GLP-1 R and amylin agonism in metabolic disease: complementary mechanisms and future opportunities. Br J Pharmacol. 2012 ; 166(1 ):121 -136). Pramlintide has been used as an adjunct to insulin in patients with diabetes who have failed to reach desired glucose control despite optimal insulin therapy (Pullman J, et. al. Pramlintide is used in the management of insulin-using patients with type 2 and type 1 diabetes. Vase Health Risk Manag. 2006;2(3):203-212). Pramlintide analogues conjugated to lipids to extend their half-life are also known.

[0013] Existing agents are not without their problems. GLP-1 agonists, glucagon / GLP-1 agonists and some amylin analogues are reported to be associated with poor tolerability, as nausea and vomiting are common side effects. In addition, GLP-1 agonists and glucagon / GLP-1 agonists are known to result in the loss of lean muscle mass, which is clinically undesirable. Moreover, GLP-1 agonists and glucagon / GLP-1 dual agonists alone may not achieve weight loss to a sufficiently desirable level.

[0014] Accordingly, there remains a need for treatments that can treat and / or prevent a disease or disorder, improve glycemic control, reduce weight, treat type 2 diabetes mellitus (T2DM), and / or treat NASH in a subject, while minimizing burdens associated with a reduction in lean muscle mass. Further, there remains a need for treatments that can achieve greater levels of weight loss and the concomitant improvements in health outcomes. It is an object of the present invention to address one or more of these issues.

[0015] SUMMARY OF THE INVENTION

[0016] AZD6234 is a potent agonist of human, cynomolgus monkey, and rat amylin receptors (AMYR), displaying in vitro selectivity over calcitonin receptor activation. AZD9550 is a synthetic 30-mer peptide with balanced dual activity for GLP-1 and GCG receptors. Both peptides have been acylated (i.e., lipidated) to confer binding to serum albumin, and therefore have a long half-life enabling once-weekly administration in humans. In vitro studies and in vivo toxicology studies have demonstrated acceptable safety profiles in rats and cynomolgus monkey for both peptides.

[0017] The present inventors sought to determine, for the first time, how a combination of AZD6234 and AZD9550 behaves when administered to humans at various doses. The inventors have previously established through Phase I human clinical trials that AZD6234 monotherapies are generally safe and well tolerated when administered to humans. The inventors have now further established through Phase I human clinical trials that AZD9550 monotherapies are generally safe and well tolerated when administered to humans. The inventors have combined in vivo pharmacokinetic and safety data obtained from the in-human trial with preclinical efficacy data obtained from animal models to devise dosages for a combination therapy of AZD6234 and AZD9550 with the potential to achieve an efficacious weight reducing effect in humans without compromising patient safety.

[0018] Further, the inventors have established that combining a particular class of AMYR agonists {e.g. AMYR agonists which have selectivity for AMYR as compared with calcitonin receptor (CTR)) and GLP-1 R agonists {e.g., GLP-1 R / GCGR dual agonists) result in improved tolerability {e.g., reduction in nausea and / or vomiting), e.g., as compared to other antiobesity drugs, such as a therapeutically effective dose of a dual amylin-calcitonin receptor agonist (DACRA e.g., davalintide); a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). By way of further benefit, the combination treatments with an AMYR agonist and a GLP1-R agonist provided herein can promote fat mass loss and preserve lean mass without compromising tolerability, making this a clinically attractive treatment paradigm. As further demonstrated herein, this combination treatment has the potential to provide synergistic effects beyond those observed using AMYR agonists and GLP1-R agonists as monotherapies.

[0019] Hence, administering a combination of an AMYR agonist, such as AZD6234, and a GLP-1 R agonist {e.g., a GLP-1 R / GCGR dual agonist), such as AZD9550, at the doses described herein has the potential to achieve clinical benefit when administered to humans for treating and / or preventing a disease. For example, the combination therapy may be useful in reducing body weight, including the treatment of obesity and obesity-related conditions.

[0020] Such treatments may be particularly suitable for achieving additional reduction in body weight over and above treatment with other weight loss actives, such as GLP-1 receptor (GLP-1 R) agonists (e.g. semaglutide) and / or GLP-1 R / glucagon receptor (GCGR) dualagonists (e.g. tirzepatide), and / or AMYR or DACRA agonists, and particularly monotherapies using such actives.

[0021] Accordingly, the present invention provides a method for treating and / or preventing a disease or disorder in a subject, the method comprising administering to the subject (a) about 1 mg to about 15 mg of an amylin receptor (AMYR) agonist; and (b) about 0.1 mg to about 10 mg of a GLP-1 receptor (GLP-1 R) agonist.

[0022] The GLP-1 R agonist may activate both a GLP-1 R and a glucagon receptor (GCGR).

[0023] The method may further comprise administering to the subject a glucagon receptor (GCGR) agonist.

[0024] The amount of GLP-1 R agonist may be from about 0.1 mg to about 7 mg.

[0025] The amount of GLP-1 R agonist may be from about 0.1 mg to about 5 mg.

[0026] The amount of GLP-1 R agonist may be from about 0.1 mg to about 1 .5 mg

[0027] The amount of GLP-1 R agonist may be from about 0.1 mg to about 1 mg.

[0028] The amount of GLP-1 R agonist may be from about 0.1 mg to about 0.5 mg

[0029] The amount of GLP-1 R agonist may be from about 0.1 mg to about 0.2 mg

[0030] The amount of GLP-1 R agonist may be from about 0.2 mg to about 10 mg.

[0031] The amount of GLP-1 R agonist may be from about 0.2 mg to about 7 mg.

[0032] The amount of GLP-1 R agonist may be from about 0.2 mg to about 5 mg.

[0033] The amount of GLP-1 R agonist may be from about 0.2 mg to about 1 .5 mg

[0034] The amount of GLP-1 R agonist may be from about 0.2 mg to about 1 mg.

[0035] The amount of GLP-1 R agonist may be from about 0.2 mg to about 0.5 mg

[0036] The amount of GLP-1 R agonist may be from about 0.5 mg to about 10 mg.

[0037] The amount of GLP-1 R agonist may be from about 0.5 mg to about 7 mg.

[0038] The amount of GLP-1 R agonist may be from about 0.5 mg to about 5 mg.

[0039] The amount of GLP-1 R agonist may be from about 0.5 mg to about 1 .5 mg

[0040] The amount of GLP-1 R agonist may be from about 0.5 mg to about 1 mg.

[0041] The amount of GLP-1 R agonist may be from about 1 mg to about 10 mg.

[0042] The amount of GLP-1 R agonist may be from about 1 mg to about 7 mg.

[0043] The amount of GLP-1 R agonist may be from about 1 mg to about 5 mg.

[0044] The amount of GLP-1 R agonist may be from about 1 mg to about 1 .5 mg. The amount of GLP-1 R agonist may be from about 1 .5 mg to about 5 mg.

[0045] The amount of GLP-1 R agonist may be from about 2 mg to about 10 mg.

[0046] The amount of GLP-1 R agonist may be from about 2 mg to about 7 mg.

[0047] The amount of GLP-1 R agonist may be from about 2 mg to about 5 mg.

[0048] The amount of GLP-1 R agonist may be from about 4 mg to about 10 mg.

[0049] The amount of GLP-1 R agonist may be from about 4 mg to about 7 mg.

[0050] The amount of GLP-1 R agonist may be from about 4 mg to about 5 mg.

[0051] The amount of GLP-1 R agonist may be from about 5 mg to about 10 mg.

[0052] The amount of GLP-1 R agonist may be from about 5 mg to about 7 mg.

[0053] The amount of GLP-1 R agonist may be from about 8 mg to about 10 mg.

[0054] The amount of GLP-1 R agonist may be about 0.15 mg, about 0.3 mg, about 0.6 mg, about

[0055] 1.2 mg, about 2.3 mg, about 4.6 mg, about 7.0 mg, or about 9.4 mg, preferably about 1.2 mg, about 4.6 mg, about 7 mg, or about 9.4 mg.

[0056] The amount of AMYR agonist may be from about 1 mg to about 10 mg.

[0057] The amount of AMYR agonist may be from about 1 mg to about 5 mg.

[0058] The amount of AMYR agonist may be from about 4 mg to about 10 mg.

[0059] The amount of AMYR agonist may be from about 1 mg to about 3 mg.

[0060] The amount of AMYR agonist may be from about 2.5 mg to about 5 mg.

[0061] The amount of AMYR agonist may be from about 7 mg to about 10 mg.

[0062] The amount of AMYR agonist may be about 1 .5 mg {e.g. 1 .6 mg), about 4.5 mg, about 6 mg, or about 9 mg.

[0063] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist may be from about 8 mg to about 10 mg, optionally about 9.4 mg. The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist may be from about 5 mg to about 10 mg, optionally about 7 mg.

[0064] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist may be from about 3 mg to about 5 mg, optionally about 4.6 mg.

[0065] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist may be from about 2 mg to about 4 mg, optionally about 2.3 mg.

[0066] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist may be from about 1 mg to about 2 mg, optionally about 1 .2 mg.

[0067] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist may be from about 8 mg to about 10 mg, optionally about 9.4 mg.

[0068] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 7 mg , optionally about 6 mg, and the amount of GLP-1 R agonist may be from about 5 mg to about 10 mg, optionally about 7 mg.

[0069] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist may be from about 3 mg to about 5 mg, optionally about 4.6 mg.

[0070] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist may be from about 2 mg to about 4 mg, optionally about 2.3 mg.

[0071] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist may be from about 1 mg to about 2 mg, optionally about 1 .2 mg. The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist may be from about 8 mg to about 10 mg, optionally about 9.4 mg.

[0072] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist may be from about 5 mg to about 10 mg, optionally about 7 mg.

[0073] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist may be from about 3 mg to about 5 mg, optionally about 4.6 mg.

[0074] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist may be from about 2 mg to about 4 mg, optionally about 2.3 mg.

[0075] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist may be from about 1 mg to about 2 mg, optionally about 1 .2 mg.

[0076] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 1 mg to about 2 mg, optionally about 1 .5 mg {e.g. 1 .6 mg), and the amount of GLP-1 R agonist may be from about 8 mg to about 10 mg, optionally about 9.4 mg.

[0077] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 1 mg to about 2 mg, optionally about 1 .5 mg e.g. 1 .6 mg), and the amount of GLP-1 R agonist may be from about 5 mg to about 10 mg, optionally about 7 mg.

[0078] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 1 mg to about 2 mg, optionally about 1 .5 mg e.g. 1 .6 mg), and the amount of GLP-1 R agonist may be from about 3 mg to about 5 mg, optionally about 4.6 mg.

[0079] The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 1 mg to about 2 mg, optionally about 1 .5 mg {e.g. 1 .6 mg), and the amount of GLP-1 R agonist may be from about 2 mg to about 4 mg, optionally about 2.3 mg. The amount of AMYR agonist may be from about 7 mg to about 10 mg, optionally about 1 mg to about 2 mg, optionally about 1 .5 mg {e.g. 1 .6 mg), and the amount of GLP-1 R agonist may be from about 1 mg to about 2 mg, optionally about 1 .2 mg.

[0080] In any method of the invention, the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be administered by subcutaneous injection.

[0081] In any method of the invention the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered to the subject by self-administration.

[0082] In any method of the invention the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be administered about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. The AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be administered about once a week.

[0083] In any method of the invention the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be administered to the subject multiple times over a period of at least 3 months, 6 months, 9 months, 1 year, 2 years, or 5 years.

[0084] In any method of the invention the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be titrated to a final dose over a period between about 4 weeks and about 36 weeks, optionally over a period of about 5 weeks, about 17 weeks or about 21 weeks.

[0085] The dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be increased every one week, every two weeks or every four weeks until the final dose is reached; optionally wherein: (a) a first dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered for the first two weeks; (b) following (a) the dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is increased for the next two weeks; and (c) following (b) the dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is increased every four weeks for the next 16 weeks.

[0086] In any method of the invention the subject’s body weight may be reduced by >5%, optionally, the subject’s body weight may be reduced by >10%, >15%, or >20%.

[0087] The disease or disorder may be obesity. In any method of the invention, the disease or disorder may be an obesity-related condition; optionally wherein the obesity-related condition is overweight, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease, sleep apnoea and respiratory problems, hyperlipidaemia, degeneration of cartilage, osteoarthritis, or reproductive health complications of obesity or overweight such as infertility.

[0088] In any method of the invention, the disease or disorder may be a metabolic disease, optionally the metabolic disease may include diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes, pre-diabetes, insulin resistance, impaired glucose tolerance (IGI), disease states associated with elevated blood glucose levels, metabolic syndrome, or hyperglycaemia (e.g. abnormal postprandial hyperglycaemia).

[0089] In any method of the invention, the disease or disorder may be hepatic steatosis ("fatty liver"), e.g., Metabolic dysfunction associated steatohepatitis (MASH).

[0090] In any method of the invention, the method may further comprise treating, improving, and / or protecting liver and / or kidney function in the subject.

[0091] The method of treating, improving, and / or protecting liver function may comprise reducing steatohepatitis and / or fibrosis in the liver.

[0092] In any method of the invention the method of treatment may reduce the body weight of a subject, optionally wherein the subject’s reduction in body weight is fat-specific weight loss.

[0093] In any method of the invention the reduction in the body weight of the subject may be greater than the reduction in body weight with a therapeutically effective dose of a dual amylin- calcitonin receptor agonist (DACRA), a GLP-1 R agonist, a GLP-1 R / GCGR dual agonist, a GLP1 / GCG / GIP triple agonist, and / or a DACRA-GLP-1 Ra combination.

[0094] In any method of the invention the subject may experience reduced nausea as compared to a therapeutically effective dose of a dual amylin-calcitonin receptor agonist (DACRA), a GLP-1 R agonist, a GLP-1 R / GCGR dual agonist; a GLP1 / GCG / GIP triple agonist; and / or a DACRA-GLP-1 Ra combination.

[0095] In any method of the invention the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be a polypeptide, small molecule drug, antibody, antibody-drug conjugate, or aptamer; or a pharmaceutically acceptable salt thereof. The AMYR agonist, GLP-1 R agonist, and / or GCGR agonist may be a polypeptide, or a pharmaceutically acceptable salt thereof.

[0096] In any method of the invention: the AMYR may be a human AMYR and / or the AMYR may be AMY1 R, AMY2R and / or AMY3R; the GLP-1 R may be a human GLP-1 R; and / or the GCGR may be a human GCGR.

[0097] In any method of the invention the AMYR agonist may have selectivity to AMYR as compared to a calcitonin receptor (CTR).

[0098] The AMYR agonist may have at least a 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, at least 17-fold, at least 20-fold, or at least 25-fold selectivity to AMYR as compared to CTR; optionally wherein the AMYR agonist has at least a 10-fold selectivity to AMYR as compared to CTR.

[0099] In any method of the invention, the AMYR agonist may be an AMYR agonist polypeptide, or a pharmaceutically acceptable salt thereof, which comprises an amino acid sequence having at least 90% identity to pramlintide (KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY- amide, SEQ ID NO: 5).

[0100] The AMYR agonist polypeptide may be lipidated and / or the lipid may be attached to an amino acid residue in the AMYR agonist polypeptide by a linker.

[0101] The AMYR agonist polypeptide may comprise an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the amino acid sequence K[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 26).

[0102] The AMYR agonist polypeptide, or pharmaceutically acceptable salt thereof, may comprise the amino acid sequence K(yE-yE-

[0103] C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11).

[0104] In any method of the invention, the GLP-1 R agonist may activate both GLP-1 R and GCGR, and optionally the GLP-1 R agonist may be selective to GLP-1 R as compared to GCGR.

[0105] The GLP-1 R agonist may activate GLP-1 R and GCGR equally, or the GLP-1 R agonist may have at least a 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, at least 17-fold, at least 20-fold, or at least 25-fold selectivity to GLP-1 R as compared to GCGR; optionally wherein the GLP-1 R agonist has at least a 1 .5-fold selectivity to GLP-1 R as compared to GCGR.

[0106] In any method of the invention the GLP-1 R agonist polypeptide, or pharmaceutically acceptable salt thereof, may comprise an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTKRARDFVQWLLE(Aib)G-acid (SEQ ID NO: 33).

[0107] The GLP-1 R agonist polypeptide may be lipidated and / or the lipid may be attached to an amino acid residue in the GLP-1 R agonist polypeptide by a linker.

[0108] The GLP-1 R agonist polypeptide, or pharmaceutically acceptable salt thereof, may comprise the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc-yE- C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35).

