How to use GCG / GLP1 coagonists for therapy

Abstract

Disclosed are the dosages and dosing regimens of incretin analogs, including once-weekly dosing of long-acting incretin analogs suitable for once-weekly dosing, such as glucagon-like peptide-1 (GLP-1) and glucagon (Gcg) coagonists, and determining and administering such dosages.

Description

[Technical Field] 【0001】 (Reference to the sequence list) This disclosure is submitted together with a sequence listing in ST.26XML format. The sequence listing is provided as a file titled "30324_WO_SeqListing" created on 18 May 2023, and is 3.1 kilobytes (kb) in size. The ST.26XML format sequence listing information is incorporated herein by reference in its entirety. 【0002】 (Field of invention) This disclosure relates to methods using incretin analogs or pharmaceutically acceptable salts thereof that are active at the glucagon (Gcg) receptor and the glucagon-like peptide-1 (GLP1) receptor, respectively, the medical use thereof, and pharmaceutical compositions having the same, in particular to diabetes (especially type 2 diabetes mellitus (T2DM)) and / or its symptoms, obesity, hypertension, cardiovascular disease, specifically 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), and non-alcoholic fatty acid liver disease. This invention relates to methods and medical uses of a specific dose of an incretin analog and a composition containing a specific dose of an incretin analog, which can be used to treat conditions, diseases, and disorders, including NAFLD, obstructive sleep apnea, etc. [Background technology] 【0003】 Over the past few decades, the prevalence of diabetes mellitus, a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, has continued to rise. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes cases. In T2DM, a combined effect of impaired insulin secretion and insulin resistance is associated with elevated blood glucose levels. 【0004】 Uncontrolled diabetes mellitus can lead to one or more conditions that affect the morbidity and mortality rates of individuals with T2DM. Obesity is one of the main risk factors for T2DM, and many individuals with T2DM (approximately 90%) are overweight or obese. It has been demonstrated that reducing body fat accumulation leads to improvement in obesity-related comorbidities. 【0005】 Current standards of treatment for T2DM, obesity, and obesity-related metabolic disorders include diet and exercise, as well as oral medications and injectable glucose-lowering drugs, including incretin-based therapies such as GLP-1 receptor agonists. Despite the success of GLP-1 receptor agonists, a significant number of individuals receiving approved therapies have not achieved their weight loss and / or glycemic control goals (see, e.g., Casagrande et al. (2013) Diabetes Care 36:2271-2279), leaving a “gap” between the efficacy of GLP-1 analogs and bariatric surgery. To bridge this gap, researchers have pursued “coagonist” strategies by combining GLP-1 with related hormones and peptides from the proglucagon family, including GIP and Gcg itself (see Sanchez-Garrido MA et al., Diabetes Care (2017) 60(10):1851-61). 【0006】 Several GLP-1 / Gcg coagonists are currently in clinical development, including cotadutide, efinopegdutide, mazdutide (described in International Patent Application Publication No. 2016 / 209707(A1)), SAR425899, BI 456906, JNJ-54729518, HM15211, NNC9204-1706, Alt-801 (pemvidutide), and G3215 (see Table 1 in Hope DCD et al., Frontiers in Endocrinology (Lausanne), 2021 Sep 8;12:735019). Certain of these GLP-1 / Gcg coagonists have shown promising weight loss, glycemic effects, or both in these early-phase clinical outcomes. However, several reports suggest that the weight loss and / or glucose-lowering effects of these coagonists may plateau, with higher doses not yielding improved efficacy and thus limiting the achievable weight loss and / or blood glucose improvement. Furthermore, tolerability may be limited at higher doses due to adverse gastrointestinal events. See, for example, Ji et al., The Lancet, EC Clinical Medicine 39(2021)101088; Nahra et al., Diabetes Care. 2021;44:1433-42; Alba et al., Clinical Obesity, 2021 Apr;11(2):e12432); and Ambery et al., British Journal of Clinical Pharmacology, 2018 Oct;84(10):2325-2335. 【0007】 Therefore, there is a need for more effective doses and dosing regimens for GLP-1 / GCG coagonists that can result in significant weight loss and / or provide improved glycemic control in individuals requiring such treatment, while also preserving an overall acceptable benefit / risk profile for the individual. [Overview of the Initiative] [Means for solving the problem] 【0008】 This invention reports on GLP-1 / Gcg coagonist doses and dosing regimens that result in unexpectedly improved weight loss, improved body composition, robust glycemic control, lipid reduction, and / or insulin sensitization, while simultaneously reducing the workload on beta-cell insulin secretion and exhibiting only mild or moderate adverse events. 【0009】 In one embodiment, the present invention provides a method for providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides in patients who require chronic weight management, improved blood glucose control, and / or reduction of LDL cholesterol or triglycerides, the method being (1) A compound of the following formula, administered once a week: 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 In the equation, Xaa2 is Aib, The Lys at position 20 is connected to the epsilon-amino group of the Lys side chain and ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 It is chemically modified by bonding with CO2H. The C-terminal amino acid is amidated (SEQ ID NO: 1), a compound. Or a pharmaceutically acceptable salt thereof It should be administered to patients who need it for at least about two weeks, (2) Subsequently, the dose is increased to more than approximately 6 mg to approximately 16 mg, and the increased dose is administered to the patient once a week for at least approximately two weeks. 