Methods of using GCG / GLP1 co-agonists for treatment

Abstract

The present invention discloses doses and dosing regimens of an insulinotropic analogue, including determining and administering doses of a long-acting insulinotropic analogue, such as a glucagon-like peptide-1 (GLP-1) and glucagon (Gcg) co-agonist, suitable for once weekly administration.

Description

[0001] Reference sequence list

[0002] The present disclosure is submitted with a sequence listing in ST.26 XML format. The sequence listing is provided in the form of a file named "30324_WO_SeqListing", created on May 18, 2023, and is 3.1 kilobytes (kb) in size. The sequence listing information in ST.26 XML format is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods of using incretin analogs or pharmaceutically acceptable salts thereof, medical uses, and pharmaceutical compositions containing incretin analogs or pharmaceutically acceptable salts thereof, wherein the incretin analogs or pharmaceutically acceptable salts thereof are active on both glucagon (Gcg) receptors and glucagon-like peptide-1 (GLP1) receptors, and in particular to methods of using and medical uses of a certain dose of incretin analogs and compositions containing a certain dose of incretin analogs, wherein the incretin analogs and compositions containing a certain dose of incretin analogs can be used to treat diabetes, The present invention relates to conditions, diseases and disorders including type 2 diabetes mellitus (T2DM) and / or its symptoms, obesity, hypertension, cardiovascular disease, especially MACE (including death, myocardial infarction; stroke, hospitalization for heart failure; and revascularization, including percutaneous coronary intervention and coronary artery bypass grafting) and atherosclerosis, chronic kidney disease, diabetic nephropathy, osteoarthritis, polycystic ovary syndrome, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty acid liver disease (NAFLD), obstructive sleep apnea, etc. Background Art

[0004] Over the past few decades, the prevalence of diabetes has continued to rise, a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. Type 2 diabetes is the most common type of diabetes, accounting for approximately 90% of all diabetes. In T2DM, the combination of impaired insulin secretion and insulin resistance is associated with elevated blood glucose levels.

[0005] Uncontrolled diabetes can lead to one or more conditions that affect morbidity and mortality in such individuals. One of the major risk factors for T2DM is obesity, and many individuals with T2DM (~90%) are overweight or obese. It is documented that a reduction in body adiposity will lead to improvements in obesity-related comorbidities.

[0006] Currently, standard treatments for T2DM, obesity, and obesity-related metabolic disorders include diet and exercise, as well as oral and injectable glucose-lowering drugs (including incretin-based therapies such as GLP-1 receptor agonists). Despite the success of GLP-1 receptor agonists, a large number of individuals receiving approved therapies do not achieve their weight loss and / or glycemic control goals (see, e.g., Casagrande et al. (2013) Diabetes Care 36: 2271-2279), and there remains a "gap" between the efficacy of GLP-1 analogs and the efficacy of bariatric surgery. To fill this gap, researchers have adopted a "co-agonist" strategy that combines GLP-1 with related hormones and related peptides in the proglucagon family, including GIP and Gcg itself (see Sanchez-Garrido MA et al., Diabetologia (2017) 60(10): 1851-61).

[0007] There are a variety of GLP-1 / Gcg co-agonists in clinical development, including cotadutide, efinopegdutide, mazdutide (described in International Patent Application Publication No. WO 2016 / 209707A1), SAR425899, BI 456906, JNJ-54729518, HM15211, NNC9204-1706, Alt-801 (pemvidutide), and G3215 (see Hope DCD et al., Frontiers in Endocrinology (Lausanne), Sep 8, 2021; 12:735019, Table 1). In these early clinical results, some GLP-1 / Gcg co-agonists have been shown to have promising weight loss, blood sugar effects, or both. However, some reports suggest that the weight loss and / or glucose lowering effects of these co-agonists may plateau, such that higher doses do not result in improved efficacy, thereby limiting the achievable weight loss and / or glycemic improvement; in addition, adverse gastrointestinal events may limit the tolerability of high doses. See, e.g., Ji et al., The Lancet, EClinicalMedicine 39(2021)101088; Nahra et al., Diabetes Care.2021;44:1433-42;, Clinical Obesity, April 2021;11(2):e12432); Ambery et al., British Journal of Clinical Pharmacology, October 2018;84(10):2325-2335.

[0008] Therefore, there is a need for more effective GLP-1 / GCG co-agonist doses and dosing regimens that are capable of achieving high weight loss and / or providing improved glycemic control in individuals in need of such treatment, while also maintaining an overall acceptable benefit / risk profile for the individual. Summary of the invention

[0009] The present invention reports doses and dosing regimens of GLP-1 / Gcg co-agonists that result in unexpectedly improved weight loss, improved body composition, potent glucose control, lipid lowering and / or insulin sensitization, reduced β-cell insulin secretory workload, while exhibiting only mild or moderate adverse events.

[0010] In one aspect, the present invention provides a method of providing long-term weight management, improving glycemic control and / or lowering LDL cholesterol or triglycerides in a patient in need thereof, wherein the method comprises:

[0011] (1) administering a once-weekly dose of a compound of the formula:

[0012] His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly

[0013] wherein Xaa2 is Aib;

[0014] The Lys at position 20 is linked to the ([2-(2-aminoethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 CO 2 H conjugation for chemical modification; and

[0015] The C-terminal amino acid is amidated (SEQ ID NO: 1),

[0016] or a pharmaceutically acceptable salt thereof,

[0017] to patients in need for at least approximately two weeks; and

[0018] (2) thereafter increasing the dose to greater than about 6 mg to about 16 mg, and administering the increased dose to the patient once a week for at least about two weeks.

[0019] In some embodiments, provided herein is a method for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity; dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake, and / or inducing satiety in a patient, wherein the method comprises:

[0020] (1) administering a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof once a week for at least about two weeks; and

[0021] (2) thereafter increasing the dose to greater than about 6 mg to about 16 mg, and administering the increased dose to the patient once a week for at least about two weeks.

[0022] In another aspect of the present disclosure, there is provided a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein:

[0023] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0024] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0025] In some embodiments, a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is provided for use in preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, for reducing weight, for reducing food intake and / or for inducing satiety in a patient, wherein:

[0026] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0027] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0028] In another aspect of the present disclosure, there is provided a use of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein:

[0029] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0030] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0031] In some embodiments, provided is a use of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake and / or inducing satiety in a patient, wherein:

[0032] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0033] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0034] In another aspect of the disclosure, the once weekly increasing dose is from about 6.25 mg to about 16.0 mg, from about 6.5 mg to about 16.0 mg, from about 8.0 mg to about 16.0 mg, from about 10 mg to about 16.0 mg, from about 11.0 mg to about 16 mg, from about 12.0 mg to about 16.0 mg, from about 13.0 mg to about 16.0 mg, or from about 14.0 mg to about 16.0.

[0035] In another aspect of the present disclosure, the dose increased once a week is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg. In some embodiments, the dose increased once a week is about 6.5 mg. In some embodiments, the dose increased once a week is about 7.0 mg. In some embodiments, the dose increased once a week is about 8.0 mg. In some embodiments, the dose increased once a week is about 9.0 mg. In some embodiments, the dose increased once a week is about 10.0 mg. In some embodiments, the dose increased once a week is about 11.0 mg. In some embodiments, the dose increased once a week is about 12.0 mg. In some embodiments, the dose increased once a week is about 13.0 mg. In some embodiments, the dose increased once a week is about 14.0 mg. In some embodiments, the weekly increase in dose is about 15.0 mg. In some embodiments, the weekly increase in dose is about 16.0 mg.

[0036] In a preferred aspect of the present disclosure, the dose increased once a week is about 8.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the dose increased once a week is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0037] In another preferred aspect of the present disclosure, the dosage increased once a week is about 10.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the dosage increased once a week is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0038] In one aspect of the present disclosure, the dosage once a week in step (1) is about 1.0 mg to about 6.0 mg. In still another aspect of the present disclosure, the dosage about once a week is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg.

[0039] In still another aspect of the present disclosure, a plurality of different weekly doses are administered to the patient in steps (1) and (2).

[0040] In one aspect of the present disclosure, a first or initial weekly dose of about 1.0 mg to about 6.0 mg is administered to a patient. Therefore, in some embodiments, the first weekly dose is about 1.0 mg to about 6.0 mg. In another aspect of the present disclosure, the first weekly dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg. In a preferred aspect of the present disclosure, the first weekly dose is about 1.0 mg, about 1.5 mg, about 2.0 mg or about 3.0 mg. In some embodiments, the first weekly dose is about 1.0 mg. In some embodiments, the first weekly dose is about 1.5 mg. In some embodiments, the first weekly dose is about 2.0 mg. In some embodiments, the first weekly dose is about 3.0 mg.

[0041] In one aspect of the disclosure, the first dose and each subsequent increased dose are increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and wherein each dose is administered for at least about two weeks. Therefore, the first dose is selected from about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, and about 6.5 mg, and each subsequent dose is increased by about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof relative to the previously administered dose. In a preferred aspect, the first dose is selected from about 1.5 mg, about 2.0 mg, and about 3.0 mg, and each subsequent dose is increased by about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, or any combination thereof relative to the previously administered dose.

[0042] In another aspect of the present disclosure, the dose can be reduced after the maximum or highest dose is administered to the patient. For example, 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg and 10.0 mg of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is administered to the patient once a week, each dose lasting three weeks. After three weeks of administration at a maximum dose of 10 mg, the dose is reduced to 8 mg.

[0043] In another aspect of the present disclosure, the method or use comprises administering each dose once a week for at least about four weeks. In still another aspect of the present disclosure, the method or use comprises administering each dose once a week for at least about six weeks. In still another aspect of the present disclosure, the method or use comprises administering each dose once a week for at least about eight weeks.

[0044] In a preferred aspect, the method or use comprises applying each dose once a week for at least about two weeks, and applying the maximum dose once a week for at least about four weeks. In another preferred aspect, the method or use comprises applying each dose once a week for at least about 4 weeks, and applying the maximum dose once a week for at least about 4 weeks. In another preferred aspect, the method or use comprises applying each dose once a week for at least about 4 weeks, and applying the maximum dose once a week for at least about 8 weeks.

[0045] In another aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 10%. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 15%. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 20%.

[0046] In another aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in HbA1c in a patient. In another aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in LDL cholesterol and / or triglycerides in a patient. In another aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof does not result in unacceptable tolerability.

[0047] In one aspect, the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0048] In one aspect, the patient is overweight. In another aspect, the patient is obese. In another aspect, the patient has type 2 diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The distribution of participants in the clinical study of Compound 1 described in Example 1 is shown.

[0050] Figure 2 Shown are mean body weight changes from baseline for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1.

[0051] Figure 3 Shown are mean waist circumference changes from baseline for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1.

[0052] Figure 4 Mean fasting glucose for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0053] Figure 5 The mean fasting insulin for the placebo, Cohort 1 and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0054] Figure 6The mean fasting C-peptide for the placebo, Cohort 1 and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0055] Figure 7a Mean fasting cholesterol for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0056] Figure 7b Shown are the mean cholesterol profiles for the placebo, Cohort 1, and Cohort 2 treatment groups following a sMMTT performed as part of the clinical study of Compound 1 described in Example 1.

[0057] Figure 7c The percent change from baseline (Day 1) in fasting HDL for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0058] Figure 7d The percent change from baseline (Day 1) in fasting LDL for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0059] Figure 7e Shown are the mean HDL profiles for the placebo, Cohort 1, and Cohort 2 treatment groups following a sMMTT conducted as part of the clinical study of Compound 1 described in Example 1.

[0060] Figure 7f Shown are the mean LDL profiles for the placebo, Cohort 1, and Cohort 2 treatment groups following sMMTT conducted as part of the clinical study of Compound 1 described in Example 1.

[0061] Figure 7g The percent change from baseline (Day 1) in fasting triglycerides for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1 is shown.

[0062] Figure 7h Shown are mean triglyceride profiles for the placebo, Cohort 1, and Cohort 2 treatment groups following sMMTT conducted as part of the clinical study of Compound 1 described in Example 1.

[0063] Figure 8 VAS appetite assessments - hunger, fullness, and overall appetite - are shown for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical study of Compound 1 described in Example 1. DETAILED DESCRIPTION

[0064] Overview

[0065] Many peptides derived from preproglucagon and its analogs have been proposed as therapeutics for the treatment of T2D and obesity, especially Gcg, GLP-1 and oxyntomodulin (OXM). These molecules are involved in a variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying and intestinal growth, as well as the regulation of food intake.

[0066] Gcg is a 29 amino acid peptide that corresponds to amino acids 53 to 81 of preproglucagon. OXM is a 37 amino acid peptide that consists of the complete 29 amino acid sequence of Gcg with an octapeptide carboxyl-terminal extension (amino acids 82 to 89 of preproglucagon, called "intervening peptide 1" or IP-1). Gcg helps maintain glucose levels in the blood by binding to Gcg receptors on liver cells, causing the liver to release glucose stored in the form of glycogen through glycogenolysis. When these stores are depleted, Gcg stimulates the liver to synthesize additional glucose through gluconeogenesis. This glucose is released into the blood, preventing hypoglycemia from occurring.

[0067] GLP-1 has different biological activities compared to Gcg. Its effects include stimulating insulin synthesis and secretion, inhibiting Gcg secretion and inhibiting food intake. GLP-1 has been shown to reduce hyperglycemia in diabetic patients. Several GLP-1 agonists have been approved for the treatment of human T2D, including exenatide, liraglutide, lixisenatide, albiglutide and dulaglutide. Such GLP-1 agonists are effective in blood sugar control and have a favorable effect on body weight without the risk of hypoglycemia. However, due to dose-dependent gastrointestinal side effects, weight loss is moderate.

[0068] OXM activates the Gcg receptor and the GLP-1 receptor, with a slightly higher potency for the Gcg receptor relative to the GLP-1 receptor. Its potency for each receptor is lower than that of native Gcg and GLP-1. Human Gcg is also able to activate both receptors, although the Gcg receptor is strongly preferred relative to the GLP-1 receptor. GLP-1 cannot activate the Gcg receptor. OXM is involved in the regulation of food intake and body weight. It has been shown to suppress human appetite and food intake. International Patent Application Publication No. WO 2016 / 209707A1 describes the structure, function, production and use of OXM analogs (GLP-1 / Gcg co-agonists), which can be used to treat diabetes, obesity, obesity-related comorbidities and other medical conditions. Of particular interest herein is the OXM analog (GLP-1 / Gcg co-agonist) described in Example 2, which is a fatty acid-acylated long-acting OXM analog (GLP-1 / Gcg co-agonist) (SEQ ID NO: 1).