[0109] In any method of the invention, the AMYR agonist may be a polypeptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence K(yE-yE- C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11) in an amount of about 1.5 mg {e.g. 1.6 mg), about 4.5 mg, about 6 mg, or about 9 mg; and the GLP-1 R agonist may be a polypeptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc- O2Oc-yE-C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35) in an amount of about 0.15 mg, about 0.3 mg, about 0.6 mg, about 1.2 mg, about 2.3 mg, about 4.6 mg, about 7 mg, or about 9.4 mg.

[0110] The subject may have obesity or an obesity-related condition.

[0111] The invention also provides a method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0112] The invention also provides a cosmetic method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist. The invention also provides a method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0113] The invention also provides a cosmetic method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0114] The invention also provides a method of improving glycemic and / or metabolic control in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0115] The method of improving glycemic and / or metabolic control in a subject may comprise increasing insulin secretion, delaying gastric emptying, increasing mitochondria function, inhibiting de novo lipogenesis, decreasing HbAlc, enhancing fatty oxidation, decreasing hepatic mitochondrial oxidative stress, decreasing steatosis, decreasing fibrosis, decreasing glycogen synthesis, increasing gluconeogenesis, reducing or reversing fibrosis (e.g., liver fibrosis), reducing steatohepatitis, and / or reducing risk of death due to cirrhosis, hepatocellular carcinoma, and / or cardiorenal disease in the subject.

[0116] In any method of the invention, the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, may be administered simultaneously.

[0117] In any method of the invention, the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, may be administered sequentially.

[0118] In any method of the invention, the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, may be formulated in a dual-chamber device.

[0119] The invention also provides a method of treating and / or preventing obesity or an obesity- related condition in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0120] The invention also provides a method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist. The invention also provides a method of reducing the body weight of a subject, in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0121] The invention also provides a cosmetic method of reducing the body weight of a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0122] The invention also provides an AMYR agonist and a GLP-1 R agonist for use in a method of treating and / or preventing obesity or an obesity-related condition in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0123] The invention also provides an AMYR agonist and a GLP-1 R agonist for use in a method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0124] The invention also provides an AMYR agonist and a GLP-1 R agonist for use in a method of reducing body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

[0125] The subject may have a disease or disorder selected from obesity, an obesity-related condition, and metabolic disease.

[0126] The invention also provides an article of manufacture comprising (a) an AMYR agonist at a dose of about 1 mg to about 15 mg; and (b) a GLP-1 R agonist at a dose of about 0.1 to about 10 mg.

[0127] The invention also provides a kit comprising (a) an AMYR agonist, (b) a GLP-1 R agonist, and (c) instructions for use of the same for treating or preventing obesity or an obesity- related condition at a dose of about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist.

[0128] The kit may comprise a dual-chamber device.

[0129] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows that an AMYR agonist demonstrated dose dependent weight loss following a single dose of either 0.3 mg, 0.9 mg, 1.5 mg, 2.7 mg, or 4.2 mg AMYR agonist in a Phase I trial of healthy subjects who are overweight or obese.

[0130] Figure 2 shows that administration of the AMYR agonist demonstrated a good tolerability profile in the Phase I trial, in which no safety concerns were identified at single doses up to 4.2 mg.

[0131] Figure 3 shows that sustained weight loss was achieved following (A) six weeks of repeat dosing (once weekly) of 2.7 mg AMYR agonist (s.c.) and (B) twelve weeks of repeat dosing (once weekly) gradually titrated from 1.5 mg to 9 mg AMYR agonist (s.c.) in preliminary data from a Phase lb trial of healthy subjects who are overweight or obese.

[0132] Figure 4 shows that good tolerability was achieved (A) on repeat dosing of 2.7 mg AMYR agonist (s.c.) and (B) on repeat dosing of AMYR agonist (s.c.) gradually titrated from 1 .5 mg to 9 mg in preliminary data from the Phase lb trial.

[0133] Figure 5 shows that a GLP-1 R / GCGR dual agonist treatment led to a dose-dependent decrease in body weight with improved hepatic lipid and circulating insulin levels in a pre- clinical mouse model.

[0134] Figure 6 shows a Phase I single ascending dose (SAD) study design for a GLP-1 R / GCGR dual agonist treatment in humans.

[0135] Figure 7 shows a plasma concentration-time profile following single subcutaneous (SC) or intravenous (IV) administration of a GLP-1 R / GCGR dual agonist in a Phase I SAD study.

[0136] Figure 8 shows an exposure response for decreased appetite, nausea, and vomiting following administration of a GLP-1 R / GCGR dual agonist in a Phase I SAD study.

[0137] Figure 9 shows a Phase l / ll repeat dose study design for a GLP-1 R / GCGR dual agonist treatment in humans.

[0138] Figure 10 shows that sustained weight loss was achieved following repeat dosing (once weekly) of a GLP-1 R / GCGR dual agonist (s.c.) in preliminary data from a Phase l / ll trial of healthy subjects who are overweight or obese. Figure 11 shows that sustained weight loss (approximately 6.8%; 6.6 % placebo-corrected) was achieved following 16 weeks of multiple-once weekly ascending doses of GLP- 1 R / GCGR dual agonist (sc) for 16 weeks treatment titrated up to a (non-final) dose of 7 mg in preliminary data from a Phase l / ll trial of healthy subjects who are overweight or obese.

[0139] Figure 12 shows: A Graph showing Day 20 % body weight change for DIO rats treated SC once daily with Vehicle, long-acting AMYR agonist (LAA) (10 nmol / kg), GLP-1 / GCG agonist (GLP-1 / GCG) (5.4 nmol / kg) or combination of both (10 and 5.4 nmol / kg respectively), with an n=8 / group. Data reported as mean ± standard error of the mean (SEM); data analysis performed using GraphPad Prism - statistical analysis performed using One-way ANOVA with Tukey ad hoc analysis. (*p<0.05, **p<0.01 , ***0<0.001 , ****p<0.0001 ). B Graph showing Day 26 change in lean mass for DIO rats treated with LAA, GLP-1 / GCG or combination of both. C Graph showing Day 26 change in fat mass for DIO rats treated with LAA, GLP-1 / GCG or combination of both.

[0140] Figure 13 shows Day 26 body composition data for DIO rats treated with long-acting LAA, GLP-1 / GCG or combination of both, with an n=8 / group. A Body composition measured by nuclear magnetic resonance (NMR) - Mean % fat and lean mass reflected as percentage of overall body weight and B Day 26 body weight reflected as % of non-obese control as also shown with data from study day 26.

[0141] Figure 14 shows percent change in body weight normalized to Vehicle. A Rats were dosed once daily SC for 28 days with Vehicle, GLP-1 / GCG (1.5 nmol / kg), LAA (7.5 nmol / kg) or a combination of GLP-1 / GCG and LAA (1.5 and 7.5 nmol / kg, respectively) with an n=6 / group. B Rats were dosed once daily SC for 28 days with Vehicle, GLP-1 / GCG (5 nmol / kg), LAA (7.5 nmol / kg) or a combination of GLP-1 / GCG and LAA (5 nmol / kg and 7.5 nmol / kg, respectively) with an n=6 / group. Data reported as mean ± standard error of the mean (SEM); data analysis performed using GraphPad Prism - statistical analysis performed using One-way ANOVA with Tukey ad hoc analysis (*p<0.05, **p<0.01 , ****p<0.0001 )

[0142] Figure 15 shows percent change in body weight normalized to Vehicle. Rats were dosed every other day (Q2D) SC for 19 days with Vehicle, GLP1 -Fc (0.1 or 1 mg / kg), Fc-LAA (0.1 or 2 mg / kg) or a combination of GLP1 -Fc and Fc-LAA (0.1+0.1 mg / kg, 0.1+2 mg / kg, 1+0.1 mg / kg or 1 +2 mg / kg, respectively) with an n=7 / group. Data reported as mean ± standard error of the mean (SEM); data analysis performed using GraphPad Prism. Figure 16 shows an AMYR agonist adjunct therapy while maintaining an existing GLP-1 therapy. Rats were dosed SC for 15 days with Vehicle (n=16) or GLP-1 RA agonist (GLP- 1 RA) (n=32) (5 nmol / kg) once-daily (QD). Beginning on day 16, rats initially treated with Vehicle either continued with Vehicle (n=8) or were switched to LAA (7.5 nmol / kg QD, n=8) administration. Rats initially receiving GLP-1 RA treatment either continued with GLP-1 RA, were switched to LAA (7.5 nmol / kg QD), were switched to Vehicle, or continued with GLP- 1 RA with addition of LAA treatment (7.5 nmol / kg QD) for duration of study (day 30), with n=8 / group. A Graph showing % Day 0 body weight change over time. B Graph showing % body weight change normalised to Vehicle over time. C Change in body weight at the end of the study. D Food intake at the end of the study.

[0143] Figure 17 shows a combination of an AMYR agonist with a GLP / GIP agonist. DIO rats were dosed once daily SC for 28 days (n=8 / group) with either Vehicle, LAA (10 nmol / kg), GLP / GIP dual agonist (2, 10 or 30 nmol / kg), or a combination of LAA (10 nmol / kg for all groups) and GLP / GIP dual agonist (2, 10 or 30 nmol / kg). Control rats were dosed SC with Vehicle. Graphs showing: A Body weight during study over time. B Baseline-corrected body weight change (%). C Body composition data represented as change in fat mass (g). D Body composition data represented as change in lean mass (g). E Body composition data represented as percentage fat mass (%) of total body weight at both week -1 (baseline) or week 4 (end of study). F Body composition data represented as percentage lean mass (%) of total body weight at both week -1 (baseline) or week 4 (end of study). Statistical analysis performed using two-way RM ANOVA with Dunnett analysis (***p<0.001 , ****p<0.0001 ).

[0144] Figure 18 shows that a SARA has improved body weight reduction as compared to a DACRA. DIO rats were dosed QD for 4 weeks with either Vehicle, AMYR agonist (2.5 or 10 nmol / kg), or DACRA (1 , 3, 10 or 20 nmol / kg). A Graph showing body weight change (%) normalized to vehicle over time. B. Body composition change (fat mass (L) and fat-free mass (R), g) at end of study. C Total body weight change (%) normalized to vehicle and corresponding proportion of fat mass loss and fat-free mass-loss at end of study. D Emax model showing relationship between calcitonin receptor engagement with lean-mass change (g, corrected for control) (L) and amylin receptor engagement with fat-mass change (g, corrected for control) (R).

[0145] Figure 19 shows aversion data for a SARA as compared to a DACRA. A Graph showing result of saccharin conditioned tasted aversion dose response experiment for AZD6234 and a DACRA. Data reported as mean ± standard error of the mean (SEM); data analysis performed using GraphPad Prism - statistical analysis performed using One-way ANOVA with Tukey ad hoc analysis. (*p<0.05, **p<0.01 , ***0<0.001 , ****p<0.0001 vs. Vehicle). B Emax model showing relationship between calcitonin receptor engagement (L) or amylin receptor engagement (R) (fold in vitro potency normalised for fraction unbound) with saccharine aversion in lean rats.

[0146] Figures 20-23 show exemplary titration schedules for a Phase lib study evaluating the coadministration of an AMYR agonist and a GLP-1 / GCG dual agonist in subjects living with obesity or overweight with co-morbidity.

[0147] DETAILED DESCRIPTION

[0148] Definitions

[0149] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure.

[0150] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0151] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognise. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0152] The headings provided herein are not limitations of the various aspects or embodiments of this disclosure.

[0153] As used herein, the term "capable of' when used with a verb, encompasses, or means the action of the corresponding verb. For example, "capable of activating" also means activates, "capable of agonising" also means agonises, "capable of binding" also means binds and "capable of specifically activating..." also means specifically activates.

[0154] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0155] As used herein, the articles "a" and “an” may refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting.

[0156] “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used.

[0157] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention.

[0158] As used herein the term "consisting essentially of" refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e., inactive, or non- immunogenic ingredients).

[0159] Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and / or “consisting essentially of” such features, of the corresponding embodiments "consisting of" such features.

[0160] Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation, or the single letter abbreviation. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation.

[0161] The term “protein", as used herein, includes proteins, polypeptides, and peptides. As used herein, the term “amino acid sequence” is synonymous with the term “polypeptide” and / or the term “protein”. In some instances, the term “amino acid sequence” is synonymous with the term “peptide”. The terms "protein" and "polypeptide" are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three-letter codes for amino acid residues may be used. The 3-letter code for amino acids as defined in conformity with the IUPACIUB Joint Commission on Biochemical Nomenclature (JCBN). It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code.

[0162] A “fragment” of a polypeptide typically comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% or more of the original polypeptide.

[0163] A “variant” amino acid sequence has substantial homology or substantial similarity to a reference amino acid sequence (or a fragment thereof). A amino acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate amino acid insertions or deletions) with the other amino acid (or its complementary strand), there is nucleotide sequence identity in at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more % of the amino acids. Methods for homology determination of amino acid sequences are known in the art. Typically, a variant polypeptide of the invention retains the function or activity of the full-length polypeptide.

[0164] A variant polypeptide may be one in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or nonconserved positions. Variants of amylin receptor agonists and / or GLP-1 R agonists disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure / property-activity relationships [see for example, Wold, et al. Multivariate data analysis in chemistry. Chemometrics-Mathematics and Statistics in Chemistry (Ed.: B. Kowalski); D. Reidel Publishing Company, Dordrecht, Holland, 1984 (ISBN 90-277-1846-6] quantitative activity-property relationships of DNMTs can be derived using well-known mathematical techniques, such as statistical regression, pattern recognition and classification [see for example Norman et al. Applied Regression Analysis. Wiley- Interscience; 3rd edition (April 1998) ISBN: 0471170828; Kandel, Abraham et al. Computer- Assisted Reasoning in Cluster Analysis. Prentice Hall PTR, (May 11 , 1995), ISBN: 0133418847; Krzanowski, Wojtek. Principles of Multivariate Analysis: A User's Perspective (Oxford Statistical Science Series, No 22 (Paper)). Oxford University Press; (December 2000), ISBN: 0198507089; Witten, Ian H. et al Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations. Morgan Kaufmann; (October 11 , 1999), ISBN:1558605525; Denison David G. T. (Editor) et al Bayesian Methods for Nonlinear Classification and Regression (Wiley Series in Probability and Statistics). John Wiley & Sons; (July 2002), ISBN: 0471490369; Ghose, Arup K. et al. Combinatorial Library Design and Evaluation Principles, Software, Tools, and Applications in Drug Discovery. ISBN: 0- 8247-0487-8]. The properties of a DNMT can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of the DNMT sequence, functional and three-dimensional structures and these properties can be considered individually and in combination.

[0165] Amino acid residues at non-conserved positions may be substituted with conservative or non-conservative residues. In particular, conservative amino acid replacements are contemplated. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, or histidine), acidic side chains (e.g., aspartic acid or glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, or cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, or tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, or histidine). Thus, if an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the amino acid substitution is considered to be conservative. The inclusion of conservatively modified variants in a DNMT of the invention does not exclude other forms of variant, for example polymorphic variants, interspecies homologs, and alleles.

[0166] “Non-conservative amino acid substitutions” include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, lie, Rhe or Vai), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Vai, His, lie or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly).

[0167] As used herein, the terms “polynucleotides”, "nucleic acid" and "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid, or an analogue thereof. The nucleic acid can be either singlestranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other examples of nucleic acid molecules are RNA, including siRNA, shRNA, and antisense oligonucleotides. Typically, the methods of the invention relate to the production of oligonucleotides (short DNA or RNA sequences typically less than about 300 bases in length).

[0168] Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation. The polynucleotides of the present invention may be prepared by any means known in the art. For example, large amounts of the polynucleotides may be produced by replication in a suitable host cell. The natural or synthetic DNA fragments coding for a desired fragment will be incorporated into recombinant nucleic acid constructs, typically DNA constructs, capable of introduction into and replication in a prokaryotic or eukaryotic cell. Usually, the DNA constructs will be suitable for autonomous replication in a unicellular host, such as yeast or bacteria, but may also be intended for introduction to and integration within the genome of a cultured insect, mammalian, plant, or other eukaryotic cell lines.

[0169] The polynucleotides of the present invention may also be produced by chemical synthesis, e.g., by the phosphoramidite method or the tri-ester method and may be performed on commercial automated oligonucleotide synthesisers. A double-stranded fragment may be obtained from the single stranded product of chemical synthesis either by synthesising the complementary strand and annealing the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.

[0170] In view of the degeneracy of the genetic code, considerable sequence variation is possible among the polynucleotides of the present invention. One of ordinary skill in the art will appreciate that flexibility exists when determining a degenerate codon, representative of all possible codons encoding each amino acid. For example, some polynucleotides encompassed by the degenerate sequence may encode variant amino acid sequences, but one of ordinary skill in the art can easily identify such variant sequences by reference to the amino acid sequences of the present invention.