【0010】 In some embodiments, provided herein is a method for preventing and / or treating a condition selected from type 2 diabetes, hyperglycemia, insulin-independent diabetes, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac event (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease in a patient, for reducing body weight, for reducing food intake, and / or for inducing satiety, the method comprising, (1) administering to a patient in need thereof a once-weekly dose of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for at least about 2 weeks; (2) thereafter increasing the dose to more than about 6 mg to about 16 mg and administering the increased dose to the patient once a week for at least about 2 weeks. 【0011】 In another aspect of the disclosure, provided is the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides, (1) wherein a once-weekly dose of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered for at least about 2 weeks; (2) thereafter the once-weekly dose is increased to more than about 6 mg to about 16 mg and administered for at least about 2 weeks. 【0012】 In some embodiments, provided is the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a condition selected from type 2 diabetes, hyperglycemia, insulin-independent diabetes, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), major adverse cardiac event (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease in a patient, for use in reducing body weight, for use in reducing food intake, and / or for use in inducing satiety, (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0013】 Further aspects of this disclosure provide the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0014】 In some embodiments, the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the prevention and / or treatment of a condition selected from 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 kidney disease in patients, for weight reduction, reduction of food intake, and / or induction of satisfaction. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0015】 In further aspects of this disclosure, the weekly increased doses are approximately 6.25 mg to 16.0 mg, 6.5 mg to 16.0 mg, 8.0 mg to 16.0 mg, 10 mg to 16.0 mg, 11.0 mg to 16 mg, 12.0 mg to 16.0 mg, 13.0 mg to 16.0 mg, or 14.0 mg to 16.0 mg. 【0016】 In further embodiments of this disclosure, the once-weekly increased dose is approximately 6.25 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. In some embodiments, the once-weekly increased dose is approximately 6.5 mg. In some embodiments, the once-weekly increased dose is approximately 7.0 mg. In some embodiments, the once-weekly increased dose is approximately 8.0 mg. In some embodiments, the once-weekly increased dose is approximately 9.0 mg. In some embodiments, the once-weekly increased dose is approximately 10.0 mg. In some embodiments, the once-weekly increased dose is approximately 11.0 mg. In some embodiments, the once-weekly increased dose is approximately 12.0 mg. In some embodiments, the once-weekly increased dose is approximately 13.0 mg. In some embodiments, the increased weekly dose is approximately 14.0 mg. In some embodiments, the increased weekly dose is approximately 15.0 mg. In some embodiments, the increased weekly dose is approximately 16.0 mg. 【0017】 In a preferred embodiment of this disclosure, the weekly increased dose is approximately 8.0 mg to approximately 16.0 mg. In a further embodiment of this disclosure, the weekly increased dose is approximately 8.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0018】 In another preferred embodiment of this disclosure, the once-weekly increased dose is approximately 10.0 mg to approximately 16.0 mg. In yet another embodiment of this disclosure, the once-weekly increased dose is approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0019】 In one aspect of this disclosure, the once-weekly dose in step (1) is approximately 1.0 mg to approximately 6.0 mg. In yet another aspect of this disclosure, the approximately weekly dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg. 【0020】 In further aspects of this disclosure, several different once-weekly doses are administered to the patient in steps (1) and (2). 【0021】 In one aspect of this disclosure, the patient is administered a first or initial once-weekly dose of about 1.0 mg to about 6.0 mg. Thus, in some embodiments, the first once-weekly dose is about 1.0 mg to about 6.0 mg. In further embodiments of this disclosure, the first once-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 preferred embodiments of this disclosure, the first once-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 once-weekly dose is about 1.0 mg. In some embodiments, the first once-weekly dose is about 1.5 mg. In some embodiments, the first once-weekly dose is about 2.0 mg. In some embodiments, the first once-weekly dose is approximately 3.0 mg. 