[0069] Unfortunately, many diabetic individuals fail to achieve HbAlc goals and are difficult to control in terms of weight management, so new therapies and dosing regimens that can provide additional glycemic control and / or weight loss are needed. As described above, simply increasing the dose of the therapeutic agent may not necessarily achieve increased efficacy because the efficacy may plateau at certain dose levels. In addition, while increasing the dose of the therapeutic agent may be able to achieve increased efficacy in some cases, increasing the dose of the therapeutic agent, especially therapeutic agents that are active on both the GLP-1 receptor and the GCG receptor, also risks producing greater side effects, particularly gastrointestinal side effects.

[0070] The invention described herein provides doses and dosing regimens that overcome these challenges and surprisingly achieve significantly improved weight loss, improved body composition, robust glucose control, lipid lowering and / or insulin sensitization, reduced beta cell insulin secretory workload, while exhibiting only mild or moderate adverse events.

[0071] As described herein, in a 20-week study, two independent cohorts receiving doses greater than about 6 mg to about 16 mg achieved unexpectedly high weight loss (-19.4% and -20.6%) compared to the group receiving placebo. This degree of weight loss has never been reported before for any GLP-1 / Gcg co-agonist in such a short period of time.

[0072] In particular, it is surprising to find that the dosages and regimens described herein achieve significant weight loss and improved body composition, for example, weight, waist circumference, absolute body fat mass (fat body mass) and % body fat mass reduction and % lean body mass (lean body mass) increase. It is also surprising to find that the dosages and regimens described herein achieve blood sugar control, as demonstrated by the significant reduction of glucose fluctuations in, for example, HbA1c, fasting glucose and mixed meal tolerance test (Mixed Meal Tolerance Test, MMTT). It is also surprising to find that the dosages and regimens described herein achieve improved insulin sensitivity, as demonstrated by, for example, fasting insulin and C-peptide reduction, insulin fluctuation reduction in MMTT and HOMA-IR reduction. It is also surprising to find that the dosages and regimens described herein achieve reduced appetite, as demonstrated by, for example, reduced hunger and increased satiety. It is also surprising to find that the dosages and regimens described herein achieve improvements in lipid profiles, as demonstrated by, for example, the reduction of fasting and sMMTT total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. It was also surprisingly found that the doses and regimens described herein achieved Gcg-R targeting, as demonstrated by, for example, reductions in fasting and sMMTT glucagon levels.

[0073] Various aspects of dosing regimens and methods of use of GLP-1 / Gcg co-agonists suitable for once-weekly dosing are described herein. In some cases, the regimens and methods described herein include determining and administering an initial dose of such GLP-1 / Gcg co-agonist. In other aspects, the regimens and methods described herein include determining and administering a maximum dose or top dose, including when and how to adjust the dose.

[0074] In one aspect, the present invention provides a method of providing long-term weight management, improving glycemic control and / or lowering LDL cholesterol or triglycerides in a patient in need thereof, wherein the method comprises:

[0075] (1) administering a once-weekly dose of a compound of the formula:

[0076] His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly

[0077] wherein Xaa2 is Aib;

[0078] The Lys at position 20 is linked to the ([2-(2-aminoethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 CO 2 H conjugation for chemical modification; and

[0079] The C-terminal amino acid is amidated (SEQ ID NO: 1),

[0080] or a pharmaceutically acceptable salt thereof,

[0081] to patients in need for at least approximately two weeks; and

[0082] (2) thereafter increasing the dose to greater than about 6 mg to about 16 mg, and administering the increased dose to the patient once a week for at least about two weeks.

[0083] In another aspect, provided herein is a method for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity; dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake, and / or inducing satiety in a patient, wherein the method comprises:

[0084] (1) administering a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof once a week for at least about two weeks; and

[0085] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg, and the increasing dose is administered to the patient once a week for at least about two weeks.

[0086] In another aspect of the present disclosure, there is provided a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein:

[0087] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0088] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0089] In another aspect, a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is provided, and a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is provided for use in preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, for weight loss, for reducing food intake and / or for inducing satiety in a patient, wherein:

[0090] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0091] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0092] In another aspect of the present disclosure, there is provided a use of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein:

[0093] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0094] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0095] In another aspect, provided is a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for use in the preparation of a composition for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake and / or inducing satiety in a patient, wherein:

[0096] (1) a once-weekly dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for at least about two weeks; and

[0097] (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

[0098] In another aspect of the disclosure, the once weekly increasing dose is from about 6.25 mg to about 16.0 mg, from about 6.5 mg to about 16.0 mg, from about 8.0 mg to about 16.0 mg, from about 10 mg to about 16.0 mg, from about 11.0 mg to about 16 mg, from about 12.0 mg to about 16.0 mg, from about 13.0 mg to about 16.0 mg, or from about 14.0 mg to about 16.0.

[0099] In another aspect of the present disclosure, the dose increased once a week is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg. In some embodiments, the dose increased once a week is about 6.5 mg. In some embodiments, the dose increased once a week is about 7.0 mg. In some embodiments, the dose increased once a week is about 8.0 mg. In some embodiments, the dose increased once a week is about 9.0 mg. In some embodiments, the dose increased once a week is about 10.0 mg. In some embodiments, the dose increased once a week is about 11.0 mg. In some embodiments, the dose increased once a week is about 12.0 mg. In some embodiments, the dose increased once a week is about 13.0 mg. In some embodiments, the dose increased once a week is about 14.0 mg. In some embodiments, the weekly increase in dose is about 15.0 mg. In some embodiments, the weekly increase in dose is about 16.0 mg.

[0100] In a preferred aspect of the present disclosure, the dose increased once a week is about 8.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the dose increased once a week is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0101] In another preferred aspect of the present disclosure, the dose increased once a week is about 10.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the dose increased once a week is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0102] In one aspect of the present disclosure, the dosage once a week in step (1) is about 1.0 mg to about 6.0 mg. In still another aspect of the present disclosure, the dosage about once a week is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg.

[0103] In still another aspect of the present disclosure, a plurality of different weekly doses are administered to the patient in steps (1) and (2).

[0104] In one aspect of the present disclosure, a first or initial weekly dose of about 1.0 mg to about 6.0 mg is administered to a patient. Therefore, in some embodiments, the first weekly dose is about 1.0 mg to about 6.0 mg. In another aspect of the present disclosure, the first weekly dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg. In a preferred aspect of the present disclosure, the first weekly dose is about 1.0 mg, about 1.5 mg, about 2.0 mg or about 3.0 mg. In some embodiments, the first weekly dose is about 1.0 mg. In some embodiments, the first weekly dose is about 1.5 mg. In some embodiments, the first weekly dose is about 2.0 mg. In some embodiments, the first weekly dose is about 3.0 mg.

[0105] In one aspect of the disclosure, the first dose and each subsequent increased dose are increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and wherein each dose is administered for at least about two weeks. Thus, the first dose is selected from about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, and about 6.5 mg, and each subsequent dose is increased by an increment of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof relative to the previously administered dose.

[0106] In a preferred aspect, the first dose is selected from about 1.5 mg, about 2.0 mg and about 3.0 mg, and each subsequent dose is increased by about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg or any combination thereof relative to the previously administered dose. For example, a first dose of 1.5 mg, a subsequent dose of 3.0 mg (an increment of 1.5 mg relative to a previous dose of 1.5 mg), a subsequent dose of 6.0 mg (an increment of 3.0 mg relative to a previous dose of 3.0 mg), a subsequent dose of 8.0 mg (an increment of 2.0 mg relative to a previous dose of 6.0 mg) and a subsequent dose of 10.0 mg (an increment of 2.0 mg relative to a previous dose of 8.0 mg) are administered to the patient. In another instance, the patient is administered a first dose of 1.5 mg, subsequent doses of 3.0 mg (increments of 1.5 mg relative to a previous dose of 1.5 mg), subsequent doses of 6.0 mg (increments of 3.0 mg relative to a previous dose of 3.0 mg), subsequent doses of 10.0 mg (increments of 4.0 mg relative to a previous dose of 6.0 mg), subsequent doses of 13.0 mg (increments of 3.0 mg relative to a previous dose of 10.0 mg), and subsequent doses of 16.0 mg (increments of 3.0 mg relative to a previous dose of 13.0 mg).

[0107] In another aspect of the present disclosure, the dose can be reduced after the maximum or highest dose is administered to the patient. For example, a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is administered to the patient at doses of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg once a week, each dose lasting three weeks. After three weeks of administration at a maximum dose of 10 mg, the dose is reduced to 8 mg.

[0108] In another aspect of the present disclosure, the method or purposes include applying each dosage once a week for at least about four weeks. In still another aspect of the present disclosure, the method or purposes include applying each dosage once a week for at least about six weeks. In still another aspect of the present disclosure, the method or purposes include applying each dosage once a week for at least about eight weeks. Different weekly dosages can be applied in different time periods. For example, the first dose and the subsequent increased dose are applied for about four weeks, and the maximum increased dose is applied for at least about eight weeks. In another case, the first dose is applied for two weeks, each subsequent increased dose is applied for about two weeks or four weeks, and the maximum increased dose is applied for at least about eight weeks.

[0109] In a preferred aspect of the present disclosure, the maximum increased once weekly dose of the compound or a pharmaceutically acceptable salt thereof is about 6.5 mg.

[0110] In one embodiment, the method or use comprises:

[0111] a) administering a dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0112] b) increasing the dose of the compound, or a pharmaceutically acceptable salt thereof, to about 6.5 mg once per week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0113] In another embodiment, the method or use comprises:

[0114] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0115] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0116] (c) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.5 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0117] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.5 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0118] In another embodiment, the method or use comprises:

[0119] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0120] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg or about 5.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0121] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.5 mg and administering the dose once a week for at least about two weeks, at least about four weeks, or at least about eight weeks.

[0122] In another preferred aspect of the present disclosure, the maximum increased once weekly dose of the compound or a pharmaceutically acceptable salt thereof is about 8.0 mg.

[0123] In one embodiment, the method or use comprises:

[0124] a) administering a dose of about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0125] b) increasing the dose of the compound, or a pharmaceutically acceptable salt thereof, to about 8.0 mg once per week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0126] In another embodiment, the method or use comprises:

[0127] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0128] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0129] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0130] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering once per week for at least about two weeks.

[0131] In another embodiment, the method or use comprises:

[0132] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0133] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0134] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0135] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0136] In another preferred aspect of the present disclosure, the maximum increased once weekly dose of the compound or a pharmaceutically acceptable salt thereof is about 9.0 mg.

[0137] In one embodiment, the method or use comprises:

[0138] a) administering a dose of about 4.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0139] b) increasing the dose of the compound, or a pharmaceutically acceptable salt thereof, to about 9.0 mg once per week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0140] In another embodiment, the method or use comprises:

[0141] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0142] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0143] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0144] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks.

[0145] In another embodiment, the method or use comprises:

[0146] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0147] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0148] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0149] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0150] In another embodiment, the method or use comprises:

[0151] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0152] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0153] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0154] In another preferred aspect of the present disclosure, the maximum increased once weekly dose of the compound or a pharmaceutically acceptable salt thereof is about 10.0 mg.

[0155] In one embodiment, the method or use comprises:

[0156] a) administering a dose of about 5.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0157] b) increasing the dose of the compound, or a pharmaceutically acceptable salt thereof, to about 10.0 mg once per week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0158] In another embodiment, the method or use comprises:

[0159] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0160] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0161] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0162] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0163] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0164] In another embodiment, the method or use comprises:

[0165] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0166] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0167] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0168] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0169] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0170] In another embodiment, the method or use comprises:

[0171] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0172] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0173] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0174] In another preferred aspect of the present disclosure, the maximum increased dose of the compound or a pharmaceutically acceptable salt thereof is about 12.0 mg.

[0175] In one embodiment, the method or use comprises:

[0176] a) administering a dose of about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0177] b) increasing the dose of the compound, or a pharmaceutically acceptable salt thereof, to about 12.0 mg once per week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0178] In another embodiment, the method or use comprises:

[0179] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0180] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0181] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0182] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0183] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof by about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0184] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0185] In another embodiment, the method or use comprises:

[0186] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0187] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0188] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0189] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0190] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering this dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0191] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0192] In another embodiment, the method or use comprises:

[0193] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0194] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0195] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0196] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0197] In another preferred aspect of the present disclosure, the maximum increased dose of the compound or a pharmaceutically acceptable salt thereof is about 13.0 mg.

[0198] In one embodiment, the method or use comprises:

[0199] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0200] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0201] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0202] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0203] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0204] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0205] In another embodiment, the method or use comprises:

[0206] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0207] (b) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0208] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0209] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0210] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0211] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0212] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0213] In another embodiment, the method or use comprises:

[0214] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0215] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0216] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0217] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0218] In another preferred aspect of the present disclosure, the maximum increased dose of the compound or a pharmaceutically acceptable salt thereof is about 14.0 mg.

[0219] In one embodiment, the method or use comprises:

[0220] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0221] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0222] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0223] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0224] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0225] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 11.0 mg or to about 12.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0226] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 14.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0227] In another embodiment, the method or use comprises:

[0228] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0229] (b) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0230] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0231] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0232] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0233] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0234] (g) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0235] (h) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 14.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0236] In another embodiment, the method or use comprises:

[0237] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0238] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0239] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0240] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0241] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 14.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0242] In another preferred aspect of the present disclosure, the maximum incremental dose of the compound or a pharmaceutically acceptable salt thereof is about 15.0 mg.

[0243] In one embodiment, the method or use comprises:

[0244] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0245] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0246] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0247] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0248] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0249] (f) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0250] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 15.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0251] In another embodiment, the method or use comprises:

[0252] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0253] (b) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0254] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0255] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0256] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0257] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0258] (g) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0259] (h) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 15.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0260] In another embodiment, the method or use comprises:

[0261] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0262] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0263] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0264] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0265] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 15.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0266] In another preferred aspect of the present disclosure, the maximum increased dose of the compound or a pharmaceutically acceptable salt thereof is about 16.0 mg.

[0267] In one embodiment, the method or use comprises:

[0268] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0269] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0270] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0271] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0272] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 or 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0273] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0274] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0275] In another embodiment, the method or use comprises:

[0276] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0277] (b) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0278] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0279] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0280] (e) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0281] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0282] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0283] (h) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0284] In another embodiment, the method or use comprises:

[0285] (a) administering a first dose of about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0286] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0287] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0288] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg and administering the dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0289] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0290] In another embodiment, the method or use comprises:

[0291] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0292] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0293] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0294] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0295] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks; and

[0296] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0297] In another embodiment, the method or use comprises:

[0298] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0299] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0300] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0301] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0302] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0303] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks; and

[0304] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0305] In another embodiment, the method or use comprises:

[0306] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0307] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0308] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0309] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0310] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0311] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks; and

[0312] (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0313] In another embodiment, the method or use comprises:

[0314] (a) administering a first dose of about 1.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0315] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0316] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0317] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0318] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks; and

[0319] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0320] In another embodiment, the method or use comprises:

[0321] (a) administering a first dose of about 2.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0322] (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0323] (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0324] (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks;

[0325] (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks; at least about three weeks, or at least about four weeks; and

[0326] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering the dose once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0327] In one aspect, the method or use comprises administering each dose once a week for at least about two weeks. In one aspect, the method or use comprises administering each dose once a week for at least about four weeks. In one aspect, the method or use comprises administering each dose once a week for at least about eight weeks.