[0171] A “variant” nucleic acid sequence has substantial homology or substantial similarity to a reference nucleic acid sequence (or a fragment thereof). A nucleic acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more % of the nucleotide bases. Methods for homology determination of nucleic acid sequences are known in the art.

[0172] Alternatively, a “variant” nucleic acid sequence is substantially homologous with (or substantially identical to) a reference sequence (or a fragment thereof) if the “variant” and the reference sequence they are capable of hybridising under stringent (e.g., highly stringent) hybridisation conditions. Nucleic acid sequence hybridisation will be affected by such conditions as salt concentration (e.g. NaCI), temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridising nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions are preferably employed, and generally include temperatures in excess of 30°C, typically in excess of 37°C and preferably in excess of 45°C. Stringent salt conditions will ordinarily be less than 1000 mM, typically less than 500 mM, and preferably less than 200 mM. The pH is typically between 7.0 and 8.3. The combination of parameters is much more important than any single parameter.

[0173] Methods of determining nucleic acid percentage sequence identity are known in the art. By way of example, when assessing nucleic acid sequence identity, a sequence having a defined number of contiguous nucleotides may be aligned with a nucleic acid sequence (having the same number of contiguous nucleotides) from the corresponding portion of a nucleic acid sequence of the present invention. Tools known in the art for determining nucleic acid percentage sequence identity include Nucleotide BLAST (as described below).

[0174] One of ordinary skill in the art appreciates that different species exhibit “preferential codon usage”. As used herein, the term “preferential codon usage” refers to codons that are most frequently used in cells of a certain species, thus favouring one or a few representatives of the possible codons encoding each amino acid. For example, the amino acid threonine (Thr) may be encoded by ACA, ACC, ACG, or ACT, but in mammalian host cells ACC is the most commonly used codon; in other species, different codons may be preferential. Preferential codons for a particular host cell species can be introduced into the polynucleotides of the present invention by a variety of methods known in the art. Introduction of preferential codon sequences into recombinant DNA can, for example, enhance production of the protein by making protein translation more efficient within a particular cell type or species.

[0175] A “fragment” of a polynucleotide of interest comprises a series of consecutive nucleotides from the sequence of said full-length polynucleotide. By way of example, a “fragment” of a polynucleotide of interest may comprise (or consist of) at least 30 consecutive nucleotides from the sequence of said polynucleotide (e.g., at least 35, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800 850, 900, 950 or 1000 consecutive nucleic acid residues of said polynucleotide). Typically, a fragment as defined herein retains the same function as the full-length polynucleotide. When applied to a nucleic acid sequence, the term “isolated” denotes that the polynucleotide sequence has been removed from its natural genetic milieu and is thus free of other extraneous or unwanted coding sequences (but may include naturally occurring 5' and 3' untranslated regions such as promoters and terminators) and is in a form suitable for use within genetically engineered protein production systems. When applied to a protein, such as an amylin receptor agonist or GLP-1 R agonist amino acid sequence, the term “isolated” denotes that the protein has been removed from its natural cellular milieu and is thus free of other extraneous or unwanted coding proteins and / or genetic material and is in a form suitable for use within genetically engineered protein production systems. Such isolated molecules are those that are separated from their natural environment. In the context of the invention, an isolated protein nucleic acid is one which has been separated from one or more of the reagents used in its production according to methods of the invention; one which has been separated from the other proteins and / or nucleic acid sequences synthesised in the same iteration of the method and / or one which has been separated from the one or more units on which it was synthesised.

[0176] The terms "decrease", "reduce", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, 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%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e., abrogation) as compared to a reference level.

[0177] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1 .5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level.

[0178] As used herein, the term “sample” refers to a sample of biological materials (cells, tissue, fluid, etc.) obtained from an individual. The sample may be any suitable biological material, for example blood, plasma, saliva, serum, sputum, urine, cerebral spinal fluid, cells, a cellular extract, a tissue sample, a tissue biopsy, a stool sample and the like. Typically, the sample is blood sample. The precise biological sample that is taken from the individual may vary, but the sampling preferably is minimally invasive and is easily performed by conventional techniques. The sample may be a whole blood sample, a purified peripheral blood leukocyte sample or a cell type sorted leukocyte sample, such as a sample of the individual’s neutrophils.

[0179] The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognised pharmacopeia.

[0180] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. All documents cited herein are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.

[0181] Treatment and Dosage Regimens

[0182] The invention relates to therapies comprising an amylin receptor (AMYR) agonist and a GLP-1 receptor (GLP-1 R) agonist. An AMYR agonist is a molecule that is capable of binding to, and inducing signalling by, one or more receptors or receptor complexes regarded as physiological receptors for human amylin. A GLP-1 R agonist is a molecule that is capable of binding to, and inducing signalling by, one or more receptors or receptor complexes regarded as physiological receptors for human GLP-1 R. Suitable AMYR agonists and GLP-1 R agonists are described in more detail below.

[0183] Treatment methods

[0184] The present invention encompasses therapies which involve administering (a) between about 1 mg to about 15 mg of an AMYR agonist and (b) about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) to a subject for preventing, treating, or ameliorating symptoms associated with a disease, disorder, or infection. In any method, therapeutic indication, use or other disclosure herein, the subject may be any animal, typically a mammal, preferably a human.

[0185] Accordingly, the invention provides a method of treating and / or preventing a disease or disorder in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof.

[0186] The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in therapy, for example in a method of treating and / or preventing a disease or disorder, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0187] Also provided is the use of an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) in the manufacture of a medicament for treating and / or preventing a disease or disorder in a subject, wherein the medicament comprises about 1 mg to about 15 mg of the AMYR agonist and about 0.1 mg to about 10 mg of the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist).

[0188] The use or method may comprise administering a therapeutically effective schedule that has less frequent doses of the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) than the therapeutically effective dosing schedule of a different anti-obesity drug, such as pramlintide, cotadutide, or a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri- sema”).

[0189] The invention further provides (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt for use in the treatment and / or prevention of obesity, metabolic diseases (such as diabetes, e.g. type 1 or type 2 diabetes), and / or obesity-related conditions. The invention also provides a method of treating and / or preventing obesity, metabolic diseases (such as diabetes, e.g. type 1 or type 2 diabetes), and / or obesity-related conditions in a subject, the method comprises administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, in the subject.

[0190] In preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be used in a method of treating and / or preventing obesity. Said method may comprise administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject.

[0191] In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be used in a method of treating and / or preventing an obesity-related condition in a subject. Said method may comprise administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the obesity-related condition is overweight, morbid obesity, obesity prior to surgery, obesity- linked inflammation, obesity-linked gallbladder disease, sleep apnoea and respiratory problems, hyperlipidaemia, degeneration of cartilage, osteoarthritis, or reproductive health complications of obesity or overweight such as infertility in a subject. In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be used in a method of treating and / or preventing a metabolic disease. Said method may comprise administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Said metabolic disease may be diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes, pre-diabetes, insulin resistance, impaired glucose tolerance (IGI), disease states associated with elevated blood glucose levels, metabolic disease including metabolic syndrome, or hyperglycaemia, e.g. abnormal postprandial hyperglycaemia. In preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) of the invention are used for the treatment of type 1 diabetes or type 2 diabetes. In particularly preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) of the invention are used for the treatment of type 2 diabetes.

[0192] In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be used in a method of treating and / or preventing metabolic dysfunction associated steatohepatitis (MASH). Said method may comprise administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject.

[0193] The treatment and / or prevention of a disease or disorder using (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, may further comprise treating, improving, and / or protecting liver and / or kidney function in the subject. Treating, improving, and / or protecting liver function may comprise reducing steatohepatitis and / or fibrosis in the liver.

[0194] Also provided is a method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Said method may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or a metabolic disease. Alternatively, said method may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons.

[0195] Thus, the invention also provides a cosmetic use of an AMYR agonist and a GLP-1 R agonist to inhibit or reduce weight gain, promote weight loss, reduce food intake, increase satiety, and / or reduce excess body weight in a subject, comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof.

[0196] In particular, the invention provides a method of reducing the body weight of a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. In the context of the invention, “reducing the body weight of a subject” can be measured by any suitable means, and may be determined by a reduction in the absolute amount of body weight in a subject e.g., in grams) from baseline, and / or a percent change in body weight from baseline. Treatment according to the present invention may reduce the body weight of a subject by > 5% from baseline, > 6% from baseline, > 7% from baseline^ > 8% from baseline, > 9% from baseline, > 10% from baseline^ > 15% from baseline^ > 20% from baseline^ > 25% from baseline, > 30% from baseline, or more. Thus, the subject may have a weight reduction of > 5% from baseline following treatment. The subject may have a weight reduction of > 10% from baseline following treatment. The subject may have a weight reduction of > 15% from baseline following treatment. The subject may have a weight reduction of > 20% from baseline following treatment.

[0197] The reduction in body weight may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons. Thus, the invention provides a cosmetic method of reducing the body weight of a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides a cosmetic use of an AMYR agonist and a GLP-1 R agonist, or pharmaceutically acceptable salts thereof, of the invention for reducing the body weight of a subject, wherein said use comprises administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject.

[0198] The reduction in body weight may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or suffers from a metabolic disease.

[0199] In a method of the invention, the reduction in the body weight of the subject is typically greater than the reduction in body weight as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP- 1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Typically, said reduction is compared with an equivalent or corresponding dose of the different anti-obesity drug, such as common clinically used doses thereof. Treatment according to the present invention may reduce the body weight of a subject by > 5%, > 6%, > 7%s> 8%, > 9%, > 10%3> 15%s> 20%s> 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Thus, the subject may have a weight reduction greater than > 5% compared to a different anti-obesity drug following treatment. The subject may have a weight reduction of > 10% compared to a different anti-obesity drug following treatment. The subject may have a weight reduction of > 15% compared to a different antiobesity drug following treatment. The subject may have a weight reduction of > 20% compared to a different anti-obesity drug following treatment.

[0200] There is also provided a method of reducing fat mass-specific body weight in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. In the context of the invention, “reducing fat massspecific body weight” (also referred to as “reducing fat-specific weight) may comprise reducing the absolute amount of fat-specific body weight in a subject {e.g., in grams), and / or reducing the proportion of the fat-specific body weight component of total body weight {e.g., as a percentage of total body weight). A method of the invention may preferentially reduce fat-mass specific body weight as compared to lean mass-specific {e.g. muscle) body weight {e.g., preserving lean-mass specific body weight while reducing overall body weight). For the avoidance of doubt, any and all reference herein to “reducing the body weight of a subject” applies equally and without reservation to “reducing fat mass-specific body weight of a subject”, unless expressly stated to the contrary.

[0201] In a method of the invention, the reduction in the fat-mass specific body weight of the subject is typically greater than the reduction in fat-mass specific body weight as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Typically, said reduction is compared with an equivalent or corresponding dose of the different anti-obesity drug, such as common clinically used doses thereof. Treatment according to the present invention may reduce the fat-mass specific body weight of a subject by > 5%, > 6%, > 7%s> 8%, > 9%, > 10%3> 15%s > 20%s> 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Thus, the subject may have a fat-mass specific weight reduction greater than > 5% compared to a different anti-obesity drug following treatment. The subject may have a fat-mass specific weight reduction of > 10% compared to a different anti-obesity drug following treatment. The subject may have a fat-mass specific weight reduction of > 15% compared to a different antiobesity drug following treatment. The subject may have a fat-mass specific weight reduction of > 20% compared to a different anti-obesity drug following treatment.

[0202] The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in a method of reducing fat mass-specific body weight in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. Said method may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or a metabolic disease. Alternatively, said method may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons.

[0203] Thus, the invention also provides a cosmetic use of (a) about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof to reduce fat-mass specific body weight in a subject.

[0204] Also provided herein is a method of treating, improving, or protecting liver and / or kidney function in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Also provided herein is a method of improving glycemic and / or metabolic control in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Improving glycemic and / or metabolic control may comprise one or more of: increasing insulin secretion, delaying gastric emptying, increasing mitochondria function, inhibiting de novo lipogenesis, decreasing HbAlc, enhancing fatty oxidation, decreasing hepatic mitochondrial oxidative stress, decreasing steatosis, decreases fibrosis, decreasing glycogen synthesis, increasing gluconeogenesis, improving glycemic control, reducing or reversing fibrosis e.g., liver fibrosis), reducing steatohepatitis, and / or reducing risk of death due to cirrhosis, hepatocellular carcinoma, and / or cardiorenal disease in a subject in need thereof.

[0205] There is also provided a method of improving glucose homeostasis, p-cell function, and / or insulin sensitivity in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. An improvement in glucose homeostasis, p-cell function, and / or insulin sensitivity may be measured by change from baseline in the updated homeostatic model assessment (HOMA) scores (HOMA-IR, HOMA-B, and HOMA-S) over time. HOMA is well-known in the art, such as described in Levy et al. (Diabetes Care (1998) 21 (12):2191 -2192), which is herein incorporated by reference in its entirety. An improvement in glucose homeostasis, p-cell function, and / or insulin sensitivity may be measured by change from baseline in HbAlc, fasting serum glucose, fasting serum insulin, fasting serum c-peptide, plasma proinsulin levels over time, proinsulin / c-peptide ratio over time and / or adiponectin levels over time. Also provided is a method of promoting end-organ protection e.g., cardiovascular, renal and / or liver) in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof, to the subject. End-organ protection may be measured by assessing change from baseline on cardiovascular endpoints, such as ApoB / ApoA1 and / or high sensitivity Troponin T (hs Troponin T) or Tropinin I (hs Troponin I). Alternatively or in addition, end-organ protection can be measured by assessing change on renal endpoints, such as estimated glomerular filtration rate (eGFR, calculated using creatinine and cystatin C), UACR (urine albumin and creatinine ratio), and / or renin. Further alternatively or in addition, end-organ protection can be measured by: assessing change from baseline on liver endpoints, such as pro-peptide of type III collagen (ProC3), alanine transaminase (ALT), aspartate aminotransferase (AST), FIB-4 (which is a standard clinical index for measuring liver fibrosis, calculated using AST, ALT, age, and / or platelet), and / or an enhanced liver fibrosis (ELF) test (which is a standard clinical index for measuring cirrhosis, calculated using hyaluronic acid (HA), procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1 )); biomarkers of chronic inflammation (e.g. hs CRP, hs IL-6), the sarcopenia index (based on creatinine / cystatin C); and / or thyroid function (e.g. based on TSH, total T3 or fT4). Said method may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or a metabolic disease. Alternatively, said method may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons.

[0206] Also provided is a method of improving weight-loss quality in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Weight loss quality may be measured by change from baseline in waist circumference, hip circumference and / or waist:hip ratio. Alternatively, or in addition, weight loss quality may be measured by change from baseline to on metabolic / adipokine health, as assessed by levels of adiponectin and / or leptin, lipid profile (such as levels of triglycerides (TG), total cholesterol, non-esterified fatty acids (NEFA), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and / or very low-density lipoprotein (VLDL)), and / or change from baseline in systemic inflammation (such as levels of C-reactive protein (CRP), e.g. a high-sensitivity CRP test (hsCRP), and / or interleukin-6 (IL-6), e.g. a high- sensitivity IL-6 test (hslL6)). Said method may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or a metabolic disease. Alternatively, said method may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons.

[0207] Also provided is a method of improving the lipid profile of a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Lipid profile may be measured by a change in based line in total cholesterol, HDL-cholesterol, LDL-cholesterol, non-HDL-cholesterol, VLDL-cholesterol, triglycerides and / or non-esterified fatty acids. Said method may be therapeutic, e.g. when the subject is obese, suffers from an obesity-related condition and / or a metabolic disease. Alternatively, said method may be cosmetic (non-therapeutic), e.g. when the patient wishes to lose weight for aesthetic reasons.

[0208] Also provided is a method of improving physical function and / or mood or cognitive function in a subject, the method comprising administering (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. The invention also provides an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in such a method, the method comprising administering (a) between about 1 mg to about 15 mg of an AM YR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof, to the subject. Improving physical function in a subject may be assessed by change from baseline in IWQoL-Lite CT Physical Function score, SF-36 v2 Physical functioning score, IWQoL-Lite CT Total Score, SF-36 v2 physical component, mental component scores, Patient Global Impression (PGI) of Limitation in Physical Function, and / or FACIT-GP5 scores. Mood and / or cognitive function may be assessed by change in the Columbia-suicide severity rating scale (C-SSRS) and / or Patient Health Questionnaire (PHQ-9). Treatment according to the invention may also result in a reduction in alcohol consumption (e.g. as measured by change in phophatidylethanol value over time).