【0022】 In one aspect of this disclosure, the first dose and each subsequent increased dose are increased in increments of approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, or any combination thereof, and each dose is administered for at least approximately two weeks. Therefore, the first dose is selected from approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, and 6.5 mg, and each subsequent dose is increased from the previously administered dose by approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, or any combination thereof. In a preferred embodiment, 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 an increment of 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. 【0023】 In another aspect of this disclosure, the dose may be reduced after administering the maximum or highest dose to the patient. For example, once-weekly doses of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg are administered to the patient for three weeks each. After three weeks at the maximum dose of 10 mg, the dose is reduced to 8 mg. 【0024】 In another aspect of this disclosure, the method or use includes administering a dose once per week for at least about four weeks. In yet another aspect of this disclosure, the method or use includes administering a dose once per week for at least about six weeks. In yet another aspect of this disclosure, the method or use includes administering a dose once per week for at least about eight weeks. 【0025】 In one preferred embodiment, the method or use comprises administering a dose once per week for at least about two weeks and administering a maximum dose once per week for at least about four weeks. In another preferred embodiment, the method or use comprises administering a dose once per week for at least about four weeks and administering a maximum dose once per week for at least about four weeks. In yet another preferred embodiment, the method or use comprises administering a dose once per week for at least about four weeks and administering a maximum dose once per week for at least about eight weeks. 【0026】 In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction in the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 10% of the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 15% of the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 20% of the patient's body weight. 【0027】 In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's HbA1c. In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's LDL cholesterol and / or triglycerides. In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in unacceptable tolerability. 【0028】 In one embodiment, the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered subcutaneously. 【0029】 In one embodiment, the patient is overweight. In another embodiment, the patient is obese. In yet another embodiment, the patient has type 2 diabetes. [Brief explanation of the drawing] 【0030】 [Figure 1]The participant arrangement in the clinical trial of compound 1 described in Example 1 is shown. [Figure 2] The mean change in body weight from baseline in the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical trial of Compound 1 described in Example 1 is shown. [Figure 3] This shows the mean change in waist circumference from baseline in the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical trial of Compound 1 described in Example 1. [Figure 4] The mean fasting glucose levels for the placebo, Cohort 1, and Cohort 2 treatment groups in the clinical trial of Compound 1 described in Example 1 are shown. [Figure 5] The mean fasting insulin levels for the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1 are shown. [Figure 6] The mean fasting C-peptide levels for the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1 are shown. [Figure 7a] The mean fasting cholesterol levels for the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1 are shown. [Figure 7b] The mean cholesterol profiles for the placebo, Cohort 1, and Cohort 2 treatment groups after sMMTT, conducted as part of a clinical trial of Compound 1 described in Example 1, are shown. [Figure 7c] The percentage change in fasting HDL from baseline (day 1) in the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1 is shown. [Figure 7d] This shows the percentage change in fasting LDL from baseline (day 1) for the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1. [Figure 7e]The mean HDL profiles for the placebo, Cohort 1, and Cohort 2 treatment groups after sMMTT, conducted as part of a clinical trial of Compound 1 described in Example 1, are shown. [Figure 7f] The mean LDL profiles for the placebo, Cohort 1, and Cohort 2 treatment groups after sMMTT, conducted as part of a clinical trial of Compound 1 described in Example 1, are shown. [Figure 7g] This shows the percentage change from fasting baseline (day 1) for the placebo, cohort 1, and cohort 2 treatment groups in the clinical trial of compound 1 described in Example 1. [Figure 7h] The mean triglyceride profiles for the placebo, Cohort 1, and Cohort 2 treatment groups after sMMTT, conducted as part of a clinical trial of Compound 1 described in Example 1, are shown. [Figure 8-1] VAS appetite assessments—showing hunger, satiety, and overall appetite—for the placebo, cohort 1, and cohort 2 treatment groups in clinical trials of compound 1 described in Example 1. [Figure 8-2] VAS appetite assessments—showing hunger, satiety, and overall appetite—for the placebo, cohort 1, and cohort 2 treatment groups in clinical trials of compound 1 described in Example 1. [Figure 8-3] VAS appetite assessments—showing hunger, satiety, and overall appetite—for the placebo, cohort 1, and cohort 2 treatment groups in clinical trials of compound 1 described in Example 1. [Modes for carrying out the invention] 【0031】 overview Several peptides derived from preproglucagon, and their analogues, specifically Gcg, GLP-1, and oxyntomodulin (OXM), have been proposed as therapeutic agents for the treatment of T2D and obesity. 