[0328] In a preferred aspect, the method or use comprises applying each dose once a week for at least about two weeks, and applying the maximum dose once a week for at least about four weeks. In another preferred aspect, the method or use comprises applying each dose once a week for at least about 4 weeks, and applying the maximum dose once a week for at least about 4 weeks. In another preferred aspect, the method or use comprises applying each dose once a week for at least about 4 weeks, and applying the maximum dose once a week for at least about 8 weeks.

[0329] In one aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 10%. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 15%. In some embodiments, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in body weight in a patient of at least about 20%.

[0330] In one aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in HbA1c in a patient. In one aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in LDL cholesterol and / or triglycerides in a patient. In one aspect, administration of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof does not result in unacceptable tolerability.

[0331] In one aspect, the patient is overweight. In another aspect, the patient is obese. In another aspect, the patient has type 2 diabetes.

[0332] In another aspect, the present invention provides a method of providing long-term weight management, improving glycemic control and / or lowering LDL cholesterol or triglycerides in a patient in need thereof, wherein the method comprises:

[0333] (1) administering to a patient in need thereof an increasing dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0334] (2) thereafter administering a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0335] In some embodiments, provided herein is a method for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake, and / or inducing satiety in a patient, wherein the method comprises:

[0336] (1) administering to a patient in need thereof an increasing dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0337] (2) thereafter administering a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0338] In another aspect of the present disclosure, there is provided a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for use in long-term weight management, improving blood sugar control and / or lowering LDL cholesterol or triglycerides, wherein:

[0339] (1) administering increasing doses of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0340] (2) thereafter a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof is administered once a week for at least about two weeks.

[0341] In another aspect, a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is provided for use in preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, for reducing weight, for reducing food intake and / or for inducing satiety in a patient, wherein:

[0342] (1) administering increasing doses of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0343] (2) thereafter administering a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0344] In another aspect of the present disclosure, there is provided a use of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for long-term weight management, improving blood sugar control and / or lowering LDL cholesterol or triglycerides, wherein:

[0345] (1) administering increasing doses of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0346] (2) thereafter administering a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0347] In another aspect, provided is a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy, reducing weight, reducing food intake and / or inducing satiety in a patient, wherein:

[0348] (1) administering increasing doses of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and

[0349] (2) thereafter administering a maintenance dose of greater than about 6 mg to about 16 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0350] In another aspect of the disclosure, the once weekly maintenance dose is about 6.25 mg to about 16.0 mg, about 6.5 mg to about 16.0 mg, about 8.0 mg to about 16.0 mg, about 10 mg to about 16.0 mg, about 11.0 mg to about 16 mg, about 12.0 mg to about 16.0 mg, about 13.0 mg to about 16.0 mg, or about 14.0 mg to about 16.0 mg.

[0351] In another aspect of the disclosure, the weekly maintenance dose is 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0352] In another aspect of the present disclosure, the weekly maintenance dose is about 8.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the weekly maintenance dose is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0353] In still another aspect of the present disclosure, the weekly maintenance dose is about 10.0 mg to about 16.0 mg. In still another aspect of the present disclosure, the weekly maintenance dose is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg.

[0354] In still another aspect of the disclosure, the method or use comprises administering a maintenance dose once a week for at least about four weeks. In still another aspect of the disclosure, the method or use comprises administering a maintenance dose once a week for at least about six weeks. In still another aspect of the disclosure, the method or use comprises administering a maintenance dose once a week for at least about eight weeks.

[0355] In still another aspect of the present disclosure, the weekly increasing dose is about 1.0 mg to about 6.0 mg. In still another aspect of the present disclosure, the weekly increasing dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg.

[0356] In still another aspect of the disclosure, multiple weekly ascending doses are administered to the patient in steps (1) and (2).

[0357] In a preferred aspect of the present disclosure, the first weekly increasing dose is about 1.0 mg to about 6.0 mg. In another aspect of the present disclosure, the first weekly increasing dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg or about 6.0 mg. In a preferred aspect of the present disclosure, the first weekly increasing dose is about 1.0 mg, about 1.5 mg, about 2.0 mg or about 3.0 mg.

[0358] In another preferred aspect of the present disclosure, the first and each subsequent weekly ascending dose is increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and wherein each weekly ascending dose is administered for at least about two weeks.

[0359] In another preferred aspect of the present disclosure, the final or maximum incremental dose is higher than the maintenance dose. For example, the patient is administered an incremental dose of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg and 10.0 mg of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week, each dose lasting three weeks. After three weeks of administration at the highest dose of 10 mg, the maintenance dose is reduced to 8 mg.

[0360] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 6.5 mg.

[0361] Preferably, the method or use comprises:

[0362] a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least two weeks, at least about three weeks, or at least about four weeks; and

[0363] b) administering increasing doses of about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0364] Or preferably, the method or use comprises:

[0365] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0366] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0367] (c) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.5 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0368] (d) administering increasing doses of about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0369] Or preferably, the method or use comprises:

[0370] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0371] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg or about 5.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0372] (c) administering a maintenance dose of about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, or at least about eight weeks.

[0373] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 8.0 mg.

[0374] Preferably, the method or use comprises:

[0375] a) administering increasing doses of about 4.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0376] b) administering increasing doses of about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0377] Or preferably, the method or use comprises:

[0378] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0379] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0380] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0381] (d) administering increasing doses of about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0382] Or preferably, the method or use comprises:

[0383] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0384] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0385] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0386] (d) administering increasing doses of about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0387] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 9.0 mg.

[0388] Preferably, the method or use comprises:

[0389] a) administering increasing doses of about 4.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0390] b) administering a maintenance dose of about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0391] Or preferably, the method or use comprises:

[0392] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0393] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0394] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0395] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks.

[0396] Or preferably, the method or use comprises:

[0397] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0398] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0399] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0400] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks.

[0401] Alternatively, preferably, the method or use comprises:

[0402] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0403] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0404] (c) administering a maintenance dose of about 9.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0405] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 10.0 mg.

[0406] Preferably, the method or use comprises:

[0407] a) administering increasing doses of about 5.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0408] b) administering a maintenance dose of about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0409] Or preferably, the method or use comprises:

[0410] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0411] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0412] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0413] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0414] (e) administering a maintenance dose of about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0415] Or preferably, the method or use comprises:

[0416] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0417] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0418] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0419] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0420] (e) administering a maintenance dose of about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0421] Alternatively, preferably, the method or use comprises:

[0422] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0423] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0424] (c) administering a maintenance dose of about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0425] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 12.0 mg.

[0426] Preferably, the method or use comprises:

[0427] a) administering increasing doses of about 6.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0428] b) administering a maintenance dose of about 12.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0429] Or preferably, the method or use comprises:

[0430] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0431] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0432] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0433] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0434] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0435] (f) administering a maintenance dose of about 12.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0436] Or preferably, the method or use comprises:

[0437] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0438] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0439] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0440] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0441] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0442] (f) administering a maintenance dose of about 12.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0443] Or preferably, the method or use comprises:

[0444] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0445] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0446] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0447] (d) administering a maintenance dose of about 12.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0448] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 13.0 mg.

[0449] Preferably, the method or use comprises:

[0450] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0451] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0452] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0453] (d) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0454] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0455] (f) administering a maintenance dose of about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0456] Or preferably, the method or use comprises:

[0457] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0458] (b) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0459] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0460] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0461] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0462] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0463] (g) administering a maintenance dose of about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0464] Or preferably, the method or use comprises:

[0465] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0466] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0467] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0468] (d) administering a maintenance dose of about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0469] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 14.0 mg.

[0470] Or preferably, the method or use comprises:

[0471] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0472] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0473] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0474] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0475] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0476] (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 11.0 mg or to about 12.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0477] (g) administering a maintenance dose of about 14.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0478] Or preferably, the method or use comprises:

[0479] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0480] (b) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0481] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0482] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0483] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0484] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0485] (g) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0486] (h) administering a maintenance dose of about 14.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0487] Or preferably, the method or use comprises:

[0488] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0489] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0490] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0491] (d) optionally increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks; and

[0492] (e) administering a maintenance dose of about 14.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0493] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 15.0 mg.

[0494] Preferably, the method or use comprises:

[0495] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0496] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0497] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0498] (d) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0499] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0500] (f) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0501] (g) administering a maintenance dose of about 15.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0502] Or preferably, the method or use comprises:

[0503] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0504] (b) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0505] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0506] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0507] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0508] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0509] (g) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0510] (h) administering a maintenance dose of about 15.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0511] Or preferably, the method or use comprises:

[0512] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0513] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0514] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0515] (d) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose once per week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0516] (e) administering a maintenance dose of about 15.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0517] In another preferred aspect of the present disclosure, the maintenance dose of the compound or a pharmaceutically acceptable salt thereof is 16.0 mg.

[0518] Preferably, the method or use comprises:

[0519] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0520] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0521] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 5.0 mg or to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0522] (d) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0523] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 or about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0524] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0525] (g) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0526] Or preferably, the method or use comprises:

[0527] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0528] (b) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0529] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0530] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0531] (e) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0532] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0533] (g) optionally increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose to the patient once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0534] (h) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0535] Or preferably, the method or use comprises:

[0536] (a) administering increasing doses of about 3.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0537] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks;

[0538] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg or to about 10.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0539] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg or to about 13.0 mg, and administering the increasing dose once a week for at least about two weeks, at least about three weeks, or at least about four weeks; and

[0540] (e) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks, at least about four weeks, at least about six weeks, or at least about eight weeks.

[0541] Or preferably, the method or use comprises:

[0542] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks;

[0543] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks;

[0544] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks;

[0545] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the increasing dose once a week for at least about two weeks;

[0546] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the increasing dose once a week for at least about two weeks; and

[0547] (f) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0548] Or preferably, the method or use comprises:

[0549] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks;

[0550] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks;

[0551] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks;

[0552] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the increasing dose once a week for at least about two weeks;

[0553] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the increasing dose once a week for at least about two weeks;

[0554] (f) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the increasing dose once a week for at least about two weeks; and

[0555] (g) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0556] Or preferably, the method or use comprises:

[0557] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks;

[0558] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks;

[0559] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks;

[0560] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the increasing dose once a week for at least about two weeks;

[0561] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the increasing dose once a week for at least about two weeks; and

[0562] (f) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0563] Or preferably, the method or use comprises:

[0564] (a) administering increasing doses of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks;

[0565] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg, and administering the increasing dose once a week for at least about two weeks;

[0566] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks;

[0567] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the increasing dose once a week for at least about two weeks;

[0568] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the increasing dose once a week for at least about two weeks; and

[0569] (f) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0570] Or preferably, the method or use comprises:

[0571] (a) administering increasing doses of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks;

[0572] (b) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg, and administering the increasing dose once a week for at least about two weeks;

[0573] (c) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the increasing dose once a week for at least about two weeks;

[0574] (d) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the increasing dose once a week for at least about two weeks;

[0575] (e) increasing the increasing dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the increasing dose once a week for at least about two weeks; and

[0576] (f) administering a maintenance dose of about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks.

[0577] More preferably, the method or use comprises administering the ascending dose once a week for at least about two weeks and administering the maintenance dose once a week for at least about four weeks.

[0578] Even more preferably, the method or use comprises administering each increasing dose once a week for at least about four weeks and administering the maintenance dose once a week for at least about four weeks.

[0579] Even more preferably, the method or use comprises administering each ascending dose once a week for at least about four weeks and administering the maintenance dose once a week for at least about eight weeks.

[0580] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of GLP-1 / Gcg co-agonists, pharmaceutical compositions and methods, preferred methods and materials are described herein.

[0581] Furthermore, use of the indefinite article "a" or "an" to refer to an element does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the element. Thus, the indefinite article "a" or "an" generally means "at least one".

[0582] definition

[0583] As used herein, "about" means within a statistically significant range of a value or values, such as a specified concentration, length, molecular weight, pH, sequence identity, time range, temperature, or volume. Such a value or range can be within the order of magnitude of a given value or range, typically within 20%, more typically within 10%, and even more typically within 5%. The permissible variations encompassed by "about" will depend on the particular system being studied and will be readily understood by those skilled in the art.

[0584] As used herein, "activity," "activation," "activation," and the like, when referring to one or more GLP-1 receptors or Gcg receptors, refers to the ability of a compound (e.g., a GLP-1 / Gcg co-agonist described herein) to bind to and induce a receptor response, as measured using assays known in the art.

[0585] As used herein, "amino acid" refers to a molecule characterized from a chemical point of view as containing one or more amine groups and one or more carboxylic acid groups and may contain other functional groups. As known in the art, there is a group of twenty amino acids designated as standard amino acids and used as the structural unit (building block) of most peptides / polypeptides / proteins produced by any organism.

[0586] As used herein, "analog" or "like" refers to a compound, such as a synthetic peptide or polypeptide, that activates a target receptor and elicits at least one in vivo or in vitro effect elicited by a natural receptor agonist.

[0587] As used herein, "dose" or "doses" refers to the amount of a GLP-1 / Gcg co-agonist administered once a week, which is administered to an individual in discrete amounts at specific time points. When used in conjunction with the terms dose, doses, etc., "adjustment" refers to any amount of reduction or increase in the dose administered the previous week. When used in conjunction with the terms dose, doses, etc., "regimen" refers to a set of guidelines for determining and administering one or more doses and / or adjustments thereto.

[0588] As used herein, "effective amount" refers to the amount, concentration or dosage of one or more GLP-1 / Gcg co-agonists herein or a pharmaceutically acceptable salt thereof, which, after administration of a single or multiple doses to an individual in need thereof, provides the desired effect in the individual being diagnosed or treated (i.e., can produce a clinically measurable difference in the individual's condition, e.g., glucose reduction, HbA1c reduction, body weight or body fat reduction, and / or body composition change). An effective amount can be readily determined by one skilled in the art by using known techniques and by observing the results obtained under similar circumstances. In determining the effective amount for an individual, many factors are considered, including, but not limited to, the species of mammal, its size, age and general health, the specific disease or disorder involved, the extent or involvement or severity of the disease or disorder, the response of the individual, the GLP-1 / Gcg co-agonist administered, the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosage regimen, the use of concomitant medications, and other relevant circumstances.