[0209] Treatment according to the present invention may result in a good immunogenicity profile. Immunogenicity of the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist) may be assessed using any appropriate means, which are within the routine practice of one of ordinary skill in the art, e.g. using a bioanalytical assay on a blood sample from a subject. Non-limiting examples of parameters which may be used to assess tolerance include measuring the prevalence, incidence and / or titres of anti-drug antibodies (ADAs). Prevalence, incidence and / or titres in ADAs may be assessed using any suitable means. Treatment according to the present invention may increase the prevalence, incidence and / or titres of ADAs of a subject by < 5%, < 6 %, < 7%, < 8%, < 9%, < 10%, < 15%, < 20%, < 25%, < 50%, < 75%, < 100%, < 200%, or < 400% from baseline.

[0210] Also provided herein is (a) about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for use in the manufacture of a medicament. Said medicament may be for use in the treatment and / or prevention of any disease or disorder, or for any clinical purpose (e.g. (e.g. improving glycemic and / or metabolic control, improving glucose homeostasis, p-cell function, and / or insulin sensitivity, or promoting endorgan protection) as described herein.

[0211] The subject may tolerate the combination of the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) well. Tolerance of the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be assessed using any appropriate means, which are within the routine practice of one of ordinary skill in the art. Non-limiting examples of parameters which may be used to assess tolerance include nausea and vomiting. A subject who tolerates the combination of the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) well may exhibit reduced nausea and / or vomiting (e.g. reduced incidence of nausea and / or vomiting). Alternatively or in addition, tolerance to the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) may be assessed by change in growth / differentiation factor 15 (GDF15) from baseline ( / .e. reduced GDF15). Change in GDF15 may be assessed using any suitable sample from the subject, as described herein, e.g. a blood sample. The subject may have increased tolerability to the combination of the AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) (such as reduced nausea and / or vomiting) as compared with their tolerance to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Typically, said tolerability is compared with an equivalent or corresponding dose of the different anti-obesity drug, such as common clinically used doses thereof. Treatment according to the present invention may reduce the incidence of nausea of a subject by > 5%, > 6%, > 7%s> 8%, > 9%, > 10%3> 15%s> 20%s> 25%, > 30%, or more, as compared to a therapeutically effective dose of a different antiobesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Treatment according to the present invention may reduce the incidence of vomiting of a subject by > 5%, > 6%, > 7%s> 8%, > 9%, > 10%3> 15%s> 20%s> 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin- calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Treatment according to the present invention may reduce the levels of GDF-15 of a subject by > 5%, > 6%, > 7%, > 8%, > 9%, > 10%, > 15%, > 20%, > 25%, > 30%, or more, from baseline.

[0212] Treatment according to the present invention may reduce the need for the subject to be administered an anti-emetic medication as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist (e.g., semaglutide); a GLP- 1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). Suitable anti-emetic medications will be familiar to a person skilled in the art. Thus, treatment according to the present invention may allow the subject to be administered a reduced dose of an anti-emetic medication as compared to a therapeutically effective dose of a different anti-obesity drug. Alternatively or in addition, treatment according to the present invention may allow the subject to be administered an anti-emetic medication at a reduced dosing frequency as compared to a therapeutically effective dose of a different anti-obesity drug. Treatment according to the present invention may eliminate the need for a subject to be administered an anti-emetic medication, i.e., the subject is not administered an anti-emetic medication.

[0213] Treatment according to the present invention may result in an equivalent reduction in body weight as compared to a therapeutically effective dose of a different anti-obesity drug, such a dual amylin-calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”), but with a reduction in side effects as compared to the different anti-obesity drug. Typically, said reduction is compared with an equivalent or corresponding dose of the different anti-obesity drug, such as common clinically used doses thereof. Side-effects (or adverse effects) may be assessed using any appropriate means, which are within the routine practice of one of ordinary skill in the art. Non-limiting examples of parameters which may be used to assess a reduction in sideeffects include incidence and / or severity of nausea, vomiting, (reduction in) appetite, and / or headache, as discussed herein. Thus, treatment according to the present invention may result in a reduction in the incidence of nausea in a subject by > 5%, > 6%, > 7%, > 8%, > 9%, > 10%, > 15%, > 20%, > 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug. Thus, treatment according to the present invention may result in a reduction in the incidence of vomiting in a subject by > 5%, > 6%, > 7%, > 8%, > 9%, > 10%, > 15%, > 20%, > 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug, Treatment according to the present invention may result in a reduction in the incidence of reduced appetite of a subject by > 5%, > 6%, > 7%, > 8%, > 9%, > 10%, > 15%, > 20%, > 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug. Treatment according to the present invention may result in a reduction in the incidence of headache in a subject by > 5%, > 6%, > 7%, > 8%, > 9%, > 10%, > 15%, > 20%, > 25%, > 30%, or more, as compared to a therapeutically effective dose of a different anti-obesity drug.

[0214] The route of administration of an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutical compositions thereof, can be, for example, oral, parenteral, by inhalation or topical. In preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered by parenteral administration to a subject or patient. The term “parenteral” as used herein includes, e.g., intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration. In preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered by injection, such as by intravenous, subcutaneous or intramuscular injection, to a subject or patient. In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered orally. In particularly preferred embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dualagonist) or pharmaceutical compositions thereof are administered by subcutaneous injection. Oral administration, or administration by injection, such as by subcutaneous injection, offers the advantage of better comfort for the subject or patient and the opportunity to administer to a subject or patient outside of a hospital setting. In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered by self-administration.

[0215] In some embodiments the subject or patient is a mammal, in particular a human.

[0216] The subject to be treated may have diabetes (e.g. type 1 or type 2 diabetes). Alternatively, the subject may not have type 1 or type 2 diabetes. Alternatively or in addition, the subject may not have obesity induced by other endocrine disorders, such as insulinoma, Cushing’s syndrome or Prader-Willi syndrome. Further alternatively or in addition, the subject may not have previous or planned (within the treatment course) bariatric surgery or fitting of a weight loss device (e.g. a gastric balloon or duodenal barrier). Further alternatively or in addition, the subject may not have gastroparesis.

[0217] The subject to be treated may be a human having a BMI of at least 25 kg / m2at baseline.

[0218] The subject to be treated may be a human having a BMI of at least 27 kg / m2at baseline.

[0219] The subject to be treated may be a human having a BMI of at least 30 kg / m2. The subject may be a human having a BMI of at least 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37,

[0220] 38, 39 or 40 kg / m2at baseline. The subject may be a human having a BMI of less than or equal to 50 kg / m2at baseline. The subject may be a human having a BMI of less than or equal to 50, 49, 48, 47, 46, 45, 44, 43, 42, 41 , or 40 kg / m2at baseline. The subject may be a human having a BMI of 25-40 kg / m2at baseline. The subject may be a human having a BMI of 27-40 kg / m2at baseline. The subject may be a human having a BMI of 30-40 kg / m2at baseline. Preferably, the subject is a human having a BMI of at least 30 kg / m2at baseline. Preferably, the subject is a human having a BMI of at least 27 kg / m2at baseline with at least one weight-related comorbidity {e.g., hypertension, dyslipidaemia, and / or obstructive sleep apnoea).

[0221] The subject may have previously been administered an anti-obesity drug, such as a dual amylin and calcitonin receptor agonist (DACRA, e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); an incretin mimetic drug, such as a GLP-1 R agonist (e.g., semaglutide); a GLP-1 R / GCGR dual agonist e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”). In some embodiments, the subject experiences increased body weight reduction as compared to an anti-obesity drug, such as a dual amylin and calcitonin receptor agonist (DACRA e.g., davalintide);an incretin mimetic drug, such as a GLP-1 R agonist {e.g., semaglutide); a GLP-1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri-sema”).

[0222] In some embodiments, the subject does not tolerate an anti-obesity drug, such as a DACRA (e.g., davalintide); an incretin mimetic drug, such as a GLP-1 R agonist (e.g., semaglutide; a GLP-1 R / GCGR dual agonist {e.g. survodutide); a GLP1 / GCG / GIP triple agonist {e.g. retatrutide); and / or a DACRA-GLP-1 Ra combination {e.g., semaglutide-cagrilintide, “cagri- sema”). As used herein, a subject that does not or cannot tolerate a drug may have had, or be at risk of, adverse events (such as nausea and / or vomiting) in response to the drug. Thus, the subject may have experienced adverse events following administration of an antiobesity drug; discontinued administration of the anti-obesity drug due to the burden of adverse events of the drug; or been advised that they are at risk of adverse events if administered an anti-obesity drug.

[0223] In some embodiments, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered to the subject in combination with insulin.

[0224] In some aspects, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dualagonist) or pharmaceutical compositions thereof are administered once a week, every two weeks, every three weeks, or every four weeks. In some aspects, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered about once every 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 days. In a preferred embodiment, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof are administered about once a week.

[0225] The AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof may be administered simultaneously. Alternatively, the AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof may be administered sequentially.

[0226] The AMYR agonist and the GLP-1 R agonist (e.g. the GLP-1 R / GCGR dual-agonist) or pharmaceutical compositions thereof may be administered using a dual-chamber device, as described herein.

[0227] Any AMYR agonist which has selectivity for AMYR as compared with CTR, and any GLP-1 R agonist as described herein may be used for therapy, in a method of treatment or in the manufacture of a medicament according to the present invention. Preferably, the AMYR agonist with selectivity for AMYR as compared with CTR is an AMYR agonist polypeptide and GLP-1 R agonist is a GLP-1 R agonist polypeptide, as described herein. In some preferred embodiments, the AMYR agonist with selectivity for AMYR as compared with CTR is combined with a GLP-1 R / GCGR dual-agonist, as described herein. Thus, in some particularly preferred embodiments, the AMYR agonist with selectivity for AMYR as compared with CTR is an AMYR agonist polypeptide and GLP-1 R agonist is a GLP-1 R / GCGR dual-agonist polypeptide, as described herein. By way of non-limiting example, an AMYR agonist polypeptide, or pharmaceutically acceptable salt thereof, comprising the amino acid sequence K(yE-yE-

[0228] C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11); and a GLP-1 R agonist polypeptide, or pharmaceutically acceptable salt thereof, comprising the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc-yE- C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35) may be used in a therapy as described herein. By way of further non-limiting example, an AMYR agonist polypeptide, consisting of the amino acid sequence K(yE-yE- C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11), or pharmaceutically acceptable salt thereof; and a GLP-1 R agonist polypeptide consisting of the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc- yE-C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35), or pharmaceutically acceptable salt thereof may be used in a therapy as described herein. Alternatively, any AMYR agonist which has selectivity for AMYR as compared with CTR, and any GLP-1 R agonist as described herein may be used for therapy, in a method of treatment or in the manufacture of a medicament according to the present invention in combination with a GCGR agonist. Thus, a method of the invention may comprise administering an AMYR agonist which has selectivity for AMYR as compared with CTR, and a GLP-1 R agonist as described herein to a subject, and further comprise administering to the subject a GCGR agonist.

[0229] Dosage regimens

[0230] The invention provides a combination of an AMYR agonist and a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) for the treatment and / or prevention of a disease or disorder, or for a clinical purpose (e.g. improving glycemic and / or metabolic control, improving glucose homeostasis, p-cell function, and / or insulin sensitivity, or promoting end-organ protection) as described herein. In particular, said AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) are used at: (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof.

[0231] Dosage regimens for said treatments are provided below. For the avoidance of doubt, any dosage regimen herein may be used in relation to the treatment and / or prevention of any disease or disorder, or for any clinical purpose as described herein.

[0232] In particular, the invention provides a method of treating and / or preventing a disease or disorder in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in therapy, for example in a method of treating and / or preventing a disease or disorder, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof. The invention also provides a method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP- 1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0233] The invention also provides a method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0234] The invention also provides a method of improving glycemic and / or metabolic control in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of improving glycemic and / or metabolic control in a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP- 1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof. The invention also provides a method of treating and / or preventing obesity or an obesity- related condition in a subject in need thereof, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of treating and / or preventing obesity or an obesity-related condition in a subject in need thereof, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0235] The invention also provides a method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0236] The invention also provides a method of reducing the body weight of a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salt thereof. The invention also provides an AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salts thereof of the invention for use in a method of reducing the body weight of a subject, the method comprising administering to the subject (a) between about 1 mg to about 15 mg of the AMYR agonist, and (b) between about 0.1 mg to about 10 mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist), or pharmaceutically acceptable salts thereof.

[0237] Also provided is a kit comprising (a) an AMYR agonist, (b) a GLP-1 R agonist, and (c) instructions for use of the same for treating or preventing a disease or disorder as disclosed herein (such as obesity or an obesity-related condition, or a metabolic disease as described herein) at a dose of about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist. Also provided is an article of manufacture comprising (a) an AMYR agonist at a dose of about 1 mg to about 15 mg; and (b) a GLP-1 R agonist at a dose of about 0.1 to about 10 mg.

[0238] The AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) of the invention may be any AMYR agonist and GLP-1 R agonist (e.g. a GLP-1 R / GCGR dualagonist) as disclosed herein.

[0239] Preferably, the doses as disclosed herein are fixed doses. As used herein, the term "fixed dose" refers to a dose which is used for all subjects, e.g., the dose is an amount that does not vary based on the weight of the subject. A fixed dose may be a specific, unchanging amount, wherein the same dose is used for all subjects, or for all adult subjects, such as a unit dosage form as disclosed herein. A fixed dose is typically expressed in terms of an amount of the active agent, such as the amylin receptor agonist, GLP-1 R agonist (e.g. GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salts thereof, rather than an amount that is expressed relative to the weight or mass of the subject to be treated.

[0240] The methods, uses, compositions, and kits of the invention utilise a dose (such as a fixed dose) of about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, and about 0.1 mg to about 10mg of a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) or pharmaceutically acceptable salt thereof, for example comprise administering such a (fixed) dose to a subject.

[0241] AMYR agonist dosages

[0242] The amylin receptor agonist in a method of the invention, an amylin receptor agonist for use in the invention, and the uses, compositions or kits of the invention may be any amylin receptor agonist as disclosed herein.

[0243] The (fixed) dose of amylin receptor agonist of about 1 mg to about 15 mg may be, for example, at least 1 mg, such as at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, or at least 12 mg. The (fixed) dose of about 1 mg to about 15 mg may be up to 15 mg, such as up to 12 mg, up to 11 mg, up to 10 mg, up to 9 mg, up to 8 mg, up to 7 mg, up to 6 mg, up to 5 mg, up to 4 mg, up to 3 mg, or up to 2 mg. Any of these upper and lower end points may be combined within the range of about 1 mg to about 15 mg. For example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 4 mg to about 10 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 7 mg to about 10 mg.

[0244] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg to about 9 mg.

[0245] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, or about 1 mg to about 5 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg to about 8 mg, about 1 .5 mg to about 7 mg, about 1 .5 mg to about 6 mg, about 1.5 mg to about 5 mg, or about 1.5 mg to about 4.5 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg to about 4.5 mg.

[0246] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.6 mg to about 8 mg, about 1.6 mg to about 7 mg, about 1.6 mg to about 6 mg, about 1.6 mg to about 5 mg, or about 1.6 mg to about 4.5 mg.

[0247] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose of about 2 mg to about 15 mg, about 3 mg to about 15 mg, about 4 mg to about 15 mg, about 4.5 mg to about 15 mg, or about 6 mg to about 15 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose of about 2 mg to about 12 mg, about 3 mg to about 12 mg, about 4 mg to about 12 mg, about 4.5 mg to about 12 mg, or about 6 mg to about 12 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose of about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 4.5 mg to about 10 mg, or about 6 mg to about 10 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose of about 2 mg to about 9 mg, about 3 mg to about 9 mg, about 4 mg to about 9 mg, about 4.5 mg to about 9 mg, or about 6 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 15 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, or about 6 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg to about 15 mg, about 6 mg to about 12 mg, about 6 mg to about 10 mg, or about 6 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg to about 15 mg, about 4.5 mg to about 12 mg, about 4.5 mg to about 10 mg, or about 4.5 mg to about 9 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 9 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg to about 9 mg.

[0248] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose of about 1 mg to about 4 mg, about 1 mg to about 3 mg, or about 1 mg to about 2 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 3 mg.