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. 【0032】 Gcg is a 29-amino acid long peptide corresponding to amino acids 53-81 of preproglucagon. OXM is a 37-amino acid long peptide consisting of the complete 29-amino acid sequence of Gcg (amino acids 82-89 of preproglucagon, called "intermediate peptide 1" or IP-1) with an octapeptide carboxyl-terminated extension. Gcg helps maintain blood glucose levels by binding to Gcg receptors on hepatocytes and causing the liver to release glucose (stored in the form of glycogen) through glucogenolysis. As these stores are depleted, Gcg stimulates the liver to synthesize additional glucose through gluconeogenesis. This glucose is released into the bloodstream, preventing the onset of hypoglycemia. 【0033】 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 alleviate hyperglycemia in diabetic patients. Several GLP-1 agonists, including exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide, are approved for use in the treatment of T2D in humans. Such GLP-1 agonists have a beneficial effect on weight, carry no risk of hypoglycemia, and are effective in glycemic control. However, weight loss is moderate due to dose-dependent gastrointestinal side effects. 【0034】 OXM activates both Gcg and GLP-1 receptors, exhibiting slightly higher potency towards the Gcg receptor than the GLP-1 receptor. It is less potent towards each of these receptors than natural Gcg and GLP-1. Human Gcg can also activate both receptors, but has a stronger preference for the Gcg receptor than the GLP-1 receptor. GLP-1 cannot activate the Gcg receptor. OXM is involved in the control of food intake and body weight. It has been shown to suppress appetite and inhibit food intake in humans. International Patent Application Publication No. 2016 / 209707(A1) describes the structure, function, production, and use of an OXM analog (GLP-1 / Gcg coagonist) that can be used to treat diabetes mellitus, obesity, obesity-related comorbidities, and other medical conditions. Of particular interest herein is the fatty acid acylated long-acting OXM analog (GLP-1 / Gcg coagonist) (SEQ ID NO: 1), described in Example 2 herein. 【0035】 Unfortunately, many individuals with diabetes are unable to reach their HbA1c targets and struggle with weight management, highlighting the need for new therapies and medication regimens that can provide further glycemic control and / or weight loss. As mentioned above, simply increasing the dose of a therapeutic agent may not always achieve increased efficacy, as efficacy can plateau at certain dose levels. Furthermore, while increasing the dose of a therapeutic agent may in some cases achieve increased efficacy, increasing the dose of a therapeutic agent, specifically one that is active on GLP-1 and GCG receptors respectively, also carries a greater risk of side effects, particularly gastrointestinal side effects. 【0036】 The present invention, as described herein, overcomes these challenges and provides doses and drug regimens that result in substantially improved weight loss, improved body composition, robust glycemic control, lipid reduction, and / or insulin sensitization, while simultaneously reducing the workload on beta-cell insulin secretion and exhibiting only mild or moderate adverse events. 【0037】 As described herein, unexpectedly high weight loss (-19.4% and -20.6% respectively) was achieved in two separate cohorts receiving doses of approximately 6 mg to over 16 mg compared to a placebo-receiving cohort during a 20-week trial. Such magnitude of weight loss in such a short period has not been previously reported for any GLP-1 / Gcg coagonist. 【0038】 Specifically, surprisingly, the doses and regimens described herein have been found to achieve substantial weight loss and improved body composition, as evidenced, for example, by reduced body weight, waist circumference, absolute body fat mass and body fat percentage, and increased lean body mass percentage. Surprisingly, the doses and regimens described herein have also been found to achieve glycemic control, as evidenced, for example, by substantial reductions in HbA1c, fasting glucose, and glucose variability in the Mixed Meal Tolerance Test (MMTT). Surprisingly, the doses and regimens described herein have also been found to achieve improved insulin sensitivity, as evidenced, for example, by reduced fasting insulin and C-peptide, reduced insulin variability in the MMTT, and reduced HOMA-IR. Surprisingly, the doses and regimens described herein have also been found to achieve reduced appetite, as evidenced, for example, by reduced hunger and increased satiety. Surprisingly, the doses and regimens described herein have also been found to achieve improvements in the fat profile, as evidenced, for example, by reductions in fasting and sMMTT total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Surprisingly, the doses and regimens described herein have also been found to achieve Gcg-R targeted engagement, as evidenced by reductions in fasting and sMMTT glucagon levels. 【0039】 Multiple embodiments of dosing regimens and methods of use of GLP-1 / Gcg coagonists suitable for once-weekly administration are described herein. In certain examples, the regimens and methods described herein include determining and administering an initial dose of such GLP-1 / Gcg coagonist. In other embodiments, the regimens and methods described herein include determining and administering a maximum or highest dose, including when and how to adjust the dose. 