[0589] As used herein, "fasting glucose" refers to the blood glucose level in a blood sample taken after an individual has fasted for at least about 8 hours.

[0590] As used herein, "glycemic control" refers to a reduction in an individual's HbA1c level. Likewise, "improvement" and / or "improvement" of glycemic control refers to a reduction in HbA1c. Furthermore, "needing further" glycemic control refers to a need to reduce HbA1c.

[0591] As used herein, "hemoglobin A1c" or "HbA1c" refers to glycated hemoglobin and its levels, which are produced when hemoglobin combines with glucose in the blood. HbA1c levels are a common measure of glycemic control in patients with diabetes, and reduced HbA1c levels generally indicate improved glycemic control. In the context of the present disclosure, the doses, regimens, and methods herein result in a reduction in HbA1e. In some cases, the reduction in HbA1c is relative to the reduction in HbA1c levels caused by existing treatments using the same or even different GLP-1 / Gcg co-agonists (including other GLP-1 / Gcg co-agonists).

[0592] As used herein, "incretin analogs" refer to compounds that have structural similarities to each of OXM, GLP-1 and GCG, especially human OXM, human GLP-1 and human GCG, but have multiple differences. The incretin analogs herein include amino acid sequences that have affinity and activity (i.e., dual receptor agonist activity) for both the GLP-1 receptor and the GCG receptor. Exemplary incretin analogs and sequences of human OXM, GLP-1 and GCG used herein are described in International Patent Application Publication No. WO2016 / 209707A1. Particularly used herein is the GLP-1 / Gcg co-agonist described in Example 2 of International Patent Application Publication No. WO 2016 / 209707A1, which has the following sequence:

[0593] His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly

[0594] wherein Xaa2 is Aib;

[0595] The Lys at position 20 is linked to the ([2-(2-aminoethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 CO 2 H conjugation for chemical modification; and

[0596] The C-terminal amino acid is amidated (SEQ ID NO: 1),

[0597] or a pharmaceutically acceptable salt thereof, including any protein that is the subject of a regulatory submission seeking approval of a GLP-1 / Gcg co-agonist product that relies in whole or in part on data related to such incretin mimetic submitted to a regulatory agency by Eli Lilly and Company, regardless of whether the party seeking product approval actually identifies the incretin mimetic as a GLP-1 / Gcg co-agonist or uses some other term.

[0598] As used herein, "subject in need thereof" refers to a mammal, such as a human, suffering from a condition, disease, disorder or symptom for which treatment or therapy is required, including, for example, those conditions listed herein. In particular, the preferred subject to be treated is a human.

[0599] In certain aspects as used herein, a "titration dose" or "escalating dose" refers to a dose that is less than the highest effective dose required for a patient. As used herein, the present disclosure contemplates that a "titration dose" or "escalating dose" may be the highest effective dose required, or if the dose is observed to be the effective dose required for the patient, it may be a "maintenance dose", and that the dose may be administered chronically for a period of more than at least two weeks. Alternatively, in certain aspects as used herein, a "titration dose" or "escalating dose" refers to a dose that is higher than the maintenance dose for the patient. This aspect of the disclosure is particularly useful in situations where a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof is administered, such as to reduce weight, treat obesity, or control weight. Significant weight loss can be obtained at the highest dose, and weight loss can be maintained at lower doses.

[0600] As used herein, "maintenance dose" refers to both the highest required effective dose for a patient and, when such maintenance dose is less than the highest required effective dose, the maintenance dose may become an incremental dose. That is, if the "about 8 mg" maintenance dose contemplated by the present disclosure is not the highest required effective dose for a particular patient, then in retrospect, the 8 mg maintenance dose will become a titration or incremental dose because the dose for the particular patient will increase until the next highest dose contemplated by the present disclosure is reached, for example, 10 mg for at least about 2 weeks or 12 mg for at least about 2 weeks. The present disclosure contemplates that patients who reach a maintenance dose of about 12 mg to about 16 mg may need to reduce their dose to a lower maintenance dose, as determined by a physician or other health care provider.

[0601] As used herein, "anticipated weekly maintenance dose" refers to a dose of a therapeutic agent, such as a GLP-1 / Gcg co-agonist, suitable for once-weekly administration that is expected to be required to provide glycemic control or weight management for a particular individual based on factors including, but not limited to, the individual's fasting glucose, HbA1c, frequency and severity of hypoglycemia and other AEs, and / or BW.

[0602] As used herein, "obesity" or "obesity" refers to a BMI > 30 kg / m 2 .

[0603] As used herein, "overweight" means that, for an individual, his or her BMI is > 27 kg / m 2 But <30kg / m 2 .

[0604] As used herein, "treat," "treating," and the like means inhibiting, slowing, stopping or reversing the progression or severity of an existing condition, disease, disorder or symptom.

[0605] As used herein, for incretin analogs, "dual receptor agonist activity" means that the incretin analogs have activity on both the GLP-1 receptor and the GCG receptor, and in particular, analogs that have balanced and sufficient activity on each receptor to provide the benefits of the receptor agonism while avoiding the adverse side effects associated with excessive activity of the receptor. In addition, incretin analogs with dual receptor agonist activity have a prolonged duration of action on both the GLP-1 receptor and the GCG receptor, which advantageously allows dosing at a frequency of once a day, three times a week, twice a week, or once a week.

[0606] As used herein, "weight management" refers to losing weight and / or changing body fat composition, as well as maintaining weight and / or body fat composition.

[0607] Composition

[0608] The compositions herein include a GLP-1 / Gcg co-agonist having, for example, a structure of SEQ ID NO: 1. GLP-1 / Gcg co-agonists can be produced synthetically (see, for example, International Patent Application Publication No. WO 2016 / 209707A1). Formulations of GLP-1 / Gcg co-agonists that can be used herein are disclosed in International Patent Application No. PCT / US2021 / 064592.

[0609] In some cases, the compositions herein are formulated to contain a GLP-1 / Gcg co-agonist at a dose of about 1.5 mg to about 16.0 mg. In other cases, the dose of the GLP-1 / Gcg co-agonist can be about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 6.0 mg, about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 10.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg or about 16.0 mg. The compositions herein can be administered intravenously (IV), intramuscularly (IM) or subcutaneously (SC), especially SC. The compositions can be provided reconstituted after lyophilization, or administered as a solution formulation using a prefilled disposable pen, a reusable pen or an automatic pen-type syringe. Alternatively, the compositions can be administered using a multi-purpose vial or a pump device. In some cases, the device is an automatic injection device, such as described in US Pat. No. 8,734,394.

[0610] Therefore, the compositions herein can be contained in pre-filled syringes / multi-use vials. Such pre-filled syringes / multi-use vials can be used to administer about 0.5 mL to about 2.0 mL of the composition per dose to each patient. The dosage of the composition can be administered using a dosing regimen determined by a clinician, physician, or other trained medical professional.

[0611] Alternatively, the composition may be prepared as a cartridge and thus differ from the above-described composition in that it contains a preservative.

[0612] Alternatively, the composition may be prepared as part of an article of manufacture comprising the composition, wherein the article of manufacture may be a multi-use vial, a reusable pen injector, a pre-filled disposable pen, an autoinjector, or a pump.

[0613] In view of the above, the compositions herein are associated with acceptable shelf-life stability, stability in use, and acceptable injection site experience.

[0614] Treatments and medical uses

[0615] The dosing regimen of the GLP-1 / Gcg co-agonists described herein is suitable for providing long-term weight management. The dosing regimen of the GLP-1 / Gcg co-agonists described herein is also suitable for improving glycemic control (e.g., measured by glucose levels, HbA1c and / or fructosamine). The dosing regimen of the GLP-1 / Gcg co-agonists described herein is also suitable for reducing LDL cholesterol and / or triglycerides.

[0616] The dosing regimen of the GLP-1 / Gcg co-agonist described herein may be suitable for preventing or treating a variety of conditions, including but not limited to: preventing or treating type 2 diabetes, preventing or treating hyperglycemia, preventing non-insulin-dependent diabetes, preventing or treating obesity, reducing body weight and / or food intake, preventing or treating dyslipidemia, preventing or treating non-alcoholic fatty acid liver disease (NAFLD), preventing or treating non-alcoholic steatohepatitis (NASH), preventing or treating atherosclerosis, obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease and diabetic nephropathy. It is also suitable for inducing satiety, reducing fasting blood sugar, reducing postprandial blood sugar levels, reducing HbA1c, reducing adverse gastrointestinal events (e.g., nausea and vomiting), reducing systolic blood pressure, treating hypertension, reducing fructosamine levels and improving the quality of life of individuals treated.

[0617] In addition, the dosing regimen of the GLP-1 / Gcg co-agonist described herein may be suitable for the following situations: treating obesity, controlling appetite, reducing caloric intake, reducing food intake, suppressing appetite, inducing anorexia, treating impaired glucose tolerance, treating postprandial hyperglycemia, treating hyperglycemic conditions, lowering triglycerides, lowering cholesterol, treating impaired glucose tolerance, treating prediabetes (blood glucose levels are higher than normal but not yet high enough to be diagnosed as diabetes), treating type 1 diabetes (e.g., used in combination with insulin), reducing the risk of cardiovascular events due to impaired glucose tolerance, reducing the risk of cerebrovascular events due to impaired glucose tolerance, delaying the progression of diabetes, improving diabetes, delaying the onset of diabetes, inducing β-cell protection and restoring β-cell function, restoring normal blood sugar, providing normal blood sugar control, treating gestational diabetes, treating or preventing renal disease, treating or preventing cardiovascular disease (e.g., heart failure, atherosclerosis and acute coronary syndrome), and treating or preventing metabolic syndrome.

[0618] In preferred embodiments, the dosing regimen of the GLP-1 / Gcg co-agonist described herein is suitable for the following situations: providing long-term weight management, improving blood sugar control, lowering LDL cholesterol and / or triglycerides, reducing weight, reducing food intake and / or inducing satiety. In some preferred embodiments, the dosing regimen of the GLP-1 / Gcg co-agonist described herein is suitable for preventing or treating a condition selected from the following: type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes, obesity; dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease or diabetic nephropathy.

[0619] The following non-limiting examples are provided for purposes of illustration and not limitation.

[0620] Example

[0621] Example 1: Clinical study

[0622] Overview

[0623] The study is a Phase 1, single-site, patient- and investigator-blinded, placebo-controlled, randomized, non-crossover, multiple ascending dose study titrating each cohort in patients with T2DM to investigate the safety, tolerability, PK, and PD of a GLP-1 / glucagon co-agonist peptide of SEQ ID NO: 1 (Compound 1), administered as multiple SC injections QW for 12 weeks in Cohort 1 and 16 weeks in Cohort 2.

[0624] Study Group

[0625] Before screening participants for this study, the researchers recruited participants with T2DM for at least 6 months.

[0626] include

[0627] The following patients were considered eligible for participation in the study:

[0628] - Otherwise generally healthy with no known secondary diseases to diabetes.

[0629] - Glycated hemoglobin (HbA1c) value >= 7.0% and <= 10.5% at screening and treated with diet and exercise alone or a stable dose of metformin for at least 3 months prior to screening / first visit

[0630] exclude

[0631] The following patients were considered unsuitable for participation in this study:

[0632] - Have adult-onset type 1 diabetes or latent autoimmune diabetes.

[0633] - Have uncontrolled diabetes, defined as an episode of ketoacidosis or hyperosmolar state requiring hospitalization in the 6 months prior to screening.

[0634] - Have had a severe hypoglycemic episode or have a history of hypoglycemia but are unaware or have insufficient awareness of the symptoms of hypoglycemia.

[0635] treat

[0636] Two planned dosing regimens of study compound 1 were administered weekly by SC injection in this study. The study was blinded to both patients and investigators. To maintain blinding of the study of compound 1 and placebo, personnel at all study sites were blinded to treatment assignment, except for pharmacy staff who prepared and dispensed study medication. Blinding of compound 1 and placebo was maintained throughout the trial until all data were assessed to an acceptable level of quality and locked.

[0637] The first dosing regimen (also called cohort 1) lasted 12 weeks and required 1.5 mg dose increments starting at 1.5 mg:

[0638] -1.5 mg QW compound 1 for 4 weeks;

[0639] -3,0 mg QW Compound 1 for 4 weeks; and

[0640] -4.5 mg QW Compound 1 for 4 weeks.

[0641] The second dosing regimen (also called Cohort 2) lasted 16 weeks and required 2-mg dose increments starting at 2 mg:

[0642] -2 mg QW compound 1 for 3 weeks;

[0643] - 4 mg QW compound 1 for 3 weeks;

[0644] -6 mg QW compound 1 for 3 weeks;

[0645] -8 mg QW Compound 1 for 3 weeks; and

[0646] -10 mg QW Compound 1 for 4 weeks.

[0647] For the second dosing regimen, the 10 mg QW dose should be continued only if the patient first tolerates a titration step of 4 mg QW for 3 doses, 6 mg QW for 3 doses, and then 8 mg QW for 3 doses.

[0648] For each dosing regimen, Compound 1 was administered SC into the abdomen of patients after they had fasted overnight for at least 8 hours.

[0649] Of the 82 patients who gave informed consent and were screened for the study, 24 were randomized and received at least 1 dose of the study intervention. A total of 23 patients completed the study. Figure 1 shown.

[0650] Dosage Considerations

[0651] Dose levels or increments, sampling schedules, and length of stay in the Clinical Research Unit (CRU) may be adjusted based on safety, tolerability, or PK data that emerge during the study. In particular, dose increments within a cohort may be reduced (but not increased) or a lower dose administered accordingly.

[0652] At each dose level, the actual dose, increment and / or duration of dosing within each cohort may be adjusted based on emerging safety, tolerability or PK data. Essentially, this is a multiple ascending dose study with dose titration, so data will be continuously evaluated until the MTD is determined or stopping criteria are met.

[0653] Safety data will be the primary criterion for dose escalation. Dose titration within a cohort cannot occur without prior discussion and agreement between the investigator and the designated clinical pharmacologist. All safety and available pharmacokinetic (PK) and pharmacodynamic (PD) data from the week prior to dosing will be used to support dosing within a cohort. All safety and available PK and PD data through Week 11 will be used to support dosing between Cohorts 1 and 2.

[0654] After reviewing these data, the investigators and sponsors will escalate the dose to the next dose level within the cohort. If half of the patients in any cohort cannot tolerate the dose titration, the dose increment can be halved and the dose can be titrated up every 2 weeks.