[0249] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, or about 2 mg to about 5 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, or about 3 mg to about 5 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, or about 4 mg to about 5 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.5 mg to about 8 mg, about 3 mg to about 8 mg, or about 4 mg to about 8 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.5 mg to about 7 mg, about 3 mg to about 7 mg, or about 4 mg to about 7 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.5 mg to about 6 mg, about 3 mg to about 6 mg, or about 4 mg to about 6 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.5 mg to about 5 mg, about 3 mg to about 5 mg, or about 4 mg to about 5 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.5 mg to about 5 mg.

[0250] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 12 mg, about 5 mg to about 10 mg, or about 5 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg to about 12 mg, about 6 mg to about 10 mg, or about 6 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 12 mg, about 7 mg to about 10 mg, or about 7 mg to about 9 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 9 mg. Preferably, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg.

[0251] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 15 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 4 mg to about 10 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 7 mg to about 10 mg.

[0252] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 12 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 4 mg to about 10 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 7 mg to about 10 mg.

[0253] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 10 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 4 mg to about 10 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 7 mg to about 10 mg.

[0254] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 9 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9 mg, about 1 mg to about 5 mg, about 4 mg to about 9 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, about 7 mg to about 9 mg, or about 9 mg.

[0255] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 8 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 8 mg, about 1 mg to about 5 mg, about 4 mg to about 8 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 7 mg to about 8 mg.

[0256] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 7 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg, about 1 mg to about 5 mg, about 4 mg to about 7 mg, about 1 mg to about 3 mg, or about 2.5 mg to about 5 mg.

[0257] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 6 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 4 mg to about 6 mg, about 1 mg to about 3 mg, or about 2.5 mg to about 5 mg.

[0258] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 5 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg, about 4 mg to about 5 mg, about 1 mg to about 3 mg, about 2.5 mg to about 5 mg, or about 4.5 mg.

[0259] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 4 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 4 mg, about 1 mg to about 3 mg, or about 2.5 mg to about 4 mg. The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 3 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 3 mg.

[0260] The AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of up to 2 mg. For example, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg, or about 1 .5 mg {e.g. 1 .6 mg).

[0261] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg e.g., about 1 .6 mg), about 4.5 mg, about 6 mg, or about 9 mg.

[0262] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg e.g. 1 .6 mg), about 4.5 mg, or about 9 mg.

[0263] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg, such as a dose of 1 .5 mg.

[0264] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 1 .6 mg, such as a dose of 1 .6 mg.

[0265] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, such as a dose of 4.5 mg.

[0266] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, such as a dose of 6 mg.

[0267] Preferably, the AMYR agonist may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, such as a dose of 9 mg.

[0268] GLP-1R agonist dosages

[0269] The GLP-1 R receptor agonist in a method of the invention, an GLP-1 R agonist for use in the invention, and the uses, compositions or kits of the invention may be any GLP-1 R agonist as disclosed herein.

[0270] The (fixed) dose of GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof of about 0.1 mg to about 10 mg may be, for example, at least 0.1 mg, such as at least 0.15 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, at least 1.5 mg, at least 1 .2 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 4.5 mg, at least 4.6 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 9.4 mg, or at least 10 mg. The (fixed) dose of about 0.1 mg to about 10 mg may be up to 10 mg, such as up to 9.4 mg, up to 9 mg, up to 8 mg, up to 7 mg, up to 6 mg, up to 5 mg, up to 4.6 mg, up to 4.5 mg, up to 4 mg, up to 3 mg, up to 2 mg, up to 1 .5 mg, up to 1 .2 mg, up to 1 mg, up to 0.9 mg, up to 0.8 mg, up to 0.7 mg, up to 0.6 mg, up to 0.5 mg, up to 0.4 mg, up to 0.3 mg, or up to 0.2 mg. Any of these upper and lower end points may be combined within the range of about 0.1 mg to about 10 mg.

[0271] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9 mg, for example, from about 0.1 mg to about 8 mg, from about 0.1 mg to about 7 mg, from about 0.1 mg to about 6 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 4 mg, from about 0.1 mg to about 3 mg, from about 0.1 mg to about 2 mg, or from about 0.1 mg to about 1 mg.

[0272] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.15 mg to about 10 mg, for example, from about 0.15 mg to about 9 mg, from about 0.15 mg to about 8 mg, from about 0.15 mg to about 7 mg, from about 0.15 mg to about 6 mg, from about 0.15 mg to about 5 mg, from about 0.15 mg to about 4 mg, from about 0.15 mg to about 3 mg, from about 0.15 mg to about 2 mg, or from about 0.15 mg to about 1 mg.

[0273] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.30 mg to about 10 mg, for example, from about 0.30 mg to about 9 mg, from about 0.30 mg to about 8 mg, from about 0.30 mg to about 7 mg, from about 0.30 mg to about 6 mg, from about 0.30 mg to about 5 mg, from about 0.30 mg to about 4 mg, from about 0.30 mg to about 3 mg, from about 0.30 mg to about 2 mg, or from about 0.30 mg to about 1 mg.

[0274] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.60 mg to about 10 mg, for example, from about 0.60 mg to about 9 mg, from about 0.60 mg to about 8 mg, from about 0.60 mg to about 7 mg, from about 0.60 mg to about 6 mg, from about 0.60 mg to about 5 mg, from about 0.60 mg to about 4 mg, from about 0.60 mg to about 3 mg, from about 0.60 mg to about 2 mg, or from about 0.60 mg to about 1 mg.

[0275] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.20 mg to about 10 mg, for example, from about 1.20 mg to about 9 mg, from about 1.20 mg to about 8 mg, from about 1.20 mg to about 7 mg, from about 1.20 mg to about 6 mg, from about 1.20 mg to about 5 mg, from about 1.20 mg to about 4 mg, from about 1.20 mg to about 3 mg, or from about 1 .20 mg to about 2 mg.

[0276] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.30 mg to about 10 mg, for example, from about 2.30 mg to about 9 mg, from about 2.30 mg to about 8 mg, from about 2.30 mg to about 7 mg, from about 2.30 mg to about 6 mg, from about 2.30 mg to about 5 mg, from about 2.30 mg to about 4 mg, or from about 2.30 mg to about 3 mg.

[0277] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.60 mg to about 10 mg, for example, from about 4.60 mg to about 9 mg, from about 4.60 mg to about 8 mg, from about 4.60 mg to about 7 mg, from about 4.60 mg to about 6 mg, or from about 4.60 mg to about 5 mg.

[0278] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg, for example, about 9 mg to about 10 mg, about 9.5 mg to about 10 mg, about 9.4 mg to about 10 mg, or about 9.4 mg.

[0279] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.15 mg to about 10 mg, about 0.20 to about 10 mg, about 0.30 mg to about 10 mg, about 0.50 mg to about 10 mg, about 0.60 mg to about 10 mg, about 1.00 mg to about 10 mg, about 1.20 mg to about 10 mg, about 1.50 mg to about 10 mg, about 2 mg to about 10 mg, about 2.30 mg to about 10 mg, about 2.50 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 4.50 mg to about 10 mg, about 4.60 mg to about 10 mg, about 5 mg to about 10 mg, about 6 mg to about 10 mg, about 7 mg to about 10 mg, or about 9 mg to about 10 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.5 mg {e.g. about 9.4 mg), for example, about 0.15 mg to about 9.5 mg e.g. about 9.4 mg), about 0.20 mg to about 9.5 mg e.g. about 9.4 mg), about 0.30 mg to about 9.5 mg {e.g. about 9.4 mg), about 0.50 mg to about 9.5 mg {e.g. about 9.4 mg), about 0.60 mg to about 9.5 mg {e.g. about 9.4 mg), about 1.00 mg to about 9.5 mg {e.g. about 9.4 mg), about 1 .20 mg to about 9.5 mg {e.g. about 9.4 mg), about 1 .50 mg to about 9.5 mg {e.g. about 9.4 mg), about 2 mg to about 9.5 mg {e.g. about 9.4 mg), about 2.30 mg to about 9.5 mg {e.g. about 9.4 mg), about 2.50 mg to about 9.5 mg {e.g. about 9.4 mg), about 3 mg to about 9.5 mg {e.g. about 9.4 mg), about 4 mg to about 9.5 mg {e.g. about 9.4 mg), about 4.50 mg to about 9.5 mg {e.g. about 9.4 mg), about 4.60 mg to about 9.5 mg {e.g. about 9.4 mg), about 5 mg to about 9.5 mg {e.g. about 9.4 mg), or about 7 mg to about 9.5 mg {e.g. about 9.4 mg).

[0280] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg, for example, about 0.15 mg to about 7 mg, about 0.20 mg to about 7 mg, about 0.30 mg to about 7 mg, about 0.50 mg to about 7 mg, about 0.60 mg to about 7 mg, about 1.00 mg to about 7 mg, about 1.20 mg to about 7 mg, about 1.50 mg to about 7 mg, about 2 mg to about 7 mg, about 2.30 mg to about 7 mg, about 2.50 mg to about 7 mg, about 3 mg to about 7 mg, about 4 mg to about 7 mg, about 4.50 mg to about 7 mg, about 4.60 mg to about 7 mg, or about 5 mg to about 7 mg.

[0281] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 5 mg, for example, about 0.15 mg to about 5 mg, about 0.2 mg to about 5 mg, about 0.30 mg to about 5 mg, about 0.50 mg to about 5 mg, about 0.60 mg to about 5 mg, about 1.00 mg to about 5 mg, about 1.20 mg to about 5 mg, about 1.50 mg to about 5 mg, about 2 mg to about 5 mg, about 2.30 mg to about 5 mg, about 2.50 mg to about 5 mg, about 3 mg to about 5 mg, about 4 mg to about 5 mg, or about 4.6 mg to about 5 mg.

[0282] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 4.60 mg, for example, about 0.15 mg to about 4.60 mg, about 0.30 mg to about 4.60 mg, about 0.60 mg to about 4.60 mg, about 1.00 mg to about 4.60 mg, about 1.20 mg to about 4.60 mg, about 1 .50 mg to about 4.60 mg, about 2 mg to about 4.60 mg, about 2.30 mg to about 4.60 mg, about 2.50 mg to about 4.60 mg, about 3 mg to about 4.60 mg, or about 4 mg to about 4.60 mg.

[0283] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 2.30 mg, for example, about 0.15 mg to about 2.30 mg, about 0.30 mg to about 2.30 mg, about 0.60 mg to about 2.30 mg, about 1.00 mg to about 2.30 mg, about 1.20 mg to about 2.30 mg, about 1 .50 mg to about 2.30 mg, or about 2 mg to about 2.30.

[0284] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1.50 mg, for example, about 0.15 mg to about 1.50 mg, about 0.20 mg to about 1.50 mg, about 0.30 mg to about 1.50 mg, about 0.50 mg to about 1.50 mg, about 0.60 mg to about 1 .50 mg, or about 1 mg to about 1 .50 mg.

[0285] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1.20 mg, for example, about 0.15 mg to about 1.20 mg, about 0.30 mg to about 1 .20 mg, about 0.60 mg to about 1 .20 mg, or about 1 mg to about 1 .20 mg.

[0286] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1 mg, for example, about 0.15 mg to about 1 mg, about 0.20 mg to about 1 mg, about 0.30 mg to about 1 mg, about 0.50 mg to about 1 mg, about 0.60 mg to about 1 mg, or about 1 mg.

[0287] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 0.60 mg, for example, about 0.15 mg to about 0.60 mg, or about 0.30 mg to about 0.60 mg.

[0288] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 0.50 mg, for example, about 0.15 mg to about 0.50 mg, about 0.20 mg to about 0.50 mg, or about 0.30 mg to about 0.50 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 0.30 mg, for example, or about 0.15 mg to about 0.30 mg.

[0289] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 0.20 mg, for example, or about 0.15 mg to about 0.20 mg.

[0290] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, for example, about 1 mg to about 9.5 mg (for example, about 1 .20 mg to about 9.4 mg).

[0291] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, for example, about 1 mg to about 7 mg (for example, about 1 .20 mg to about 7 mg).

[0292] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 5 mg, for example, about 1 mg to about 5 mg, about 1 .2 mg to about 5 mg, or about 1.2 mg to about 4.6 mg. For example, the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, about 1 mg to about 5 mg.

[0293] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 10 mg, for example, about 2 mg to about 9.5 mg, or about 2 mg to about 9.4 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg to about 10 mg, for example, about 2.3 mg to about 9.5 mg, or about 2.3 mg to about 9.4 mg.

[0294] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 7 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg to about 7 mg.

[0295] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 3 mg, for example, about 1 mg to about 3 mg, about 1 .2 mg to about 3 mg, or about 1.2 mg to about 2.3 mg. For example, the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, about 1 mg to about 3 mg.

[0296] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 5 mg, for example, about 2 mg to about 4.6 mg. The GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg to about 5 mg, for example, about 2.3 mg to about 4.6 mg.

[0297] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg, for example, about 4 mg to about 7 mg. The GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg to about 10 mg, for example, about 4.5 mg to about 7 mg. The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg to about 10 mg, for example, about 4.6 mg to about 7 mg.

[0298] The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg, for example, about 4 mg to about 9.5 mg (e.g. about 9.4 mg). The GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg to about 10 mg, for example, about 4.5 mg to about 9.5 mg (e.g. about 9.4 mg). The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg to about 10 mg, for example, about 4.6 mg to about 9.5 mg (e.g. about 9.4 mg). The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 2 mg, for example, about 1 mg to about 2 mg, about 1 mg to about 1 .5 mg, or about 1.2 mg.

[0299] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 3 mg, for example, about 2 mg to about 2.5 mg, or about 2.3 mg.

[0300] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 6 mg, for example, about 4 mg to about 5 mg, about 4.5 mg to about 5 mg, or about 4.6 mg.

[0301] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg, for example, about 5 mg to about 8 mg, about 6 mg to about 8 mg, about 6 mg to about 7.5 mg, about 6.5 mg to about 7.5 mg, or about 7 mg.

[0302] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg, for example, about 9 mg to about 10 mg, about 9 mg to about 9.5 mg, or about 9.4 mg.

[0303] The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.15 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.30 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.60 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.20 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.30 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.60 mg. The GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg. The GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg.

[0304] AMYR agonist and GLP-1R agonist combination dosages

[0305] The present invention relates to a combination therapy of an AMYR agonist and a GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salts thereof.

[0306] The present invention encompasses any combination of a fixed dose of AMYR agonist as disclosed herein and a fixed dose of GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist) as disclosed herein (or pharmaceutically acceptable salts thereof).

[0307] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0308] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.5 mg (for example, about 0.1 mg to about 9.4 mg).

[0309] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0310] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 5 mg (for example, about 0.1 mg to about 4.60 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 2.50 mg (for example, about 0.1 mg to about 2.30 mg).

[0311] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1 .50 mg (for example, about 0.1 mg to about 1 .20 mg).

[0312] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 9.5 mg (for example, about 0.30 mg to about 9.4 mg).

[0313] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 7 mg (for example, about 0.30 mg to about 7mg).

[0314] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 5 mg (for example, about 0.30 mg to about 4.60 mg).

[0315] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 2.5 mg (for example, about 0.30 mg to about 2.30 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 1 .5 mg (for example, about 0.30 mg to about 1 .20 mg).

[0316] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 9.5 mg (for example, about 0.60 mg to about 9.4 mg).

[0317] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 7 mg (for example, about 0.60 mg to about 7mg).

[0318] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 5 mg (for example, about 0.60 mg to about 4.60 mg).

[0319] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 2.5 mg (for example, about 0.60 mg to about 2.30 mg).

[0320] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 1 .5 mg (for example, about 0.60 mg to about 1 .20 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9.5 mg (for example, about 1 .2 mg to about 9.4 mg).

[0321] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .2 mg to about 7 mg).

[0322] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .2 mg to about 4.60 mg).

[0323] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2.5 mg (for example, about 1 .2 mg to about 2.30 mg).

[0324] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 9.5 mg (for example, about 2.3 mg to about 9.4 mg).

[0325] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 7 mg (for example, about 2.3 mg to about 7 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 5 mg (for example, about 2.3 mg to about 4.60 mg).

[0326] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 9.5 mg (for example, about 4.60 mg to about 9.4 mg).

[0327] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg (for example, about 4.60 mg to about 7 mg).

[0328] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 9.5 mg (for example, about 7 mg to about 9.4 mg).

[0329] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg.

[0330] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0331] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0332] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0333] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.5 mg (e.g. about 9.4 mg).

[0334] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.5 mg (for example, about 0.1 mg to about 9.4 mg).

[0335] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0336] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 5 mg (for example, about 0.1 mg to about 4.60 mg).

[0337] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 2.50 mg (for example, about 0.1 mg to about 2.30 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1 .50 mg (for example, about 0.1 mg to about 1 .20 mg).

[0338] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 9.5 mg (for example, about 0.30 mg to about 9.4 mg).