【0040】 In one embodiment, the present invention provides a method for providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides in patients who require chronic weight management, improved blood glucose control, and / or reduction of LDL cholesterol or triglycerides, the method being (1) A compound of the following formula, administered once a week: 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 In the equation, Xaa2 is Aib, The Lys at position 20 is connected to the epsilon-amino group of the Lys side chain and ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 It is chemically modified by bonding with CO2H. The C-terminal amino acid is amidated (SEQ ID NO: 1), a compound. Or a pharmaceutically acceptable salt thereof It should be administered to patients who need it for at least about two weeks, (2) Subsequently, the dose is increased to more than approximately 6 mg to approximately 16 mg, and the increased dose is administered to the patient once a week for at least approximately two weeks. 【0041】 In another embodiment, methods are provided herein for reducing body weight, reducing food intake, and / or inducing satiety in order to prevent and / or treat a condition selected from 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 kidney disease, and such methods are provided herein for reducing body weight, reducing food intake, and / or inducing satiety, (1) Administer a once-weekly dose of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, to patients in need for at least two weeks. (2) Subsequently, the dose is increased to more than approximately 6 mg to approximately 16 mg, and the increased dose is administered to the patient once a week for at least approximately two weeks. 【0042】 Another aspect of this disclosure provides a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0043】 In another embodiment, a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention and / or treatment of a condition selected from type 2 diabetes mellitus, 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 kidney disease in patients, for use in weight reduction, for use in reducing food intake, and / or for use in inducing satiety. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0044】 Further aspects of this disclosure provide the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0045】 In another embodiment, the use of the compound of Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the prevention and / or treatment of a condition selected from 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 kidney disease in a patient, for weight reduction, reduction of food intake, and / or induction of satisfaction, is provided. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least two weeks. (2) Subsequently, the weekly dose is increased to more than 6 mg to about 16 mg and administered for at least about 2 weeks. 【0046】 In further aspects of this disclosure, the weekly increased doses are approximately 6.25 mg to 16.0 mg, 6.5 mg to 16.0 mg, 8.0 mg to 16.0 mg, 10 mg to 16.0 mg, 11.0 mg to 16 mg, 12.0 mg to 16.0 mg, 13.0 mg to 16.0 mg, or 14.0 mg to 16.0 mg. 【0047】 In further embodiments of this disclosure, the once-weekly increased dose is approximately 6.25 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. In some embodiments, the once-weekly increased dose is approximately 6.5 mg. In some embodiments, the once-weekly increased dose is approximately 7.0 mg. In some embodiments, the once-weekly increased dose is approximately 8.0 mg. In some embodiments, the once-weekly increased dose is approximately 9.0 mg. In some embodiments, the once-weekly increased dose is approximately 10.0 mg. In some embodiments, the once-weekly increased dose is approximately 11.0 mg. In some embodiments, the once-weekly increased dose is approximately 12.0 mg. In some embodiments, the once-weekly increased dose is approximately 13.0 mg. In some embodiments, the increased weekly dose is approximately 14.0 mg. In some embodiments, the increased weekly dose is approximately 15.0 mg. In some embodiments, the increased weekly dose is approximately 16.0 mg. 【0048】 In a preferred embodiment of this disclosure, the weekly increased dose is approximately 8.0 mg to approximately 16.0 mg. In a further embodiment of this disclosure, the weekly increased dose is approximately 8.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0049】 In another preferred embodiment of this disclosure, the once-weekly increased dose is approximately 10.0 mg to approximately 16.0 mg. In yet another embodiment of this disclosure, the once-weekly increased dose is approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0050】 In one aspect of this disclosure, the once-weekly dose in step (1) is approximately 1.0 mg to approximately 6.0 mg. In yet another aspect of this disclosure, the approximately weekly dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg. 【0051】 In further aspects of this disclosure, several different once-weekly doses are administered to the patient in steps (1) and (2). 【0052】 In one aspect of this disclosure, the patient is administered a first or initial once-weekly dose of about 1.0 mg to about 6.0 mg. Thus, in some embodiments, the first once-weekly dose is about 1.0 mg to about 6.0 mg. In further embodiments of this disclosure, the first once-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 preferred embodiments of this disclosure, the first once-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 once-weekly dose is about 1.0 mg. In some embodiments, the first once-weekly dose is about 1.5 mg. In some embodiments, the first once-weekly dose is about 2.0 mg. In some embodiments, the first once-weekly dose is approximately 3.0 mg. 