[0655] Dosing at the current level and further dose escalations within both cohorts will be discontinued if any of the following stopping criteria occur in either cohort:

[0656] - One treatment-emergent SAE (unless due to the intended pharmacology of Compound 1 [e.g., hypoglycemia]) or two clinically significant events (CSEs) considered possibly related to Compound 1 were reported, or

[0657] =40% of subjects experienced symptomatic hypoglycemia at dose levels with blood glucose values ​​<= 2.8 mmol / L (50 mg / dL; corresponding to plasma glucose [PG] levels <= 3.1 mmol / L [56 mg / dL]), and these events were considered to be related to the administration of Compound 1, or

[0658] - Two or more subjects taking active medication develop persistent (>1 week) symptoms suggestive of acute pancreatitis.

[0659] - Two or more subjects in the same cohort experienced a 'severe' non-serious adverse reaction that was possibly related to the study drug, independent of being within the same system organ class or not.

[0660] If any of these three situations occur, dosing will be interrupted and resumed only with approval by the investigator or appropriate designee.

[0661] Research Assessment

[0662] The relevant research methods and their time arrangements are summarized below.

[0663] weight

[0664] For Cohort 1, body weight was measured at baseline and on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

[0665] For Cohort 2, body weight was measured at baseline and on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, and 109.

[0666] Whenever possible, the same scale was used for all body weight measurements throughout the study, and the scale was not moved or recalibrated. Subjects were weighed in light clothing at approximately the same time before dosing (Day 1 only) and, if possible, after an overnight fast and empty bowel and bladder. Body weight was measured twice at each scheduled time during the treatment period, with the subject stepping off the scale between measurements. The average of the two body weight measurements was recorded in the source file.

[0667] waistline

[0668] For Cohort 1, waist circumference was measured at baseline and on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

[0669] For cohort 2, waist circumference was measured at baseline and on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, and 109.

[0670] Waist circumference is measured at the midpoint between the least noticeable lower edge of the ribs and the top of the iliac crest. The patient stands with feet together, arms at sides, weight evenly distributed, and minimal clothing. The patient should be relaxed, and the measurement should be taken at the end of a normal exhalation. Waist circumference will be measured twice at each scheduled time during Screening, Baseline, Treatment, and Visits. The average of the two measurements will be recorded in the source document.

[0671] Pharmacokinetics (PK )

[0672] Collect approximately 3 mL of venous blood samples to determine the plasma concentration of Compound 1. If necessary and guaranteed and agreed by the investigator and sponsor, up to two samples may be collected at other time points during the study. Record the actual date and time (24-hour clock time) of each sampling, as well as the date and time of each dose of Compound 1.

[0673] Information on drug concentrations that could unblind the study was not reported to the investigating agency or blinding personnel until the study was unblinded.

[0674] For Cohort 1, PK sampling occurred on Day 1 (12 hours after administration of Compound 1), Day 2 (24 hours after administration of Compound 1), Day 3 (48 hours after administration of Compound 1), Day 4 (72 hours after administration of Compound 1), Day 8, Day 22, Day 29, Day 31 (48 hours after administration of Compound 1), Day 50, Day 57, Day 59 (48 hours after administration of Compound 1), Day 78 (12 hours after administration of Compound 1), Day 79 (24 hours after administration of Compound 1), Day 80 (48 hours after administration of Compound 1), and Day 81 (72 hours after administration of Compound 1).

[0675] For Cohort 2, PK sampling occurred on Day 1 (12 hours after administration of Compound 1), Day 2, (48 hours after administration of Compound 1), Day 72 (hours after administration of Compound 1), Day 8, Day 22, Day 24 (48 hours after administration of Compound 1), Day 36, Day 43, Day 45 (48 hours after administration of Compound 1), Day 64, Day 66 (48 hours after administration of Compound 1), Day 85, Day 87 (48 hours after administration of Compound 1), Day 92, Day 99, Day 106 (12 hours after administration of Compound 1), Day 107 (24 hours after administration of Compound 1), Day 108 (48 hours after administration of Compound 1), and Day 109 (72 hours after administration of Compound 1).

[0676] HbA1c

[0677] For cohort 1, HbA1c levels were determined at baseline and on days 1, 29, 57, and 78. For cohort 2, HbA1c was measured at baseline and on days 1, 22, 43, 64, 85, and 106.

[0678] Pharmacodynamics (PD)

[0679] Glucose and insulin in fasting plasma samples are explored as secondary PD markers. Exploratory PD may include but are not limited to plasma glucagon, C-peptide, native OXM, lipid panel (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), beta-cell function, and homeostasis model assessment (HOMA) index.

[0680] Plasma concentrations of at least glucose, glucagon, insulin, C-peptide, and native OXM were determined using validated analytical methods.

[0681] Samples were identified by (coded) patient number and stored for up to 1 year after the last patient visit during the study period.

[0682] For Cohort 1, PD sampling occurred at baseline and on Days 1, 3 (48 hours after Compound 1 administration), 8, 22, 29, 50, 57, 78, and 80.

[0683] For Cohort 2, PD sampling occurred at baseline and on Days 1, 3 (48 hours after Compound 1 administration), 8, 22, 43, 64, 85, 106, and 108.

[0684] Mixed Meal Tolerance Test (MMTT)

[0685] For Cohort 1, MMTT was performed at baseline and on Day 80. For Cohort 2, MMTT was performed at baseline and on Day 108.

[0686] Patients were provided with an MMTT breakfast. Patients drank water upon waking to stay hydrated, thereby easing issues with blood sample collection. Patients were provided with a personalized MMTT breakfast. Total calories were approximately 30% of estimated daily caloric needs for body weight. The macronutrient composition of the meal was designed to provide approximately 50% of calories from carbohydrates, 30% of calories from fat, and 20% of calories from protein. Patients fasted (except for water) for at least 8 hours before each test meal and consumed each meal within approximately 20 minutes. The test meal remained consistent in caloric and nutrient composition for each patient throughout all MMTT assessments in the study.

[0687] For both parts of the study, patients received BOD within approximately 3 hours after the MMTT. No drinking (except fluids provided with meals) was allowed during the measurement period.

[0688] During the patient's stay in the CRU, no food or caloric beverages other than those provided by the CRU were allowed. Patients could resume their regular diet when not in the CRU. Actual meal start and end times, total calories, and meal size (%) were recorded during the MMTT.

[0689] Appetite analysis

[0690] In order to explore the effect of compound 1 on meal intake and appetite, subjects were asked to use a 100mm visual analog scale (VAS) to assess their appetite for parameters such as hunger, fullness, satiety, and expected food consumption in the fasting state during hospitalization and scheduled outpatient visits. VAS is an effective tool for assessing appetite perception parameters (Flint et al., Int J Obes Relat Metab Disord., 2000; 24 (1): 38-48). VAS is represented by a 10cm (100mm) long line, based on a language descriptor, usually "very" and "not at all". Subjects need to evaluate their subjective feelings based on four 100mm scales, combined with questions like the following:

[0691] - "How hungry are you?"

[0692] -“How full do you feel?”

[0693] -"How full do you feel?"

[0694] -"How much do you think you can eat?"

[0695] The overall appetite score was calculated as the average of 4 individual scores: satiety plus fullness plus (100-expected food consumption) plus (100-hunger) / 4 (van Can et al., Int J Obes (Lond). 2014; 38(6): 784-793). A higher overall appetite score indicates less appetite; a lower score indicates more appetite.

[0696] For Cohort 1, the satiety VAS (fasting) was completed at baseline and on Days 1, 29, 57, 78, and 80.

[0697] For Cohort 1, the satiety VAS (fasting) was completed at baseline and on Days 1, 22, 43, 64, 85, 106, and 108.

[0698] When VAS assessment of satiety was performed simultaneously with the MMTT, VAS assessment of satiety was performed before the meal and 1 and 4 hours after the MMTT.

[0699] Gastric emptying

[0700] Acetaminophen is a well-established marker of the rate and extent of gastric emptying. It is rapidly absorbed from the duodenum upon release from the stomach. Delayed gastric emptying is reflected in an alteration in the acetaminophen concentration-time profile, specifically, a decrease in its Cmax and an increase in the time to maximum observed drug concentration (tmax), without altering the extent of absorption (total drug amount). An oral solution dose of approximately 1 g of acetaminophen was considered adequate for bioanalytical testing and was administered as indicated below for Cohorts 1 and 2. Venous blood samples of approximately 2 mL were collected to determine plasma concentrations of acetaminophen. Concentrations of acetaminophen were determined using a validated LC / MS method. Bioanalytical samples collected to measure acetaminophen concentrations were stored for up to 2 years after the last patient visit.

[0701] For Cohort 1, gastric emptying was assessed at baseline, day 2, and day 79.

[0702] For Cohort 2, gastric emptying was assessed at baseline, day 2, and day 107.

[0703] Adverse events (AEs)

[0704] The Investigator is responsible for monitoring the safety of patients participating in this study. The Investigator is responsible for appropriate medical care of patients during the study. The Investigator documents their review of each laboratory safety report. The Investigator remains responsible for following up with appropriate health care options for serious or other medically important AEs that are considered related to Compound 1 or the study, or that lead to the patient discontinuing Compound 1 prior to completing the study. Patients will be followed until the event is resolved, stabilized with appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up assessments for AEs is at the discretion of the Investigator.

[0705] The investigator recorded all relevant AE and SAE information. After obtaining patient consent, the study personnel recorded the occurrence and characteristics of each patient's pre-existing conditions, including clinically significant signs and symptoms of the disease being treated in the study. In addition, the institution personnel recorded any changes in conditions and the occurrence and characteristics of any AEs.

[0706] The investigator interprets and records whether the AE has a reasonable possibility of being related to the study treatment or investigational procedures, taking into account the disease, concomitant treatment, or pathology.

[0707] “Reasonable possibility” means that there is a potential causal relationship between Compound 1, study device and / or study method and the AE.

[0708] Planned surgeries should not be reported as AEs unless the underlying medical condition worsens during the study.

[0709] Serious adverse events (SAEs) were defined as any AEs that resulted in any of the following:

[0710] -die

[0711] - Initial or long-term hospitalization

[0712] - Life-threatening experience (i.e., risk of immediate death)

[0713] - Persistent or significant disability / incapacity

[0714] - Congenital anomalies / birth defects

[0715] - Significant medical events that may not be immediately life-threatening or result in death or hospitalization but that could endanger the patient or may require intervention to prevent one of the other outcomes listed in the above definition.

[0716] All AEs occurring after signing the ICF were recorded and assessed according to severity criteria.

[0717] Laboratory testing

[0718] For cohort 1, samples for clinical laboratory testing were collected at baseline and on days 1, 15, 29, 43, 57, and 78.

[0719] For cohort 2, samples for clinical laboratory testing were collected at baseline and on days 1, 22, 43, 64, 85, and 106.

[0720] result

[0721] Demographic and other baseline characteristics

[0722] The baseline characteristics of patients with type 2 diabetes are shown in Table 1. A total of 24 patients participated in this study, including 21 males and 3 females, aged between 40 and 68 years.

[0723]

[0724] Table 1: Summary of baseline characteristics (mean ± SD)

[0725] Concomitant and post-intervention treatment

[0726] Table 2 summarizes current diabetes treatment during the study period.

[0727]

[0728] Abbreviations: n = number of patients.

[0729] Table 2: Summary of current diabetes treatments

[0730] weight

[0731] Figure 2 The mean change in body weight from baseline is shown. The range of mean body weight change from baseline was -2.30 kg to -11.24 kg with Compound 1 vs. -0.35 kg to -2.03 kg with placebo. During the multiple-dose period with Compound 1, mean body weight decreases were observed in all treatment groups at each time point evaluated. The trend in weight loss was dose-dependent, and the mean changes in body weight from baseline observed at the end of the treatment period were as follows:

[0732] -Placebo: -0.34 kg on Day 78

[0733] - Cohort 1: -2.88 kg on day 78

[0734] - Cohort 2: -10.73 kg on Day 109.

[0735] Cohort 2 had consistent, statistically significant reductions in body weight from baseline beginning on Day 50 and continuing through Day 162 (54 days after the last dose of study drug), compared with the placebo group.

[0736] Weight circumference

[0737] Figure 3 The mean change in waist circumference from baseline is shown. During the multiple-dose administration of Compound 1, a decrease in mean waist circumference was observed in both Cohort 1 and Cohort 2. A decrease in fat mass and an increase in lean body mass were also observed in Cohort 1 and Cohort 2, as shown in Table 3.

[0738]

[0739] Pharmacokinetics

[0740] A total of 355 PK concentrations of compound 1 from 18 patients were used for population PK modeling. All available PK data were used for model development. Table 4a lists the final PK-based model parameter estimates for compound 1 and the corresponding inter-subject variability.

[0741]

[0742] Abbreviation: SEE = standard error of the estimate

[0743] Table 4a: Estimated population pharmacokinetic parameters for Compound 1

[0744] The model-predicted mean (CV%) maximum steady-state concentration (C max,ss ), mean (CV%) steady-state concentration-time curve area [AUC(0-168) ss ] and estimated half-life (t 1 / 2 ) are listed in Table 4b below.

[0745]

[0746] Abbreviation: AUC (0-168) ss = area under the steady-state concentration-time curve at weekly dosing intervals; C max,ss Steady-state maximum concentration; CV% = coefficient of variation; t 1 / 2 = Elimination half-life

[0747] Table 4b: Model-predicted steady-state pharmacokinetic exposure and half-life of compound 1

[0748] Glucose Control - HbAlc

[0749] Table 4 shows the change in HbA1c relative to baseline. During the 12th to 16th week of dosing, the mean HbA1c levels of all treatment groups (including the placebo group) decreased relative to baseline from day 29 (week 5). Compared with the placebo group, starting from day 57 and continuing to day 134, statistically significant reductions in the mean HbA1c values ​​were observed in the treatment groups of cohorts 1 and 2 relative to baseline.

[0750] Based on the mean, HbA1c levels in all treatment groups remained reduced relative to baseline at Day 106 (i.e., 28 days after the last dose of study intervention Cohort 1).

[0751]

[0752] Abbreviations: HbAlc=glycosylated hemoglobin; NC=not calculated.

[0753] a Average absolute value of the first 2 days

[0754] *p value < 0.05

[0755] Table 4: Mean Baseline and Change from Baseline (%) HbA1c

[0756] Glucose Control - Fasting Glucose

[0757] At baseline, fasting glucose measurements were similar between the treatment and placebo groups. During the multiple-dose period of Compound 1, mean fasting glucose levels decreased relative to baseline in all treatment groups, as shown in Table 1. Figure 4 The greatest reduction from baseline at the end of the treatment period, on Day 106 (Week 16), was observed in Cohort 2 when compared to placebo.