[0339] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 7 mg (for example, about 0.30 mg to about 7mg).

[0340] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 5 mg (for example, about 0.30 mg to about 4.60 mg).

[0341] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 2.5 mg (for example, about 0.30 mg to about 2.30 mg).

[0342] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 1 .5 mg (for example, about 0.30 mg to about 1 .20 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 9.5 mg (for example, about 0.60 mg to about 9.4 mg).

[0343] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 7 mg (for example, about 0.60 mg to about 7mg).

[0344] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 5 mg (for example, about 0.60 mg to about 4.60 mg).

[0345] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 2.5 mg (for example, about 0.60 mg to about 2.30 mg).

[0346] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 1 .5 mg (for example, about 0.60 mg to about 1 .20 mg).

[0347] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9.5 mg (for example, about 1 .2 mg to about 9.4 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .2 mg to about 7 mg).

[0348] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .2 mg to about 4.60 mg).

[0349] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2.5 mg (for example, about 1 .2 mg to about 2.30 mg).

[0350] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 9.5 mg (for example, about 2.3 mg to about 9.4 mg).

[0351] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 7 mg (for example, about 2.3 mg to about 7 mg).

[0352] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 5 mg (for example, about 2.3 mg to about 4.60 mg). The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 9.5 mg (for example, about 4.60 mg to about 9.4 mg).

[0353] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg (for example, about 4.60 mg to about 7 mg).

[0354] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 9.5 mg (for example, about 7 mg to about 9.4 mg).

[0355] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg.

[0356] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0357] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0358] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.5 mg (e.g. about 9.4 mg).

[0359] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.5 mg (for example, about 0.1 mg to about 9.4 mg).

[0360] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0361] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 5 mg (for example, about 0.1 mg to about 4.60 mg).

[0362] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 2.50 mg (for example, about 0.1 mg to about 2.30 mg).

[0363] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 1.50 mg (for example, about 0.1 mg to about 1.20 mg).

[0364] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 9.5 mg (for example, about 0.30 mg to about 9.4 mg).

[0365] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 7 mg (for example, about 0.30 mg to about 7mg).

[0366] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 5 mg (for example, about 0.30 mg to about 4.60 mg).

[0367] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 2.5 mg (for example, about 0.30 mg to about 2.30 mg).

[0368] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.25 mg to about 1 .5 mg (for example, about 0.30 mg to about 1 .20 mg).

[0369] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 9.5 mg (for example, about 0.60 mg to about 9.4 mg).

[0370] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 7 mg (for example, about 0.60 mg to about 7mg).

[0371] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 5 mg (for example, about 0.60 mg to about 4.60 mg).

[0372] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 2.5 mg (for example, about 0.60 mg to about 2.30 mg).

[0373] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.50 mg to about 1 .5 mg (for example, about 0.60 mg to about 1 .20 mg).

[0374] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9.5 mg (for example, about 1 .2 mg to about 9.4 mg).

[0375] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .2 mg to about 7 mg).

[0376] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .2 mg to about 4.60 mg).

[0377] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2.5 mg (for example, about 1 .2 mg to about 2.30 mg).

[0378] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 9.5 mg (for example, about 2.3 mg to about 9.4 mg).

[0379] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 7 mg (for example, about 2.3 mg to about 7 mg).

[0380] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 5 mg (for example, about 2.3 mg to about 4.60 mg).

[0381] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 9.5 mg (for example, about 4.60 mg to about 9.4 mg).

[0382] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg (for example, about 4.60 mg to about 7 mg).

[0383] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 9.5 mg (for example, about 7 mg to about 9.4 mg).

[0384] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg.

[0385] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0386] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0387] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0388] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.5 mg (e.g. about 9.4 mg).

[0389] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0390] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0391] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (e.g. about 1.5 mg to about 10 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0392] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9 mg (for example, about 1 .5 mg to about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0393] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .5 mg to about 7 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0394] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .5 mg to about 5 mg, or about 1.5 mg to about 4.5 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0395] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 3 mg {e.g., about 1 .5 mg to about 3 mg, e.g. about 1.5 mg, or about 1.6 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0396] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg (for example, about 4.5 mg to about 10 mg, about 4 mg to about 9 mg, or 4.5 mg to about 9 mg), and the GLP- 1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0397] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg e.g., about 4.5 mg to about 7 mg, or about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0398] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g., about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0399] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 7 mg to about 9 mg, or about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0400] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0401] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .6 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0402] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0403] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0404] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg.

[0405] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0406] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0407] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (for example, about 1.5 mg to about 10 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0408] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9 mg (for example, about 1 .5 mg to about 9mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0409] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .5 mg to about 7 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0410] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .5 mg to about 5 mg, or about 1.5 mg to about 4.5 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0411] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 3 mg {e.g., about 1 .5 mg to about 3 mg, e.g. about 1.5 mg, or about 1.6 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0412] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg (for example, about

[0413] 4.5 mg to about 10 mg, about 4 mg to about 9 mg, or 4.5 mg to about 9mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0414] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg e.g., e.g., about 4.5 mg to about 7 mg, or about 6 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0415] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg e.g., about 4.5 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0416] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 7 mg to about 9 mg, or about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0417] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0418] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .6 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0419] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0420] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 9.4 mg.

[0421] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0422] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 12 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0423] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 10 mg (e.g. about 1.5 mg to about 10 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0424] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 9 mg (for example, about 1 .5 mg to about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0425] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 7 mg (for example, about 1 .5 mg to about 7 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0426] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 5 mg (for example, about 1 .5 mg to about 5 mg, or about 1.5 mg to about 4.5 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0427] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 3 mg {e.g., about 1 .5 mg to about 3 mg, e.g. about 1.5 mg, or about 1.6 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0428] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 10 mg (for example, about 4.5 mg to about 10 mg, about 4 mg to about 9 mg, or 4.5 mg to about 9 mg), and the GLP- 1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0429] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg e.g., about 4.5 mg to about 7 mg, or about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0430] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g., about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0431] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 7 mg to about 9 mg, or about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0432] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0433] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .6 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0434] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0435] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0436] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 7 mg.

[0437] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg).

[0438] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg {e.g. about 7 mg).

[0439] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg).

[0440] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg).

[0441] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1 .2 mg).

[0442] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg).

[0443] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg {e.g. about 7 mg).

[0444] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg).

[0445] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg).

[0446] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg e.g. about 6 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1 .2 mg).

[0447] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg).

[0448] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg {e.g. about 7 mg).

[0449] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg).

[0450] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg).

[0451] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1 .2 mg).

[0452] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about

[0453] 1.50 mg or about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg e.g. about 9.4 mg).

[0454] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about

[0455] 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg {e.g. about 7 mg).

[0456] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about

[0457] 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg).

[0458] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about

[0459] 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg).

[0460] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about

[0461] 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1 .2 mg).

[0462] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0463] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0464] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0465] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.2 mg.

[0466] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg.

[0467] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0468] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg. The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0469] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.2 mg.

[0470] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg.

[0471] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0472] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0473] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0474] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg.

[0475] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg (for example, about 1 .60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg.

[0476] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg (for example, about 1 .60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg.

[0477] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg (for example, about 1 .60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg.

[0478] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg (for example, about 1 .60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg.

[0479] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .5 mg (for example, about 1 .60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg.

[0480] Treatment or prevention may be effected by a single administration or by multiple administrations of the combination therapy. For example, the treatment or prevention may comprise administering two doses, three doses, four doses, five doses, six doses, seven doses, eight doses, nine doses, ten doses, or more than ten doses of the combination therapy to the subject. Each dose may be a dose, such as a fixed dose, as disclosed herein. The treatment or prevention may comprise multiple administrations as described herein, such as repeated administrations, of the combination therapy over a course of treatment.

[0481] By a course of treatment is meant a treatment plan comprising several rounds of administration, as part of a method of treating and / or preventing a disease or disorder as described herein (e.g. obesity or an obesity-related condition and / or a metabolic disease) in accordance with the invention. A course of treatment may last for one or more weeks, one or more months, such as two, three, four, five, six, seven, eight, nine, ten or eleven months, or for one or more years, such as one year, two years, three years, four years, five years, or longer. A course of treatment may be continued with no fixed end-point, for example a course of treatment may be continued for the lifetime of the subject being treated. Multiple administrations, such as repeated administrations, may be continued at regular or irregular intervals during the course of the treatment as determined to be needed by a medical practitioner. A course of treatment of any duration as described herein may comprise a titration schedule as discussed below.

[0482] The combination therapy may be administered to a subject multiple times, at an interval of once a week, every two weeks, every three weeks, or every four weeks. The combination therapy may be administered about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week. Accordingly, the combination therapy may be administered to the subject at a dose, such as a fixed dose, of an AMYR agonist as disclosed herein and a fixed dose of a GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist) as disclosed herein (or pharmaceutically acceptable salts thereof), about once a week. For the avoidance of doubt, these administration intervals apply equally and without reservation to each dosing regimen herein, unless expressly stated to the contrary.

[0483] Thus, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 15 mg, and the GLP- 1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 0.1 mg to about 10 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0484] By way of example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0485] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg e.g. about 7 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0486] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0487] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg e.g., about 9 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0488] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg to about 10 mg {e.g., about 9 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1.2 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0489] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week. By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg e.g. about 7 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0490] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0491] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0492] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 7 mg {e.g. about 6 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1.2 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0493] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg {e.g. about 4.5 mg), and the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0494] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg (e.g. about 4.5 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg (e.g. about 7 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0495] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg (e.g. about 4.5 mg), and the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg (e.g. about 4.6 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0496] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg (e.g. about 4.5 mg), and the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg (e.g. about 2.3 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0497] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4 mg to about 5 mg (e.g. about 4.5 mg), and the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (e.g. about 1.2 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0498] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg), and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 8 mg to about 10 mg {e.g. about 9.4 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0499] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg), and the GLP-1 R agonist e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 5 mg to about 10 mg e.g. about 7 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0500] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 3 mg to about 5 mg {e.g. about 4.6 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0501] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2 mg to about 4 mg {e.g. about 2.3 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0502] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg), and the GLP-1 R agonist {e.g., GLP- 1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 mg to about 2 mg {e.g. about 1.2 mg); wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week. By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0503] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0504] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0505] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0506] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week. By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0507] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0508] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0509] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0510] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 6 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0511] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0512] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0513] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0514] By way of further example, the way of example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0515] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.5 mg, and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1 .2 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0516] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.5 mg (for example, about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 9.4 mg; wherein said administration is about once every 4, 5, 6, 7,

[0517] 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0518] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.5 mg (for example, about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 7 mg; wherein said administration is about once every 4, 5, 6, 7, 8,

[0519] 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0520] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.5 mg (for example, about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 4.6 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0521] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.5 mg (for example, about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 2.3 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week.

[0522] By way of further example, the AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.5 mg (for example, about 1.60 mg), and the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose, of about 1.2 mg; wherein said administration is about once every 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 days. Preferably, the combination therapy is administered about once a week. When the combination therapy is administered in multiple administrations, such as repeated administrations, each of said administrations of the AMYR agonist and / or the GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist) may be at a fixed dose as described herein. For example, each administration in a method or use of the invention may comprise a fixed dose of about 1 mg to about 15 mg of the AMYR agonist and about 0.1 mg to about 10 mg of the GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist) as disclosed herein. In such instances, the number of administrations or the frequency of administrations may be any of the options disclosed herein. The multiple administrations, such as repeated administrations of the combination therapy, may be each at the same dose. Two or more administrations of the combination therapy may be each at the same dose. The multiple administrations, such as repeated administrations of the combination therapy, may be each at a dose within a range of doses disclosed herein. For example, the combination therapy may be administered to the subject at a dose, such as a fixed dose, of:

[0523] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0524] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0525] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0526] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0527] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0528] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0529] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0530] - about 4 mg to about 7 mg e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0531] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0532] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0533] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0534] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0535] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0536] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0537] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0538] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0539] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0540] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0541] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0542] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0543] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0544] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0545] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0546] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof.

[0547] By way of example, the method may comprise administering to the subject multiple doses of:

[0548] - about 9 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 9.4 mg of the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0549] - about 9 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 7 mg of the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0550] - about 9 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 4.6 mg of the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0551] - about 9 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 2.3 mg of the GLP-1 R agonist {e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 9 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 1.2 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0552] - about 6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 9.4 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0553] - about 6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 7 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0554] - about 6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 4.6 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0555] - about 6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 2.3 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0556] - about 6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 1.2 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0557] - about 4.5 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 9.4 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0558] - about 4.5 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 7 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0559] - about 4.5 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 4.6 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0560] - about 4.5 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 2.3 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0561] - about 4.5 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 1.2 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0562] - about 1 .5 mg or 1 .6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 9.4 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 1 .5 mg or 1 .6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 7 mg of the GLP-1 R agonist e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0563] - about 1 .5 mg or 1 .6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 4.6 mg of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0564] - about 1 .5 mg or 1 .6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 2.3 mg of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0565] - about 1 .5 mg or 1 .6 mg of the AMYR agonist, or pharmaceutically acceptable salt thereof and about 1.2 mg of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof.

[0566] In accordance with the invention, the combination therapy may be administered to a subject multiple times over a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years or 5 years. The combination therapy may be administered to a subject about once a week over a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years or 5 years. The subject may have body weight reduction following administration of multiple doses after 3 months. The subject may have body weight reduction following administration of multiple doses after 6 months. The subject may have body weight reduction following administration of multiple doses after 9 months. The subject may have body weight reduction following administration of multiple doses between a period of about 3 months and about 9 months, such as a period of about 3 months and about 6 months. The combination therapy may be administered at a dosing interval of about once a week over these periods of time.

[0567] For example, the combination therapy may be administered to the subject at a dose, such as a fixed dose, as described herein about once a week over a period of at least 3 months. By way of non-limiting example, the method may comprise administering to the subject a dose of:

[0568] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0569] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0570] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0571] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about

[0572] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0573] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0574] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0575] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0576] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0577] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0578] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0579] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0580] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0581] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0582] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0583] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0584] - about 4 mg to about 5 mg e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0585] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0586] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0587] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0588] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0589] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0590] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0591] - about 1 mg to about 2 mg (for example, about 1 .50 mg or about 1 .60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; about once a week over a period of at least 3 months.

[0592] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose as described herein about once a week over a period of at least 6 months. By way of non-limiting example, the method may comprise administering to the subject a dose of:

[0593] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0594] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0595] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0596] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about

[0597] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0598] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0599] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0600] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0601] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0602] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about

[0603] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0604] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0605] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0606] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0607] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0608] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0609] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0610] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0611] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0612] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0613] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0614] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0615] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0616] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; about once a week over a period of at least 6 months.

[0617] For example, the combination therapy may be administered to the subject at a dose, such as a fixed dose, as described herein about once a week over a period of at least 9 months. By way of non-limiting example, the method may comprise administering to the subject a dose of:

[0618] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0619] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0620] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0621] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0622] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0623] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0624] - about 4 mg to about 7 mg e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0625] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0626] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0627] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0628] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0629] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0630] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0631] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0632] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0633] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0634] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0635] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0636] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0637] - about 1 mg to about 2 mg (for example, about 1 .50 mg or about 1 .60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0638] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0639] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0640] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0641] - about 1 mg to about 2 mg (for example, about 1 .50 mg or about 1 .60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; about once a week over a period of at least 9 months.

[0642] The AMYR agonist, or pharmaceutically acceptable salt thereof, may be administered to the subject at a dose, such as a fixed dose as described herein about once a week over a period of between about 3 months to about 9 months, such as about 3 months to about 6 months. By way of non-limiting example, the method may comprise administering to the subject a dose of: - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0643] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0644] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0645] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about

[0646] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0647] - about 7 mg to about 10 mg (e.g., about 9 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0648] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0649] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about

[0650] 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0651] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0652] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0653] - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0654] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 4 mg to about 7 mg {e.g. about 6 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about

[0655] 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0656] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0657] - about 4 mg to about 5 mg e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0658] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0659] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg {e.g. about

[0660] 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0661] - about 4 mg to about 5 mg {e.g. about 4.5 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0662] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 8 mg to about 10 mg (e.g. about 9.4 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0663] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 5 mg to about 10 mg (e.g. about 7 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof;

[0664] - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 3 mg to about 5 mg {e.g. about 4.6 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; - about 1 mg to about 2 mg (for example, about 1.50 mg or about 1.60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 2 mg to about 4 mg e.g. about 2.3 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; or

[0665] - about 1 mg to about 2 mg (for example, about 1 .50 mg or about 1 .60 mg) of the AMYR agonist, or pharmaceutically acceptable salt thereof, and about 1 mg to about 2 mg {e.g. about 1.2 mg) of the GLP-1 R agonist (e.g., GLP-1 R / GCGR dual agonist), or pharmaceutically acceptable salt thereof; about once a week over a period of about 3 months to about 9 months, such as about 3 months to about 6 months (e.g. about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months).