[0758] Insulin sensitivity - fasting insulin

[0759] At baseline, fasting insulin measurements were similar in the low-dose cohort and the placebo group; however, baseline fasting insulin levels were much lower in the high-dose cohort. Figure 5 Results showed that an increase in fasting insulin levels was observed in cohort 1, whereas a modest decrease in fasting insulin levels was observed in cohort 2, a pattern consistent with improved insulin sensitivity.

[0760] Insulin sensitivity – fasting C-peptide

[0761] The change from baseline in fasting C-peptide level was Figure 6 As shown. At baseline, fasting C-peptide measurements were similar in the treatment and placebo groups. During the multiple doses of Compound 1, mean fasting C-peptide levels increased relative to baseline in all treatment groups except the placebo group. However, starting on Day 106, mean fasting C-peptide levels in Cohort 2 decreased relative to baseline and persisted through Day 108, a pattern consistent with improved insulin sensitivity.

[0762] Mixed meal tolerance test

[0763] The changes in AUC (0-3h) of C-peptide, glucagon, glucose, insulin, and oxyntomodulin relative to baseline during MMTT are shown in Table 6.

[0764]

[0765]

[0766] Abbreviations: AUC(0-3h) = area under the concentration-time curve from time zero to 3 hours after administration.

[0767] a Average absolute value of the first 2 days

[0768] b Cohort 1 is day 80, cohort 2 is day 108

[0769] Table 6: AUC (0-3 hours) Mean Baseline and Change from Baseline for Parameters Assessed During MMTT

[0770] Table 7 shows the changes from baseline in β-cell function and insulin sensitivity parameters derived from the MMTT.

[0771]

[0772]

[0773] Abbreviations: HOMA2-B = homeostasis model assessment of beta-cell function; HOMA2-IR = homeostasis model assessment of insulin resistance; ISI-M = Matsuda index; first PH ISI-S = first phase Stumvoll index; second PH ISI-S = second phase Stumvoll index

[0774] a Average absolute value of the first 2 days

[0775] b Cohort 1 is day 80, cohort 2 is day 108

[0776] Table 7: Mean Baseline and Change from Baseline in MMTT-derived β-Cell Function and Insulin Sensitivity Parameters

[0777] (i) Glucose AUC(0-3)h

[0778] The mean AUC (0-3h) of glucose (as measured by MMTT) decreased relative to baseline in all treatment groups during multiple doses of Compound 1. The maximum decrease relative to baseline was observed in Cohort 2 at the end of the treatment period on Day 108 (Week 16) when compared to placebo.

[0779] (ii) Insulin and C-peptide AUC (0-3h)

[0780] The mean AUC (0-3h) of C-peptide and insulin in cohort 1, as determined by MMTT, increased relative to mean baseline levels during the 12-week dosing period with multiple doses of Compound 1. The maximum increase in mean AUC (0-3h) of C-peptide relative to baseline was observed in cohort 1 at the end of the treatment period on day 80 (week 12) when compared to placebo.

[0781] During the 16-week dosing period with multiple doses of Compound 1, the mean AUC (0-3h) of C-peptide and insulin in Cohort 2 as determined by MMTT decreased relative to mean baseline levels.

[0782] (iii) β-cell function

[0783] The mean HOMA2-B index increased from baseline in both treatment groups during multiple doses of Compound 1. The greatest increase in mean HOMA2-B was observed in Cohort 1 at Day 80 (Week 12).

[0784] (iv) Glucagon AUC (0-3h)

[0785] The mean AUC (0-3h) of glucagon (determined by MMTT) decreased relative to baseline in all treatment groups during multiple doses of Compound 1. The maximum decrease relative to baseline was observed in Cohort 2 at the end of the treatment period on Day 108 (Week 16) when compared to placebo.

[0786] (v) Insulin sensitivity parameters

[0787] The mean HOMA2-IR index decreased in all treatment groups relative to baseline, while the mean Matsuda insulin sensitivity index values ​​increased during multiple doses of compound 1. In cohort 1, glucose, insulin, and c-peptide excursions increased during the sMMTT, similar to the patterns observed with GLP-1R monoagonists and insulin secretagogues.

[0788] Lipids – cholesterol, HDL, LDL, and triglycerides

[0789] like Figure 7a As shown, mean fasting cholesterol levels decreased from baseline during the dosing period in both treatment groups. Figure 7b As shown, the dose of Compound 1 in Cohort 2 significantly reduced sMMTT total cholesterol levels.

[0790] like Figure 7c and 7d As shown, during the dosing period, mean fasting HDL and LDL levels decreased relative to baseline in Cohort 2. Similarly, Figure 7e and 7f As shown, the dose of Compound 1 in Cohort 2 significantly reduced sMMTT LDL cholesterol levels and sMMTTHDL cholesterol levels.

[0791] As shown in 7g, during the dosing period, the mean fasting triglyceride levels in both treatment groups decreased relative to baseline. Figure 7h As shown, the dose of Compound 1 in Cohort 2 significantly reduced sMMTT triglyceride levels.

[0792] Gastric emptying

[0793] The PK parameters of acetaminophen were compared between treatment groups to determine the rate and extent of gastric emptying. Table 8 provides the primary analysis of acetaminophen Cmax and Tmax. Prior to dosing with Compound 1, the PK profiles of acetaminophen on the first day were similar between treatment groups. In the treatment groups, the Cmax of acetaminophen was significantly lower than that of the control group during the 12-week period of multiple dosing with Compound 1. maxThe Cmax of acetaminophen was lowest on day 2 in both treatment groups. However, the Cmax of acetaminophen max The change from baseline increased at day 107. The median t max quite.

[0794]

[0795]

[0796] Abbreviation: C max = maximum observed drug concentration; NC = not calculated; t max = time to reach maximum observed drug concentration.

[0797] Table 8: Geometric Mean C of Paracetamol max and median t max Summary

[0798] Appetite analysis

[0799] Figure 8 Summary of appetite perception data for all time points is shown. VAS appetite assessment showed decreased hunger, increased satiety, and decreased overall appetite (higher overall scores) in the higher dose cohort.

[0800] (i) Overall appetite score

[0801] During multiple dosing with Compound 1, overall appetite scores generally increased relative to baseline during either the 12-week or 16-week dosing period for all treatment groups (including placebo).

[0802] (ii) Hunger

[0803] During multiple dosing of Compound 1, hunger scores decreased relative to baseline at most time points assessed in both treatment groups (including placebo).

[0804] (iii) Satiety

[0805] During the multiple-dose administration of Compound 1, satiety scores decreased from baseline in both treatment groups. The satiety scores of patients in the placebo group increased from baseline on Day 80.

[0806] (iv) Satiety

[0807] During the multiple-dose period of Compound 1, satiety scores increased relative to baseline in both treatment groups. Satiety scores decreased relative to baseline in patients in the placebo group at Day 80. The greatest increase in satiety scores relative to baseline was observed in Cohort 1.

[0808] Pharmacodynamic evaluation of differences with increasing doses

[0809] Fasting glucose

[0810] Patients in Cohort 1 had a mean baseline fasting plasma glucose of 10.78 mmol / L. As the dose of Compound 1 was increased to 4.5 mg, mean fasting glucose decreased to 6.52 mmol / L on Day 80, resulting in an approximately 40% decrease.

[0811] Patients in Cohort 2 had a mean baseline fasting glucose of 10.46 mmol / L. As the dose of Compound 1 was increased to 10.0 mg, the mean fasting glucose decreased to 5.91 mmol / L on Day 108, resulting in an approximate 43% decrease.

[0812] Fasting insulin

[0813] Patients in Cohort 1 had a mean fasting baseline plasma insulin level of 9.648 mIU / L. As the dose of Compound 1 was increased to 4.5 mg, mean fasting insulin levels increased to 13.362 mIU / L on Day 78 and 14.046 mIU / L on Day 80, resulting in an approximate increase of 38-46% relative to baseline.

[0814] Patients in Cohort 2 had a mean fasting baseline insulin level of 5.892 mIU / L. As the dose of Compound 1 increased to 6.0 mg, the mean fasting insulin level increased to 6.73 mIU / L, resulting in an increase of approximately 14% relative to baseline. As the dose of Compound 1 increased to 8.0 mg, the mean fasting insulin level was 6.589 mIU / L, an increase of approximately 12% relative to baseline. As the dose of Compound 1 increased to 10.0 mg, the mean fasting insulin level decreased to 5.355 mIU / L on Day 106 and to 4.74 mIU / L on Day 108, resulting in an approximately 20% decrease in fasting insulin relative to baseline. This data suggests that when the dose of Compound 1 is greater than 8.0 mg, fasting plasma glucose can be reduced without increasing fasting insulin levels, which is consistent with reduced insulin resistance.

[0815] C-Peptide

[0816] Patients in Cohort 1 had a mean fasting baseline plasma C-peptide level of 667 pmol / L. As the dose of Compound 1 was increased to 4.5 mg, the mean fasting C-peptide level increased to 820.2 pmol / L on Day 78 and 874.9 pmol / L on Day 80, resulting in an approximate increase of 22-31% relative to baseline.

[0817] Patients in cohort 2 had a mean fasting baseline C-peptide level of 532.8 pmol / L. As the dose of compound 1 was increased to 6.0 mg, the mean fasting C-peptide level increased to 596.6 pmol / L, resulting in an approximately 12% increase in fasting C-peptide levels relative to baseline. As the dose of compound 1 was increased to 8.0 mg, the mean fasting C-peptide level increased only slightly to 541.7 pmol / L (approximately 2%) relative to baseline. As the dose of compound 1 was increased to 10.0 mg, the mean fasting C-peptide level decreased to 511.1 pmol / L on day 106 and to 435.4 pmol / L on day 108, resulting in an approximately 18% decrease in fasting C-peptide levels relative to baseline. This data suggests that when the dose of compound 1 is greater than 8.0 mg, fasting plasma glucose can be reduced without increasing fasting C-peptide secretion by pancreatic β cells, which is consistent with reducing the workload of pancreatic β cells.

[0818] Fasting glucagon

[0819] Patients in Cohort 1 had mean fasting baseline plasma glucagon levels of 14.79 pmol / L. As the dose of Compound 1 was increased to 4.5 mg, mean fasting glucagon levels decreased to 6.65 pmol / L on Day 78 and 8.19 pmol / L on Day 80, resulting in an approximate 45-55% decrease from baseline.

[0820] Patients in Cohort 2 had a mean fasting baseline glucagon level of 9.83 pmol / L. As the dose of Compound 1 was increased to 6.0 mg, the mean fasting glucagon level decreased to 3.65 pmol / L, resulting in a decrease of approximately 63% relative to baseline. As the dose of Compound 1 was increased to 8.0 mg, the mean fasting glucagon level decreased to 2 pmol / L relative to baseline on Day 80. As the dose of Compound 1 was increased to 10.0 mg, the mean fasting glucagon level decreased to 1.98 pmol / L relative to baseline on Day 106, and decreased to 1.93 pmo1 / L relative to baseline on Day 108. This data indicates that when the dose of Compound 1 is greater than 6.0 mg, fasting plasma glucagon can be reduced by approximately 80%.

[0821] Fasting, total cholesterol

[0822] Patients in Cohort 1 had a mean fasting total cholesterol level of 5.065 mmol / L. As the dose of Compound 1 was increased to 4.5 mg, the mean fasting total cholesterol level decreased to 4.275 mmol / L on Day 78 and 4.461 mmol / L on Day 80, resulting in an approximate 12-16% decrease from baseline.

[0823] Patients in cohort 2 had an average fasting baseline total cholesterol level of 4.971mmol / L. As the dose of compound 1 was increased to 6.0mg, the average fasting total cholesterol level decreased to 3.673mmol / L on day 64, resulting in a decrease of approximately 26% relative to baseline. As the dose of compound 1 was increased to 8.0mg, the average fasting total cholesterol level decreased to 3.614mmol / L (approximately 27% decrease) relative to baseline on day 85. As the dose of compound 1 was increased to 10.0mg, the average total cholesterol level decreased to 3.454mmol / L on day 106 and to 3.441mmol / L on day 108, resulting in a decrease of approximately 31% in fasting total cholesterol levels relative to baseline. The data indicate that when the dose of compound 1 is greater than 8.0mg, fasting total cholesterol levels can be reduced by more than 30%.

[0824] Fasting LDL cholesterol

[0825] Patients in Cohort 1 had a mean fasting LDL cholesterol level of 2.852 mmol / L. As the dose of Compound 1 was increased to 4.5 mg, the mean fasting LDL cholesterol level decreased to 2.56 mmol / L on Days 78 and 80, approximately a 10% decrease from baseline.

[0826] Patients in cohort 2 had an average fasting baseline LDL cholesterol level of 2.796mmol / L. As the dose of compound 1 was increased to 6.0mg, the average fasting LDL cholesterol level was reduced to 1.997mmol / L on day 64, resulting in a decrease of approximately 29% relative to baseline. As the dose of compound 1 was increased to 8.0mg, the average fasting LDL cholesterol level was reduced to 1.954mmol / L (approximately 30% reduction) relative to baseline on day 85. As the dose of compound 1 was increased to 10.0mg, the average fasting LDL cholesterol level was reduced to 1.859mmol / L on day 106, and the average fasting LDL cholesterol level was reduced to 1.849mmol / L on day 108, resulting in a decrease of approximately 33-34% in fasting LDL cholesterol levels relative to baseline. This data shows that when the dose of compound 1 reaches 8.0mg or higher, fasting LDL cholesterol levels can be reduced by 30% or more.

[0827] Fasting triglycerides

[0828] Patients in Cohort 1 had a mean fasting triglyceride level of 2.938 mmol / L. As the dose of Compound 1 was increased to 4.5 mg, the mean fasting triglyceride level decreased to 1.456 mmol / L on Day 78 and 2.084 mmol / L on Day 80, resulting in an approximate 29-50% decrease relative to baseline.

[0829] Patients in cohort 2 had an average fasting baseline triglyceride level of 1.867mmol / L. As the dose of compound 1 was increased to 6.0mg, the average fasting triglyceride level decreased to 1.055mmol / L on day 64, resulting in a decrease of approximately 43% relative to baseline. As the dose of compound 1 was increased to 8.0mg, the average fasting triglyceride level decreased to 0.855mmol / L (approximately 54% decrease) relative to baseline on day 85. As the dose of compound 1 was increased to 10.0mg, the average fasting triglyceride level decreased to 0.86mmol / L on day 106 and to 0.985mmol / L on day 108, resulting in a decrease of approximately 47-54% relative to baseline in fasting triglyceride levels. This data shows that when the dose of compound 1 is greater than 6.0mg, fasting triglyceride levels can be reduced by 50% or more.