[0666] The combination therapy may be titrated to a final dose over a period of time. The combination therapy may be titrated to a final dose over a period between about 1 week to about 36 weeks. The combination therapy may be titrated to a final dose over a period between about 1 week to about 21 weeks, such as up to about 20 weeks. The combination therapy may be titrated to a final dose over a period between about 1 week to about 17 weeks, such as up to about 16 weeks. The combination therapy may be titrated to a final dose over a period between about 1 week to about 8 weeks. For example, the combination therapy may be titrated to a final dose over a period of about 20 weeks.

[0667] The combination therapy may be titrated to a final dose over a period between about 2 weeks to about 36 weeks. The combination therapy may be titrated to a final dose over a period between about 2 weeks to about 21 weeks (e.g. up to about 20 weeks). The combination therapy may be titrated to a final dose over a period between about 2 weeks to about 17 weeks (e.g. up to about 16 weeks). The combination therapy may be titrated to a final dose over a period between about 2 weeks to about 8 weeks. The combination therapy may be titrated to a final dose over a period between about 2 weeks to about 6 weeks.

[0668] The combination therapy may be titrated to a final dose over a period between about 4 weeks to about 8 weeks.

[0669] The combination therapy may be titrated to a final dose over about 2 weeks. The combination therapy may be titrated to a final dose over about 4 weeks. The combination therapy may be titrated to a final dose over about 6 weeks. The combination therapy may be titrated to a final dose over about 8 weeks. The combination therapy may be titrated to a final dose over about 17 weeks. The combination therapy may be titrated to a final dose over about 21 weeks. The combination therapy may be titrated to a final dose over about 36 weeks.

[0670] Where the combination therapy comprises a dose of about 9 mg AMYR agonist, the AMYR agonist may be titrated to a dose of about 9 mg over about 21 weeks. Where the combination therapy comprises a dose of about 9 mg AMYR agonist, the AMYR agonist may be titrated to a dose of about 9 mg over about 20 weeks. Where the combination therapy comprises a dose of about 9 mg AMYR agonist, the AMYR agonist may be titrated to a dose of about 9 mg over about 17 weeks. Where the AMYR agonist is a dose of about 9 mg, the AMYR agonist may be titrated to a dose of about 9 mg over about 8 weeks. Where the AMYR agonist is a dose of about 9 mg, the AMYR agonist may be titrated to a dose of about 9 mg over about 6 weeks. Where the combination therapy comprises a dose of about 6.0 mg AMYR agonist, the AMYR agonist may be titrated to a dose of about 6 mg over about 17 weeks. Where the AMYR agonist is a dose of about 6 mg, the AMYR agonist may be titrated to a dose of about 9 mg over about 8 weeks. Where the AMYR agonist is a dose of about 6 mg, the AMYR agonist may be titrated to a dose of about 9 mg over about 4 weeks. Where the combination therapy comprises a dose of about 1.5 mg AMYR agonist (e.g. about 1.6 mg), the AMYR agonist may be titrated to a dose of about 1.5 mg {e.g. about 1.6 mg) over about 5 weeks. Where the combination therapy comprises a dose of about 1 .5 mg AMYR agonist (e.g. about 1.6 mg), the AMYR agonist may be titrated to a dose of about 1.5 mg e.g. about 1 .6 mg) over about 4 weeks.

[0671] Where the combination therapy comprises a dose of about 9.4 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 9.4 mg over about 21 weeks. Where the combination therapy comprises a dose of about 9.4 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 9.4 mg over about 20 weeks. Where the combination therapy comprises a dose of about 9.4 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 9.4 mg over about 17 weeks. Where the combination therapy comprises a dose of about 9.4 mg GLP-1 R agonist (e.g. GLP- 1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 9.4 mg over about 8 weeks. Where the combination therapy comprises a dose of about 9.4 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 9.4 mg over about 6 weeks. Where the combination therapy comprises a dose of about 7 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 7 mg over about 21 weeks. Where the combination therapy comprises a dose of about 7 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 7 mg over about 20 weeks. Where the combination therapy comprises a dose of about 7 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 7 mg over about 17 weeks. Where the combination therapy comprises a dose of about 7 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 7 mg over about 8 weeks. Where the combination therapy comprises a dose of about 7 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 7 mg over about 6 weeks. Where the combination therapy comprises a dose of about 4.6 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 4.6 mg over about 17 weeks. Where the combination therapy comprises a dose of about 4.6 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 4.6 mg over about 8 weeks. Where the combination therapy comprises a dose of about 4.6 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 4.6 mg over about 4 weeks. Where the combination therapy comprises a dose of about 1.2 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 1 .2 mg over about 5 weeks. Where the combination therapy comprises a dose of about 1.2 mg GLP-1 R agonist (e.g. GLP-1 R / GCGR dual agonist), the GLP-1 R agonist may be titrated to a dose of about 1 .2 mg over about 4 weeks.

[0672] Titration may involve a single step-change in the dose of the AMYR agonist and / or the GLP- 1 R agonist (e.g. GLP-1 R / GCGR dual agonist). Each step-change may comprise one more administrations of a dose (e.g. 1 , 2, 3, or 4 doses) at a given titration level.

[0673] Alternatively, titration may involve multiple step-changes (e.g. 2, 3 or more step-changes) in the dose of the combination therapy. Each step-change may comprise one more administrations of a dose (e.g. 1 , 2, 3, or 4 doses) at a given titration level. Thus, the combination therapy may be titrated at a first dose over a first period of time, increased to one or more intermediate doses over a second or subsequent e.g., a third, fourth, or fifth, etc.) period of time, and then increased to a final dose. The first, second, and subsequent periods of time may be the same or different lengths of time. The first period of time may be between about 1 week to about 8 weeks. The first period of time may be between about 2 weeks to about 8 weeks. The first period of time may be between about 2 weeks to about 6 weeks. The first period of time may be between about 4 weeks to about 8 weeks. The first period of time may be about 1 week. The first period of time may be about 2 weeks. The first period of time may be about 4 weeks. The first period of time may be about 6 weeks. The first period of time may be about 8 weeks. The second and / or subsequent period of time may be between about 2 weeks to about 8 weeks. The second and / or subsequent period of time may be between about 2 weeks to about 6 weeks. The second and / or subsequent period of time may be between about 4 weeks to about 8 weeks. The second and / or subsequent period of time may be about 2 weeks. The second and / or subsequent period of time may be about 4 weeks. The second and / or subsequent period of time may be about 6 weeks. The second and / or subsequent period of time may be about 8 weeks.

[0674] By way of non-limiting example, titration to a final dose of 6 mg AMYR agonist may comprise one or more dose (e.g. 1 , 2, 3, or 4 doses) of 0.4 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 0.8 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 1 .6 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 3 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 4.5 mg, followed by the remaining doses at the final dose of 6 mg. By way of non-limiting example, titration to a final dose of 4.6 mg GLP-1 R agonist (e.g. GLP- 1 R / GCGR dual agonist) may comprise one or more dose (e.g. 1 , 2, 3, or 4 doses) of 0.3 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 0.6 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 1.2 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 2.3 mg, followed by one or more dose (e.g. 1 , 2, 3 or 4 doses) at 3.5 mg, followed by the remaining doses at the final dose of 4.6 mg. Further exemplary titration schedules are set out in Figures 14-17.

[0675] In some particularly preferred embodiments, the combination therapy comprises or consists of (a) an AMYR agonist polypeptide, consisting of the amino acid sequence K(yE-yE- C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11), or pharmaceutically acceptable salt thereof, at any dose disclosed herein; and (b) a GLP-1 R agonist (e.g. a GLP-1 R / GCGR dual-agonist) polypeptide consisting of the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc-yE-

[0676] C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35), or pharmaceutically acceptable salt thereof, at any dose disclosed herein.

[0677] Amylin Receptor Agonists

[0678] Efficacy

[0679] Typically the AMYR is human AYMR (hAMYR). Human AMYR is formed of the human calcitonin receptor hCTR complexed with at least one of the human receptor activity modifying proteins designated hRAMPI , hRAMP2 and hRAMP3. Thus, hAMYI R is a complex of hCTR and hRAMPI ; hAMY2R is a complex of hCTR and hRAMP2; and hAMY3R is a complex of hCTR and hRAMP3. An exemplary amino acid sequence for hRAMPI is given in SEQ ID NO: 1. An exemplary amino acid sequence for hRAMP2 is given in SEQ ID NO: 2. An exemplary amino acid sequence for hRAMP3 is given in SEQ ID NO: 3. An exemplary amino acid sequence for hCTR is given in SEQ ID NO: 4.

[0680] An AMYR agonist of the invention may activate one or more of hAMYI R, hAMY2R and / or hAMY3R. Thus, an AMYR agonist of the invention may activate hAMYI R; hAMY2R; hAMY3R; hhAMYI R and AMY2R; hAMYI R and AhMY3R; hAMY2R and hAMY3R; or hAMYI R, hAMY2R and hAMY3R.

[0681] An AMYR agonist is not native amylin but exhibits activity at the AMYR of about at least 1% or more relative to native amylin. In some embodiments, an AMYR agonist exhibits activity at the AMYR of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more relative to native amylin. This may be measured using a cAMP assay, and quantified by Effective Concentration (EC) values, such as asymptotic maximum attainable response, Emax, or EC5O, as described further below.

[0682] The ability to induce cAMP formation as a result of binding to the relevant receptor or receptor complex is typically regarded as indicative of agonist activity. Other intracellular signaling pathways or events may also be used as readouts for amylin receptor agonist activity. These may include calcium release, arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, inositol phosphate release, diacylglycerol release or nuclear transcription factor translocation.

[0683] EC5O values may be used as a measure of agonist potency at a given receptor. An EC5o value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay, for example a cAMP assay as described in Example 2 of WO 2022 / 129254, which is herein incorporated by reference in its entirety.

[0684] In particular, an AMYR agonist of the invention has selectivity to AMYR (preferably hAMYR) over a CTR (preferably hCTR). Such amylin agonists are described as selective amylin receptor agonists (SARAs). Thus, in some embodiments, the AMYR agonist of the invention is a SARA. In some embodiments, the AMYR agonist of the invention is not a dual amylin and calcitonin receptor agonist (DACRA). A SARA may have selectivity for AMYR over a CTR as described further below in the context of AMYR agonists of the invention. An AMYR agonist of the invention may exhibit greater or similar selectivity to hAMYR over hCTR as pramlintide, optionally as measured using cAMP release from binding to hAMYR and hCTR. Pramlintide exhibits at least 10-fold selectivity to hAMYR as compared to hCTR.

[0685] An AMYR agonist of the invention may exhibit a lower or similar selectivity to hAMYR over hCTR as pramlintide, optionally as measured using cAMP release from binding to hAMYR and hCTR. Where an AMYR agonist of the invention exhibits a lower selectivity to hAMYR over hCTR compared with pramlintide, the AMYR agonist of the invention is still selective for hAMYR over hCTR. Pramlintide exhibits at least 10-fold selectivity to hAMYR as compared to hCTR.

[0686] In some embodiments, the AMYR agonist of the invention is not pramlintide. Thus, in some embodiments, the AMYR agonist of the invention is not a DACRA and is not pramlintide. In some embodiments, the AMYR agonist of the invention is a SARA and is not pramlintide.

[0687] An AMYR agonist of the invention may have at least a 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, at least 17-fold, at least 20-fold, or at least 25-fold, at least about 50-fold, at least about 75-fold, or at least about 100-fold selectivity to hAMYR over hCTR. In preferred embodiments, the AMYR agonist has at least a 5-fold selectivity to AMYR (e.g. hAMYR) over CTR (e.g. hCTR). In other preferred embodiments, the AMYR agonist has at least a 10-fold selectivity to AMYR (e.g. hAMYR) over CTR (e.g. hCTR).

[0688] In some embodiments, an AMYR agonist of the invention has around 12-20-fold, around 14- 18-fold, optionally around 16-fold selectivity to AMYR (e.g. hAMYR) over CTR (e.g. hCTR).

[0689] In some embodiments, the AMYR agonist of the invention has an EC50 measured under the conditions described in Example 2 of WO 2022 / 129254 (i.e. containing 0.1 % bovine serum albumin (BSA)) of below about 1 .4 nM, below about 1 .2 nM, below about 1 nM, below about 0.8 nM, below about 0.6 nM, below about 0.4 nM, below about 0.3 nM, or below about 0.2 nM for an AMYR, particularly AMY3R.

[0690] In contrast, a DACRA may have less than 2-fold selectivity, less than 1.5-fold selectivity, or less than 1.2-fold selectivity for hAMYR over hCTR. A D...

Claims

1. CLAIMS1. A method for treating and / or preventing a disease or disorder in a subject, the method comprising administering to the subject(a) about 1 mg to about 15 mg of an amylin receptor (AMYR) agonist; and(b) about 0.1 mg to about 10 mg of a GLP-1 receptor (GLP-1 R) agonist.

2. The method according to claim 1 , wherein the GLP-1 R agonist activates both a GLP- 1 R and a glucagon receptor (GCGR).

3. The method according to claim 1 , wherein the method further comprises administering to the subject a glucagon receptor (GCGR) agonist.

4. The method of any one of claims 1 to 3, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 7 mg.

5. The method of any one of claims 1 to 4, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 5 mg.

6. The method of any one of the preceding claims, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 1 .5 mg.

7. The method of any one of the preceding claims, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 1 mg.

8. The method of any one of the preceding claims, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 0.5 mg.

9. The method of any one of the preceding claims, wherein the amount of GLP-1 R agonist is from about 0.1 mg to about 0.2 mg.

10. The method of any one of claims 1 to 3, wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 10 mg.

11. The method of any one of claims 1 to 4 or 10, wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 7 mg.

12. The method of any one of claims 1 to 5, 10, or 11 , wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 5 mg.

13. The method of any one of claims 1 to 6 or 10 to 12, wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 1 .5 mg.

14. The method of any one of claims 1 to 7, or 10 to 13, wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 1 mg.

15. The method of any one of claims 1 to 8 or 10 to 14, wherein the amount of GLP-1 R agonist is from about 0.2 mg to about 0.5 mg.

16. The method of any one of claims 1 to 3 or 10, wherein the amount of GLP-1 R agonist is from about 0.5 mg to about 10 mg.

17. The method of any one of claims 1 to 4, 10, 11 , or 16, wherein the amount of GLP-1 R agonist is from about 0.5 mg to about 7 mg.

18. The method of any one of claims 1 to 5 or 10 to 12, 16, or 17, wherein the amount of GLP-1 R agonist is from about 0.5 mg to about 5 mg.

19. The method of any one of claims 1 to 6, 10 to 13, or 16 to 18, wherein the amount of GLP-1 R agonist is from about 0.5 mg to about 1 .5 mg.

20. The method of any one of claims 1 to 7, 10 to 14, or 16 to 19, wherein the amount of GLP-1 R agonist is from about 0.5 mg to about 1 mg.

21. The method of any one of claims 1 to 3, 10, or 16, wherein the amount of GLP-1 R agonist is from about 1 mg to about 10 mg.

22. The method of any one of claims 1 to 4, 10, 11 , 16, 17, or 21 , wherein the amount of GLP-1 R agonist is from about 1 mg to about 7 mg.

23. The method of any one of claims 1 to 5, 10 to 12, 16 to 18, 21 or 22, wherein the amount of GLP-1 R agonist is from about 1 mg to about 5 mg, optionally from about 1 mg to about 2 mg.

24. The method of any one of claims 1 to 6, 10 to 13, 16 to 19, or 21 to 23, wherein the amount of GLP-1 R agonist is from about 1 mg to about 1 .5 mg.

25. The method of any one of claims 1 to 5, 10 to 12, 16 to 18, 21 or 22, wherein the amount of GLP-1 R agonist is from about 1 .5 mg to about 5 mg.

26. The method of any one of claims 1 to 3, 10, 16 or 21 , wherein the amount of GLP-1 R agonist is from about 2 mg to about 10 mg.

27. The method of any one of claims 1 to 4, 10, 11 , 16, 17, 21 , 22, or 26, wherein the amount of GLP-1 R agonist is from about 2 mg to about 7 mg.

28. The method of any one of claims 1 to 5, 10 to 12, 16 to 18, 21 to 23, 26 or 27, wherein the amount of GLP-1 R agonist is from about 2 mg to about 5 mg, optionally from about 3 mg to about 5 mg, or from about 2 mg to about 4 mg.