[0830] weight

[0831] Patients in Cohort 1 had a mean baseline weight of 97.19 kg, with an increase in the LY dose to 4.5 mg, which reduced the mean body weight to 94.0 kg on Day 78, with a mean percent change from baseline of -3.03%.

[0832] Patients in cohort 2 had a mean baseline weight of 94.9 kg. As the dose of compound 1 was increased to 4.0 mg, the mean body weight decreased to 90.38 kg on day 43, with a mean percentage change of -4.04% relative to baseline. As the dose of compound 1 was increased to 6.0 mg, the mean body weight decreased to 87.69 kg on day 64, with a mean percentage change of -7.07% relative to baseline. As the dose of compound 1 was increased to 8.0 mg, the mean body weight decreased to 85.88 kg on day 85, with a mean percentage change of -9.05% relative to baseline. As the dose of compound 1 was increased to 10 mg, the mean body weight decreased to 82.55 kg on day 109, with a mean percentage change of -12.71% relative to baseline.

[0833] After the 16-week dosing and administration of compound 1 was completed, body weight was still reduced relative to baseline. On day 134, the average body weight of the cohort 2 group of compound 1 was 84.05 kg, with an average percentage change of -11.14% relative to baseline. On day 162, the average body weight of the cohort 2 group of compound 1 was 88.96 kg, with an average percentage change of -6.56% relative to baseline. These results show that a dose of compound 1 greater than 6 mg can lead to a weight loss of more than 9%. In addition, when the dose of compound 1 reaches 10 mg or more, it can reduce body weight by more than 12%.

[0834] waistline

[0835] Patients in Cohort 1 had a mean baseline waist circumference of 108.66 cm. When the LY dose was increased to 4.5 mg, the mean waist circumference decreased to 105.66 cm on Day 78, a decrease of approximately 3% from baseline.

[0836] Patients in Cohort 2 had a mean baseline waist circumference of 106.93 cm. As the dose of Compound 1 was increased to 4.0 mg, the mean waist circumference decreased to 103.38 cm on Day 43, a decrease of approximately 3% relative to baseline. As the dose of Compound 1 was increased to 6.0 mg, the mean waist circumference decreased to 101.31 cm on Day 64, a decrease of approximately 5% relative to baseline. As the dose of Compound 1 was increased to 8.0 mg, the mean waist circumference decreased to 98.58 cm on Day 85, a decrease of approximately 8% relative to baseline. As the dose of Compound 1 was increased to 10 mg, the mean waist circumference decreased to 96.56 cm on Day 109, a decrease of approximately 10% relative to baseline.

[0837] After the end of 16 weeks of LY dosing and administration, waist circumference was still reduced relative to baseline. On Day 134, the average waist circumference of the Compound 1 group in Cohort 2 was 97.59 cm, a decrease of approximately 9% relative to baseline. On Day 162, the average waist circumference of the Compound 1 group in Cohort 2 was 102.79 cm, a decrease of approximately 4% relative to baseline. This data shows that a dose of Compound 1 greater than 6.0 mg can lead to improvements in body composition and a reduction in waist circumference of more than 5%.

[0838] Fasting insulin resistance

[0839] Patients in cohort 1 had a mean fasting insulin resistance HOMA-IR index of 4.704. As the dose of compound 1 was increased to 4.5 mg, the mean HOMA-IR index decreased to 4.289 on day 78 and 4.271 on day 80, resulting in an approximate 9% decrease from baseline.

[0840] Patients in cohort 2 had a mean fasting insulin resistance HOMA-IR index of 2.7. As the dose of compound 1 increased to 6.0 mg, the mean HOMA-IR index decreased to 2.158 on day 64, resulting in a decrease of approximately 20% relative to baseline. As the dose of compound 1 increased to 8.0 mg, the mean HOMA-IR index decreased to 1.976 (approximately 27% decrease) relative to baseline on day 85. As the dose of compound 1 increased to 10.0 mg, the mean HOMA-IR index decreased to 1.325 on day 108, resulting in a decrease of approximately 51% in HOMA-IR relative to baseline. This data indicates that when the dose of compound 1 is greater than 6.0 mg, the fasting insulin resistance index can be reduced by more than 25%. When the dose of compound 1 reaches 10 mg or more, the fasting insulin resistance index can be reduced by 50%.

[0841] Fasting pancreatic beta cells

[0842] Patients in Cohort 1 had a mean fasting pancreatic beta cell insulin secretion HOMA-B index of 15.791. As the dose of Compound 1 was increased to 4.5 mg, the mean HOMA-B index increased to 38.762 at Day 80, resulting in an approximate 145% increase relative to baseline.

[0843] Patients in cohort 2 had a mean fasting pancreatic beta cell insulin secretion HOMA-B index of 9.108. As the dose of compound 1 increased to 6.0 mg, the mean HOMA-B index increased to 16.072 on day 64 relative to baseline, resulting in an increase of approximately 76%. As the dose of compound 1 increased to 8.0 mg, the mean HOMA-B index increased to 16.689 (approximately 83% increase) on day 85 relative to baseline. As the dose of compound 1 increased to 10.0 mg, the mean HOMA-B index increased to 12.077 on day 108 relative to baseline, resulting in an approximately 33% increase in HOMA-B relative to baseline. This data indicates that when the dose of compound 1 is greater than 8.0 mg, the increase in the fasting insulin secretion HOMA-B index is attenuated, which is consistent with the improvement in fasting insulin sensitivity and the reduction in insulin secretion requirements in the case of lower fasting glucose levels.

[0844] MMTT - Glucose Levels

[0845] Patients in cohort 1 had a baseline mean area under the 0-3 hour curve for glucose levels during a mixed meal tolerance test of 43.06 h*mmol / L. As the dose of compound 1 was increased to mg, the mean area under the 0-3 hour curve for glucose levels decreased to 25.76 h*mmol / L on day 80, resulting in an approximate 40% decrease relative to baseline.

[0846] Patients in cohort 2 had a baseline mean area under the 0-3 hour curve for glucose levels during a mixed meal tolerance test of 38.27 h*mmol / L. As the dose of compound 1 was increased to 10.0 mg, the area under the 0-3 hour curve for glucose levels decreased to 25.76 h*mmol / L on day 108, resulting in a 38% decrease in meal-stimulated glucose levels relative to baseline.

[0847] MMTT--Insulin Level

[0848] Patients in cohort 1 had a baseline mean area under the curve for insulin levels 0-3 hours during a mixed meal tolerance test of 125.233 h*mIU / L. As the dose of compound 1 was increased to 4.5 mg, the mean area under the curve for insulin levels 0-3 hours increased to 189.435 h*mIU / L on day 80, resulting in an increase of approximately 51% relative to baseline.

[0849] Patients in cohort 2 had a baseline mean area under the curve for 0-3 hours of insulin levels during a mixed meal tolerance test of 77.692 h*mIU / L. As the dose of compound 1 increased to 10.0 mg, the area under the curve for 0-3 hours of insulin levels decreased to 69.847 h*mIU / L on day 108, resulting in a decrease in meal-stimulated insulin levels of approximately 10% relative to baseline. The data indicate that when the dose of compound 1 reaches 4.5 mg, it stimulates insulin secretion relative to baseline in response to mixed meals. When the dose of compound 1 is greater than 4.5 mg and reaches 10 mg, it does not stimulate insulin secretion relative to baseline in response to mixed meals, which is consistent with reducing the workload of pancreatic beta cells while reducing glucose levels.

[0850] MMTT-C peptide

[0851] Patients in cohort 1 had a baseline mean area under the curve for C-peptide levels 0-3 hours during a mixed meal tolerance test of 4391.4 h*pmol / L. As the dose of compound 1 was increased to 4.5 mg, the mean area under the curve for C-peptide levels 0-3 hours increased to 5850.1 h*pmol / L on day 80, resulting in an approximate increase of 33% relative to baseline.

[0852] Patients in cohort 2 had a baseline mean area under the curve for C-peptide levels of 3604.1 h*pmol / L during the mixed meal tolerance test for 0-3 hours. As the dose of compound 1 was increased to 10.0 mg, the area under the curve for 0-3 hours of C-peptide levels decreased to 3147.4 h*pmol / L on day 108, resulting in a decrease of approximately 13% in meal-stimulated C-peptide levels relative to baseline. This data indicates that when the dose of compound 1 reaches 4.5 mg, it stimulates insulin secretion processed with proinsulin in response to mixed meals relative to baseline. When the dose of compound 1 is greater than 4.5 mg and reaches 10 mg, it does not stimulate insulin secretion processed with proinsulin in response to mixed meals relative to baseline, which is consistent with reducing the pancreatic beta cell load while reducing glucose levels.

[0853] MMTT-Glucagon

[0854] Patients in Cohort 1 had a baseline mean area under the curve for glucagon levels 0-3 hours during a mixed meal tolerance test of 64.98 h*pmol / L. As the dose of Compound 1 was increased to 4.5 mg, the mean area under the curve for glucagon levels 0-3 hours decreased to 27.93 h*pmol / L on Day 80, resulting in an approximate 57% decrease relative to baseline.

[0855] Patients in Cohort 2 had a baseline mean area under the curve for 0-3 hour glucagon levels during a mixed meal tolerance test of 39.89 h*pmol / L. As the dose of Compound 1 was increased to 10.0 mg, the area under the curve for 0-3 hour glucagon levels decreased to 7.61 h*pmol / L on Day 108, resulting in a decrease in meal-stimulated glucagon levels of approximately 81% relative to baseline. The data indicate that a dose of 4.5 mg of Compound 1 can reduce glucagon secretion in response to a mixed meal by more than 50% relative to baseline. A dose of 10 mg of Compound 1 can reduce glucagon secretion in response to a mixed meal by more than 80% relative to baseline. MMTT-Matsuda Insulin Sensitivity Index (ISI-M)

[0856] Patients in cohort 1 had a baseline Matsuda insulin sensitivity index (ISI-M) of 3.568, which was calculated based on mixed meal tolerance test parameters. As the dose of compound 1 was increased to 4.5 mg, the mean Matsuda index was 3.567 at day 80, indicating no change from baseline.

[0857] Patients in cohort 2 had a baseline Matsuda insulin sensitivity index (ISI-M) of 4.616, which was calculated based on mixed meal tolerance test parameters. As the dose of compound 1 increased to 10.0 mg, the Matsuda index increased to 10.7 on day 108, an increase of approximately 132% relative to baseline, indicating an increase in insulin sensitivity. The data show that when the dose of compound 1 reaches 4.5 mg, it does not improve insulin sensitivity in response to mixed meals. When the dose of compound 1 reaches 10 mg, it significantly improves insulin sensitivity in response to mixed meals.

[0858] Adverse Events

[0859] No deaths occurred during this study. A total of 17 (94.4%) patients treated with Compound 1 and 6 (100%) patients treated with placebo reported TEAEs throughout the study, as shown in Table 9. Most TEAEs reported during the study were mild in severity (88.5%). Overall, the most commonly reported TEAEs in participants treated with LY3305677 were gastrointestinal disturbances:

[0860] Nausea: 7 (38.9%)

[0861] · 5 patients (27.8%) vomited.

[0862] · Belching: 4 (22.2%)

[0863] · Diarrhea: 4 patients (22.2%),

[0864] · Abdominal pain 1 (5.6%), and

[0865] ·Constipation occurred in 2 patients (11.1%).

[0866]

[0867] Abbreviation: N = number of patients

[0868] Table 9: Summary of Treatment-Emergent Adverse Events (All Causal) During this study, 1 SAE was reported in 1 patient who received study intervention, as shown in Table 10.

[0869]

[0870] Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; SAE = Serious Adverse Event

[0871] a Based on the first dose of study drug administered on day one.

[0872] Table 10: Reported SAEs

[0873] Example 2: Clinical study

[0874] Overview

[0875] This study aims to evaluate the safety, tolerability, PD and PK of higher doses of Compound 1 in individuals with obesity. The multiple ascending dose (MAD) study is a randomized, investigator- and participant-blind, placebo-controlled, multiple ascending dose, single-site or multi-site study in individuals with obesity (i.e., women or men aged 18-70 years (inclusive), with a BMI of 27 kg / m 2 Up to 50kg / m 2 Participants were required to have maintained a stable weight for at least 3 months before the start of the study.

[0876] treat

[0877] The dose of Compound 1 was evaluated in 2 cohorts administered once weekly for 20 weeks. Each cohort included 12 patients - 9 patients were administered Compound 1 and 3 patients were administered placebo.

[0878] Dosing for Cohort 1 is as follows:

[0879] - 1.5 mg compound 1 for 2 weeks;

[0880] - 3.0 mg compound 1 for 2 weeks;

[0881] - 6.0 mg compound 1 for 4 weeks;

[0882] -8.0 mg compound 1 for 4 weeks;

[0883] - 12.0 mg Compound 1 for 4 weeks; and

[0884] - 16.0 mg Compound 1 for 4 weeks.

[0885] Dosing for cohort 2 is as follows:

[0886] - 2.0 mg compound 1 for 3 weeks;

[0887] - 4.0 mg compound 1 for 3 weeks;

[0888] - 6.0 mg compound 1 for 3 weeks;

[0889] -8.0 mg compound 1 for 3 weeks;

[0890] - 10.0 mg compound 1 for 2 weeks;

[0891] - 13.0 mg of Compound 1 for 2 weeks, and

[0892] - 16.0 mg Compound 1 for 4 weeks.

[0893] Evaluate

[0894] Blood samples were collected periodically from day 1 to day 138 to determine the plasma concentrations of increasing doses of Compound 1 in individuals with obesity.

[0895] HbA1c, C-peptide, glucagon, serum glucose and insulin were measured at multiple time points during the dosing period from day 1 to day 138 using methods known in the art, and a mixed meal tolerance test (MMTT) was performed for each analyte at baseline before initial dosing and during week 20. The mean absolute values ​​and percentage changes of fasting glucose, insulin, C-peptide and glucagon in each cohort of compound 1 and placebo groups were calculated and compared with the baselines at multiple time points from day 1 to day 138.

[0896] Parameters from fasting samples and MMTT used to assess insulin resistance and pancreatic β-cell function include the following:

[0897] - Homeostasis model assessment (HOMA)-B;

[0898] -HOMA-IR;

[0899] - Insulin sensitivity (Matsuda index).

[0900] Insulin sensitivity (Matsuda index) was calculated according to the following formula:

[0901]

[0902] The unit of glucose is mg / dL and the unit of insulin is μU / mL.

[0903] Mean parameters of multiple indices related to glycemic control, pancreatic β-cell function, and insulin sensitivity at Day 138 will be derived from fasting and MMTT measurements in each of the Compound 1 and placebo groups and compared to baseline.

[0904] The satiety VAS was measured on an empty stomach at multiple time points during the dosing period from day 1 to day 138. Appetite sensations for parameters of hunger, satiety, fullness, and anticipated food intake were assessed using the VAS, and an overall appetite score was calculated.

[0905] During the dosing period from day 1 to day 138 and during the extended visit after the end of dosing, body weight and waist circumference were measured at frequent intervals. The mean absolute value and percentage change of body weight in each cohort were calculated for the compound 1 group and the placebo group, and compared with the baseline at multiple time points from day 1 to day 138 and during the extended visit after the end of dosing. The mean absolute value and percentage change of waist circumference in each cohort for the compound 1 group and the placebo group were calculated and compared with the baseline at multiple time points from day 1 to day 138 and during the extended visit after the end of dosing. Although the weight loss described in Example 1 occurred in a group of patients with type 2 diabetes, the weight loss in the obese patient group was generally greater. A multiplier of 1.6-1.8 can be applied to the weight loss percentage from the T2D group to the obese group.

[0906] Fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, were measured at multiple time points during the dosing period from day 1 to day 138. The mean absolute values ​​and percentage changes of fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, were calculated in each of the Compound 1 and placebo groups and compared with the baseline at multiple time points from day 1 to day 138.

[0907] Vital signs, including heart rate, pulse, systolic and diastolic blood pressure, were monitored at frequent intervals during dosing from Day 1 to Day 138.

[0908] Safety parameters assessed during the study included: AEs (with particular focus on GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examination / medical evaluation, vital signs and ECG, BW, injection site reactions, hypersensitivity reactions, and glucose monitoring (with particular focus on hypoglycemia).

[0909] weight

[0910] During the multiple-dose administration of Compound 1, mean body weight reduction was observed in all treatment groups at each time point evaluated. The trend of body weight reduction was dose-dependent, and the mean percentage change in body weight relative to baseline observed at the end of the treatment period was as follows:

[0911] - Placebo: Day 138 (Week 20) ​​+0.5%

[0912] - Cohort 1: Day 138 (Week 20) ​​- 19.4%

[0913] - Cohort 2: Day 138 (Week 20) ​​- 20.6%

[0914] The weight loss data of the two cohorts at different time points are as follows:

[0915] Day 85 / 12 weeks (after 4 weeks of 8 mg): Placebo +0.2%, Cohort 1 -10.7%, Cohort 2 -11.7%

[0916] Day 99 / Week 14 (after 2 weeks of 10 mg treatment in Cohort 2): Placebo +0.07%, Cohort 2 -13.4%

[0917] Day 113 / Week 16 (after 4 weeks of 12 mg in Cohort 1, 2 weeks of 13 mg in Cohort 2): Placebo +0.7%, Cohort 1 -15.4%, Cohort 2 -16.2%

[0918] Day 138 / 20 weeks (after 4 weeks of 16 mg): Placebo +0.5%, Cohort 1 -19.4%, Cohort 2 -20.6%.

[0919] waistline

[0920] During multiple doses of Compound 1, mean waist circumference reductions were observed in both Cohort 1 and Cohort 2.

[0921] Day 85 / 12 weeks (after 4 weeks of 8 mg) Placebo +0.04%, Cohort 1 -5.2%, Cohort 2 -7.6%

[0922] Day 99 / Week 14 (after 2 weeks of 10 mg treatment in Cohort 2) Placebo +1.0%, Cohort 2 -6.8%

[0923] Day 113 / Week 16 (after 4 weeks of 12 mg treatment for Cohort 1; after 2 weeks of 13 mg treatment for Cohort 2) Placebo +1.3%, Cohort 1 -6.3%, Cohort 2 -12.6%

[0924] Day 138 / Week 20 (after 4 weeks of 16 mg) Placebo +0.4%, Cohort 1 -11.5%, Cohort 2 -16.6%

[0925] Adverse Events

[0926] No deaths occurred during this study. No serious adverse events were observed. The most common treatment-emergent adverse events of Mastolide were gastrointestinal in nature (nausea, vomiting, diarrhea), consistent with GLP-1 receptor agonists. At high doses of 10-16 mg, the incidence of nausea, vomiting, and diarrhea was similar and the severity was mild or moderate.

[0927] Example 3: Clinical study

[0928] Overview

[0929] This study aims to further evaluate the efficacy and safety of compound 1 in obese or overweight individuals. This study is a randomized, investigator- and participant-blind, placebo-controlled study in obese or overweight individuals without diabetes (i.e., women or men aged 18-75 years (inclusive), who had obesity before randomization and had a BMI ≥ 30 kg / m at screening). 2 Or overweight before randomization and BMI ≥ 27 kg / m at screening 2 or <30kg / m 2 Participants should have maintained a stable weight for at least 3 months before the start of the study.

[0930] treat

[0931] Multiple doses of Compound 1 were evaluated over 48 weeks in groups administered Compound 1 or placebo. Approximately 60 subjects were included in each cohort.

[0932] Compound 1 is administered to multiple cohorts from week 1 to week 20 or week 32 to reach different maintenance doses or maximum doses administered between week 21 or week 32 (or the earliest week in which the dose is first reached) to week 48. The starting dose of the dosing regimen may vary from cohort to cohort, for example, a starting dose of 1.5 mg, 2,0 mg, or 3.0 mg. The time intervals of the dose steps may vary within and between cohorts, including dose increases after 2, 3, or 4 week intervals. The magnitude of the dose increase may vary within and between cohorts, with the dose in the dose step increasing by 1.5 mg, 2.0 mg, 3.0 mg, 4.0 mg, or 5.0 mg to reach the specified dose.

[0933] In this study, the first dosing schedule (Cohort 1) was as follows:

[0934] -1.5 mg QW compound 1 for 4 weeks;

[0935] - 3.0 mg QW Compound 1 for 28 weeks; and

[0936] -6 mg QW Compound 1 for 16 weeks.

[0937] The second dosing schedule (Cohort 2) was as follows:

[0938] -1.5 mg QW compound 1 for 4 weeks;

[0939] -3 mg QW compound 1 for 4 weeks;

[0940] -6 mg QW compound 1 for 4 weeks;

[0941] -8 mg QW Compound 1 for 4 weeks; and

[0942] -10 mg QW Compound 1 for 32 weeks.

[0943] The third dosing schedule (Cohort 3) is as follows:

[0944] -1,5 mg QW compound 1 for 4 weeks;

[0945] -3 mg QW compound 1 for 4 weeks;

[0946] -6 mg QW compound 1 for 4 weeks;

[0947] - 9 mg QW compound 1 for 4 weeks;

[0948] -12 mg QW Compound 1 for 4 weeks; and

[0949] -16 mg QW compound 1 for 28 weeks

[0950] Compound 1 was administered to three cohorts, with the first cohort receiving 1.5 mg in weeks 1-4, 3.0 mg in weeks 5-32, and 6.0 mg in weeks 33-48, the second cohort receiving 1.5 mg in weeks 1-4, 3.0 mg in weeks 5-8, 6.0 mg in weeks 9-12, 8.0 mg in weeks 13-16, and 10.0 mg in weeks 17-48, and the third cohort receiving 1.5 mg in weeks 1-4, 3.0 mg in weeks 5-8, 6.0 mg in weeks 9-12, 9.0 mg in weeks 13-16, 12.0 mg in weeks 17-20, and 16.0 mg in weeks 21-48.

[0951] Evaluate

[0952] Approximately 40 individuals from each cohort were evaluated by magnetic resonance imaging analysis for changes from baseline to week 48 in multiple measures of body composition, including changes in liver fat, abdominal subcutaneous adipose tissue, and visceral adipose tissue. Individuals were assessed for changes in NAFLD, characterized by liver fat ≥10% on magnetic resonance imaging.

[0953] Blood samples were collected periodically from week 1 to week 48 to determine the plasma concentrations of increasing doses of Compound 1 in individuals with obesity.

[0954] Fasting HbA1 c, C-peptide, glucagon, blood glucose, and insulin were measured during dosing and at multiple time points between Weeks 1 and 48. The mean absolute values ​​and percent changes in fasting glucose, insulin, C-peptide, and glucagon at Weeks 32 and 48 were calculated and compared to the pre-dose Week 1 baseline for each Compound 1 cohort and placebo cohort. The mean absolute values ​​and percent changes in fasting glucose, insulin, C-peptide, and glucagon were calculated for each Compound 1 cohort and compared to placebo at Weeks 32 and 48.

[0955] Parameters derived from fasting samples to assess insulin resistance and pancreatic β-cell function include homeostasis model assessment (HOMA)-B, HOMA-IR. Mean parameters of the HOMA index related to glycemic control, pancreatic β-cell function, and insulin sensitivity will be derived from fasting measurements in each compound 1 cohort and compared with placebo at weeks 32 and 48.

[0956] The satiety VAS was measured on an empty stomach during the dosing period and at multiple time points from week 1 to week 48. Appetite sensations for parameters of hunger, satiety, fullness, and anticipated food intake were assessed using the VAS, and an overall appetite score was calculated.

[0957] Body weight and waist circumference were measured at frequent intervals during dosing and from Week 1 to Week 48 and during extension visits after the end of dosing. The mean absolute values ​​and percent change in body weight at Week 32 and Week 48 were calculated and compared to the pre-dose Week 1 baseline for each Compound 1 cohort and placebo cohort. The mean absolute values ​​and percent change in waist circumference at Week 32 and Week 48 were calculated and compared to the pre-dose Week 1 baseline for each Compound 1 cohort and placebo cohort. The mean absolute values ​​and percent change in waist circumference were calculated for each Compound 1 cohort and compared to placebo at Week 32 and Week 48.

[0958] Fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, were measured during dosing and at multiple time points between Weeks 1 and 48. The mean absolute values ​​and percent changes in fasting lipid profiles at Weeks 32 and 52 were calculated and compared with the pre-dose Week 1 baseline for each Compound 1 cohort and placebo cohort. The mean absolute values ​​and percent changes in fasting lipid profiles were calculated for each Compound 1 cohort and compared with placebo at Weeks 32 and 48.

[0959] Vital signs, including heart rate, pulse, systolic and diastolic blood pressure, were monitored frequently during dosing and from Week 1 to Week 48.

[0960] Safety parameters assessed during the study included: AEs (with a particular focus on GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examination / medical evaluation, vital signs and ECG, BW, injection site reactions, hypersensitivity reactions, and glucose monitoring (with particular attention to mean parameters of the HOMA index related to glycemic control, pancreatic β-cell function, and insulin sensitivity, which will be derived from fasting measurements at Weeks 32 and 48 and compared to the Week 1 baseline before dosing for each Compound 1 and placebo cohort).

Claims

1. A method for long-term weight management, improving glycemic control, and / or lowering LDL cholesterol or triglycerides in patients in need thereof; The method comprises: (1) administering to the patient a dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; as well as (2) thereafter increasing the dose to greater than about 6 mg to about 16 mg, and administering the increased dose to the patient once a week for at least about two weeks.

2. The method of claim 1, wherein the weekly increasing dose is selected from about 6.25 mg to about 16.0 mg, about 6.5 mg to about 16.0 mg of the compound, about 8.0 mg to about 16.0 mg, about 10 mg to about 16.0 mg, about 11.0 mg to about 16 mg, about 12.0 mg to about 16.0 mg, about 13.0 mg to about 16.0 mg, or about 14.0 mg to about 16.0 mg.

3. The method of claim 1 or 2, wherein the weekly increasing dose is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

4. The method of claim 2, wherein the weekly increasing dose is from about 8 mg to about 16.0 mg.

5. The method of claim 4, wherein the weekly increasing dose is about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

6. The method of claim 2, wherein the weekly increasing dose is from about 10 mg to about 16.0 mg.

7. The method of claim 6, wherein the weekly increasing dose is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

8. The method according to any one of claims 1 to 7, wherein a plurality of different weekly doses are administered to the patient in steps (1) and (2).

9. The method of claim 8, wherein the first once weekly dose is from about 1.0 mg to about 6.0 mg.

10. The method of claim 9, wherein the first weekly dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg.

11. The method of claim 10, wherein the first weekly dose is about 1.5 mg, about 2.0 mg, or about 3.0 mg.

12. The method of any one of claims 9 to 11, wherein the first weekly dose and each subsequent increased weekly dose are increased in increments of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and wherein each dose is administered for at least about two weeks.

13. The method of claim 12, wherein the first once weekly dose is about 1.5 mg, about 2.0 mg, or about 3.0 mg, and wherein the first once weekly dose and each subsequent increased once weekly dose are increased in increments of about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, or any combination thereof.

14. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; as well as (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering this dose once a week for at least about two weeks.

15. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; as well as (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering this dose once a week for at least about two weeks.

16. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks; as well as (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering this dose once a week for at least about two weeks.

17. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 2.0 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 4.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 8.0 mg and administering the dose once a week for at least about two weeks; (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks; (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks; as well as (g) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering this dose once a week for at least about two weeks.

18. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 9.0 mg and administering the dose once a week for at least about two weeks; (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 12.0 mg and administering the dose once a week for at least about two weeks; as well as (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering once per week for at least about two weeks.

19. The method according to any one of claims 1 to 13, comprising: (a) administering a first dose of about 1.5 mg of a compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 3.0 mg and administering the dose once a week for at least about two weeks; (c) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 6.0 mg and administering the dose once a week for at least about two weeks; (d) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 10.0 mg and administering the dose once a week for at least about two weeks; (e) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 13.0 mg and administering the dose once a week for at least about two weeks; as well as (f) increasing the dose of the compound or a pharmaceutically acceptable salt thereof to about 16.0 mg and administering this dose once a week for at least about two weeks.

20. The method of any one of claims 1 to 19, comprising administering each dose once a week for at least about four weeks.

21. The method of any one of claims 1 to 20, wherein the compound or a pharmaceutically acceptable salt thereof is administered subcutaneously.

22. The method of any one of claims 1 to 21, wherein administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in weight loss in the patient.

23. The method of any one of claims 1 to 22, wherein administration of the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in HbA1c in the patient.

24. The method of any one of claims 1 to 23, wherein administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in lowering of LDL cholesterol and / or lowering of triglycerides in the patient.

25. The method of any one of claims 1 to 24, wherein administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, does not result in unacceptable tolerability.

26. The method according to any one of claims 1 to 25, wherein the patient is overweight.

27. The method of any one of claims 1 to 25, wherein the patient is obese.

28. The method according to any one of claims 1 to 27, wherein the patient suffers from type 2 diabetes.

29. A compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein: (1) administering a dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

30. Use of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for providing long-term weight management, improving blood sugar control and / or reducing LDL cholesterol or triglycerides, wherein: (1) administering a dose of a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; and (2) Thereafter the dose is increased to greater than about 6 mg to about 16 mg once a week and administered for at least about two weeks.

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