29. The method of any one of claims 1 to 3, 10, 16, 21 , or 26, wherein the amount of GLP-1 R agonist is from about 4 mg to about 10 mg.

30. The method of any one of claims 1 to 4, 10, 11 , 16, 17, 21 , 22, 26, 27, or 29, wherein the amount of GLP-1 R agonist is from about 4 mg to about 7 mg.

31. The method of any one of claims 1 to 5, 10 to 12, 16 to 18, 21 to 23, 26 to 30, wherein the amount of GLP-1 R agonist is from about 4 mg to about 5 mg.

32. The method of any one of claims 1 to 3, 10, 16, 21 , 26, or 29, wherein the amount of GLP-1 R agonist is from about 5 mg to about 10 mg.

33. The method of any one of claims 1 to 4, 10, 11 , 16, 17, 21 , 22, 26, 27, 29, 30, or 32, wherein the amount of GLP-1 R agonist is from about 5 mg to about 7 mg.

34. The method of any one of claims 1 to 3, 10, 16, 21 , 26, 29, or 32 wherein the amount of GLP-1 R agonist is from about 8 mg to about 10 mg.

35. The method of any one of the preceding claims, wherein the amount of GLP-1 R agonist is about 0.15 mg, about 0.3 mg, about 0.6 mg, about 1.2 mg, about 2.3 mg,about 4.6 mg, about 7.0 mg, or about 9.4 mg, preferably about 1 .2 mg, about 4.6 mg, about 7 mg, or about 9.4 mg.

36. The method of any one of the preceding claims, wherein the amount of AMYR agonist is from about 1 mg to about 10 mg.

37. The method of any one of the preceding claims, wherein the amount of AMYR agonist is from about 1 mg to about 5 mg.

38. The method of any one of claims 1 to 36, wherein the amount of AMYR agonist is from about 4 mg to about 10 mg, optionally from about 4 mg to about 7 mg.

39. The method of any one of claims 1 to 37, wherein the amount of AMYR agonist is from about 1 mg to about 3 mg, optionally from about 1 mg to about 2 mg.

40. The method of any one of claims 1 to 37, wherein the amount of AMYR agonist is from about 2.5 mg to about 5 mg, optionally from about 4 mg to about 5 mg.41 . The method of any one of claims 1 to 36 or 38, wherein the amount of AMYR agonist is from about 7 mg to about 10 mg.

42. The method of any one of the preceding claims, wherein the amount of AMYR agonist is about 1 .5 mg {e.g. 1 .6 mg), about 4.5 mg, about 6 mg, or about 9 mg.

43. The method of claims 34 or 41 , wherein the amount of AMYR agonist is from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist is from about 8 mg to about 10 mg, optionally about 9.4 mg.

44. The method of claims 32 or 41 , wherein the amount of AMYR agonist is from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist is from about 5 mg to about 10 mg, optionally about 7 mg.

45. The method of claims 28 or 41 , wherein the amount of AMYR agonist is from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist is from about 3 mg to about 5 mg, optionally about 4.6 mg.

46. The method of claims 28 or 41 , wherein the amount of AMYR agonist is from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist is from about 2 mg to about 4 mg, optionally about 2.3 mg.

47. The method of claims 23 or 41 , wherein the amount of AMYR agonist is from about 7 mg to about 10 mg, optionally about 9 mg, and the amount of GLP-1 R agonist is from about 1 mg to about 2 mg, optionally about 1 .2 mg.

48. The method of claims 34 or 38, wherein the amount of AMYR agonist is from about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist is from about 8 mg to about 10 mg, optionally about 9.4 mg.

49. The method of claims 32 or 38, wherein the amount of AMYR agonist is from about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist is from about 5 mg to about 10 mg, optionally about 7 mg.

50. The method of claims 28 or 38, wherein the amount of AMYR agonist is from about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist is from about 3 mg to about 5 mg, optionally about 4.6 mg.51 . The method of claims 28 or 38, wherein the amount of AMYR agonist is from about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist is from about 2 mg to about 4 mg, optionally about 2.3 mg.

52. The method of claims 23 or 38, wherein the amount of AMYR agonist is from about 4 mg to about 7 mg, optionally about 6 mg, and the amount of GLP-1 R agonist is from about 1 mg to about 2 mg, optionally about 1 .2 mg.

53. The method of claims 34 or 40, wherein the amount of AMYR agonist is from about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist is from about 8 mg to about 10 mg, optionally about 9.4 mg.

54. The method of claims 32 or 40, wherein the amount of AMYR agonist is from about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist is from about 5 mg to about 10 mg, optionally about 7 mg.

55. The method of claims 28 or 40, wherein the amount of AMYR agonist is from about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist is from about 3 mg to about 5 mg, optionally about 4.6 mg.

56. The method of claims 28 or 40, wherein the amount of AMYR agonist is from about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist is from about 2 mg to about 4 mg, optionally about 2.3 mg.

57. The method of claims 23 or 40, wherein the amount of AMYR agonist is from about 4 mg to about 5 mg, optionally about 4.5 mg, and the amount of GLP-1 R agonist is from about 1 mg to about 2 mg, optionally about 1 .2 mg.

58. The method of claims 34 or 39, wherein the amount of AMYR agonist is from about 1 mg to about 2 mg, optionally about 1.5 mg {e.g. 1.6 mg), and the amount of GLP-1 R agonist is from about 8 mg to about 10 mg, optionally about 9.4 mg.

59. The method of claims 32 or 39, wherein the amount of AMYR agonist is from about 1 mg to about 2 mg, optionally about 1.5 mg e.g. 1.6 mg), and the amount of GLP-1 R agonist is from about 5 mg to about 10 mg, optionally about 7 mg.

60. The method of claims 28 or 39, wherein the amount of AMYR agonist is from about 1 mg to about 2 mg, optionally about 1.5 mg e.g. 1.6 mg), and the amount of GLP-1 R agonist is from about 3 mg to about 5 mg, optionally about 4.6 mg.61 . The method of claims 28 or 39, wherein the amount of AMYR agonist is from about 1 mg to about 2 mg, optionally about 1.5 mg {e.g. 1.6 mg), and the amount of GLP-1 R agonist is from about 2 mg to about 4 mg, optionally about 2.3 mg.

62. The method of claims 23 or 39, wherein the amount of AMYR agonist is from about 1 mg to about 2 mg, optionally about 1.5 mg {e.g. 1.6 mg), and the amount of GLP-1 R agonist is from about 1 mg to about 2 mg, optionally about 1 .2 mg.

63. The method of any one of the preceding claims, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered by subcutaneous injection.

64. The method of any one of the preceding claims, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered to the subject by self-administration.

65. The method of any one of the preceding claims wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered about once every 4, 5, 6, 7, 8, 9, 10,11 , 12, 13, or 14 days; optionally wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered about once a week.

66. The method of any one of the preceding claims, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered to the subject multiple times over a period of at least 3 months, 6 months, 9 months, 1 year, 2 years, or 5 years.

67. The method of any one of the preceding claims, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is titrated to a final dose over a period between about 4 weeks and about 36 weeks, optionally over a period of about 5 weeks, about 17 weeks or about 21 weeks.

68. The method of claim 67, wherein the dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is increased every one week, every two weeks or every four weeks until the final dose is reached; optionally wherein:(a) a first dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is administered for the first two weeks;(b) following (a) the dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is increased for the next two weeks; and(c) following (b) the dose of the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is increased every four weeks for the next 16 weeks.

69. The method of any one of the preceding claims, wherein the subject’s body weight is reduced by >5%, optionally, wherein the subject’s body weight is reduced by >10%, >15%, or >20%.

70. The method of any one of the preceding claims, wherein the disease or disorder is obesity.71 . The method according to any one of claims 1 to 69, wherein the disease or disorder is an obesity-related condition; optionally wherein the obesity-related condition is overweight, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease, sleep apnoea and respiratory problems, hyperlipidaemia, degeneration of cartilage, osteoarthritis, or reproductive health complications of obesity or overweight such as infertility.

72. The method according to any one of claims 1 to 69, wherein the disease or disorder is a metabolic disease, optionally wherein the metabolic disease includes diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes, pre-diabetes, insulin resistance, impaired glucose tolerance (IGI), disease states associated with elevated blood glucose levels, metabolic syndrome, or hyperglycaemia (e.g. abnormal postprandial hyperglycaemia).

73. The method according to any one of claims 1 to 69, wherein the disease or disorder is hepatic steatosis ("fatty liver"), e.g., Metabolic dysfunction associated steatohepatitis (MASH).

74. The method according to any one of the preceding claims, wherein the method further comprises treating, improving, and / or protecting liver and / or kidney function in the subject.

75. The method according to claim 74, wherein the method of treating, improving, and / or protecting liver function comprises reducing steatohepatitis and / or fibrosis in the liver.

76. The method of any one of the preceding claims wherein the method of treatment reduces the body weight of a subject, optionally wherein the subject’s reduction in body weight is fat-specific weight loss.

77. The method according to claim 76, wherein the reduction in the body weight of the subject is greater than the reduction in body weight with a therapeutically effective dose of a dual amylin-calcitonin receptor agonist (DACRA), a GLP-1 R agonist, a GLP-1 R / GCGR dual agonist, a GLP1 / GCG / GIP triple agonist, and / or a DACRA-GLP- 1 Ra combination.

78. The method of any one of the preceding claims, wherein the subject experiences reduced nausea as compared to a therapeutically effective dose of a dual amylin- calcitonin receptor agonist (DACRA), a GLP-1 R agonist, a GLP-1 R / GCGR dual agonist; a GLP1 / GCG / GIP triple agonist; and / or a DACRA-GLP-1 Ra combination.

79. The method according to any one of the preceding claims, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is a polypeptide, small molecule drug, antibody, antibody-drug conjugate, or aptamer; or a pharmaceutically acceptable salt thereof.

80. The method according to claim 79, wherein the AMYR agonist, GLP-1 R agonist, and / or GCGR agonist is a polypeptide, or a pharmaceutically acceptable salt thereof.81 . The method according to any one of the preceding claims, wherein:(a) the AMYR is a human AMYR and / or the AMYR is AMY1 R, AMY2R and / or AMY3R;(b) the GLP-1 R is a human GLP-1 R; and / or(c) the GCGR is a human GCGR.

82. The method of any one of the preceding claims, wherein the AMYR agonist has selectivity to AMYR as compared to a calcitonin receptor (CTR).

83. The method according to claim 82, wherein the AMYR agonist has at least a 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8- fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, at least 17-fold, at least 20-fold, or at least 25-fold selectivity to AMYR as compared to CTR; optionally wherein the AMYR agonist has at least a 10-fold selectivity to AMYR as compared to CTR.

84. The method of any one of the preceding claims, wherein the AMYR agonist is an AMYR agonist polypeptide, or a pharmaceutically acceptable salt thereof, which comprises an amino acid sequence having at least 90% identity to pramlintide (KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-amide, SEQ ID NO: 5).

85. The method of claim 84, wherein the AMYR agonist polypeptide is lipidated and / or wherein the lipid is attached to an amino acid residue in the AMYR agonist polypeptide by a linker.

86. The method of claim 84 or claim 85, wherein the AMYR agonist polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the amino acid sequence K[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 26).

87. The method of claim 86, wherein the AMYR agonist polypeptide, or pharmaceutically acceptable salt thereof, comprises the amino acid sequence K(yE-yE- C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11 ).

88. The method of any one of the preceding claims, wherein the GLP-1 R agonist activates both GLP-1 R and GCGR, and wherein optionally the GLP-1 R agonist is selective to GLP-1 R as compared to GCGR.

89. The method of claim 88, wherein the GLP-1 R agonist activates GLP-1 R and GCGR equally, or wherein the GLP-1 R agonist has at least a 1 .5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, at least 17-fold, at least 20-fold, or at least 25-fold selectivity to GLP-1 R as compared to GCGR; optionally wherein the GLP-1 R agonist has at least a 1.5-fold selectivity to GLP-1 R as compared to GCGR.

90. The method of any one of the preceding claims, wherein the GLP-1 R agonist polypeptide, or pharmaceutically acceptable salt thereof, comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the amino acid sequenceH(Aib)QGTFTSDVSK(aMePhe)LDTKRARDFVQWLLE(Aib)G-acid (SEQ ID NO: 33).91 . The method of claim 90, wherein the GLP-1 R agonist polypeptide is lipidated and / or wherein the lipid is attached to an amino acid residue in the GLP-1 R agonist polypeptide by a linker.

92. The method according to claim 90 or 91 , wherein the GLP-1 R agonist polypeptide, or pharmaceutically acceptable salt thereof, comprises the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc-yE- C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35).

93. The method of any one of the preceding claims, wherein the AMYR agonist is a polypeptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence K(yE-yE-C18diacid)[CNTATC]ATQRLANFLRHSSNN(aMePhe)GPILPPTEVGSNTY-amide (SEQ ID NO: 11 ) in an amount of about 1.5 mg {e.g. 1.6 mg), about 4.5 mg, about 6 mg, or about 9 mg; and wherein the GLP-1 R agonist is a polypeptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence H(Aib)QGTFTSDVSK(aMePhe)LDTK(O2Oc-O2Oc-yE- C18diacid)RARDFVQWLLE(Aib)G-acid (SEQ ID NO: 35) in an amount of about 0.15mg, about 0.3 mg, about 0.6 mg, about 1.2 mg, about 2.3 mg, about 4.6 mg, about 7 mg, or about 9.4 mg.

94. The method of claim 93, wherein the subject has obesity or an obesity-related condition.

95. A method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

96. A cosmetic method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

97. A method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

98. A cosmetic method of reducing fat-mass specific body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

99. A method of improving glycemic and / or metabolic control in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

100. The method according to claim 99, wherein the method of improving glycemic and / or metabolic control in a subject comprises increasing insulin secretion, delaying gastric emptying, increasing mitochondria function, inhibiting de novo lipogenesis, decreasing HbAlc, enhancing fatty oxidation, decreasing hepatic mitochondrial oxidative stress, decreasing steatosis, decreasing fibrosis, decreasing glycogen synthesis, increasing gluconeogenesis, reducing or reversing fibrosis (e.g., liver fibrosis), reducing steatohepatitis, and / or reducing risk of death due to cirrhosis, hepatocellular carcinoma, and / or cardiorenal disease in the subject.

101. The method of any one of the preceding claims, wherein the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, are administered simultaneously.

102. The method of any one of the preceding claims, wherein the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, are administered sequentially.

103. The method of any one of the preceding claims, wherein the AMYR agonist and GLP-1 R agonist, or pharmaceutically acceptable salts thereof, are formulated in a dual-chamber device.

104. A method of treating and / or preventing obesity or an obesity-related condition in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

105. A method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

106. A method of reducing the body weight of a subject, in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

107. A cosmetic method of reducing the body weight of a subject, the method comprising administering to the subject about 1 mg to about 15 mg of an AMYR agonist and about 0.1 to about 10 mg of a GLP-1 R agonist.

108. An AMYR agonist and a GLP-1 R agonist for use in a method of treating and / or preventing obesity or an obesity-related condition in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist.

109. An AMYR agonist and a GLP-1 R agonist for use in a method of treating and / or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist.

110. An AMYR agonist and a GLP-1 R agonist for use in a method of reducing body weight in a subject, the method comprising administering to the subject about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist.

111. The AMYR agonist and the GLP-1 R agonist for use in a method according to claim 110, wherein the subject has a disease or disorder selected from obesity, an obesity-related condition, and metabolic disease.

112. A method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, increasing satiety, and / or reducing excess body weight in a subject, the method comprising administering about 1 mg to about 15 mg of an AMYR agonist, or pharmaceutically acceptable salt thereof, wherein said subject:(i) is overweight or obese and has type 2 diabetes; and(ii) who is being treated with a GLP-1 R agonist at the time treatment with the AMYR agonist commences, and optionally who continues treatment with about 0.1 mg to about 10 mg of a GLP-1 R agonist after treatment with the AMYR agonist commences.

113. An article of manufacture comprising (a) an AMYR agonist at a dose of about 1 mg to about 15 mg; and (b) a GLP-1 R agonist at a dose of about 0.1 to about 10 mg.

114. A kit comprising (a) an AMYR agonist, (b) a GLP-1 R agonist, and (c) instructions for use of the same for treating or preventing obesity or an obesity- related condition at a dose of about 1 mg to about 15 mg of the AMYR agonist and about 0.1 to about 10 mg of the GLP-1 R agonist.

115. The kit of claim 114, wherein the kit comprises a dual-chamber device.

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