【0053】 In one aspect of this disclosure, the first dose and each subsequent increased dose are increased in increments of approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, or any combination thereof, and each dose is administered for at least approximately two weeks. Therefore, the first dose is selected from approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, and 6.5 mg, and each subsequent dose is increased from the previously administered dose by approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, or any combination thereof. 【0054】 In a preferred embodiment, the first dose is selected from approximately 1.5 mg, approximately 2.0 mg, and approximately 3.0 mg, and each subsequent dose is increased by approximately 1.5 mg, approximately 2.0 mg, approximately 3.0 mg, approximately 4.0 mg, or any combination thereof, relative to the previously administered dose. For example, a patient may be administered a first dose of 1.5 mg, a subsequent dose of 3.0 mg (an increment of 1.5 mg relative to the previous dose of 1.5 mg), a subsequent dose of 6.0 mg (an increment of 3.0 mg relative to the previous dose of 3.0 mg), a subsequent dose of 8.0 mg (an increment of 2.0 mg relative to the previous dose of 6.0 mg), and a subsequent dose of 10.0 mg (an increment of 2.0 mg relative to the previous dose of 8.0 mg). In another example, the patient is administered a first dose of 1.5 mg, a subsequent dose of 3.0 mg (an increment of 1.5 mg compared to the previous dose of 1.5 mg), a subsequent dose of 6.0 mg (an increment of 3.0 mg compared to the previous dose of 3.0 mg), a subsequent dose of 10.0 mg (an increment of 4.0 mg compared to the previous dose of 6.0 mg), a subsequent dose of 13.0 mg (an increment of 3.0 mg compared to the previous dose of 10.0 mg), and a subsequent dose of 16.0 mg (an increment of 3.0 mg compared to the previous dose of 13.0 mg). 【0055】 In another aspect of this disclosure, the dose may be reduced after administering the maximum or highest dose to the patient. For example, once-weekly doses of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg are administered to the patient for three weeks each. After three weeks at the maximum dose of 10 mg, the dose is reduced to 8 mg. 【0056】 In another aspect of this disclosure, the method or use includes administering each weekly dose for at least about four weeks. In yet another aspect of this disclosure, the method or use includes administering each weekly dose for at least about six weeks. In yet another aspect of this disclosure, the method or use includes administering each weekly dose for at least about eight weeks. Different weekly doses may be administered for different durations. For example, the first dose and subsequent increased doses may be administered for about four weeks, and the maximum increased dose for at least about eight weeks. In another example, the first dose may be administered for two weeks, and each subsequent increased dose may be administered for about two or four weeks, and the maximum increased dose for at least about eight weeks. 【0057】 In a preferred embodiment of this disclosure, the maximum increased once-weekly dose of the compound, or a pharmaceutically acceptable salt thereof, is about 6.5 mg. 【0058】 In one embodiment, the method or use is a) Administering a dose of approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) The dose is increased to about 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0059】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Optionally, the dose may be increased to approximately 4.5 mg of the compound or a pharmaceutically acceptable salt thereof, administered once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0060】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg or 5.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) The dose is increased to about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, or at least about 8 weeks. 【0061】 In alternative preferred embodiments of this disclosure, the maximum increased once-weekly dose of the compound, or a pharmaceutically acceptable salt thereof, is about 8.0 mg. 【0062】 In one embodiment, the method or use is a) Administering a dose of approximately 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) The dose is increased to approximately 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0063】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately two weeks. 【0064】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0065】 In alternative preferred embodiments of this disclosure, the maximum increased once-weekly dose of the compound, or a pharmaceutically acceptable salt thereof, is about 9.0 mg. 【0066】 In one embodiment, the method or use is a) Administering a dose of approximately 4.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) The dose is increased to approximately 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0067】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. 【0068】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0069】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) The dose is increased to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0070】 In alternative preferred embodiments of this disclosure, the maximum increased once-weekly dose of the compound, or a pharmaceutically acceptable salt thereof, is about 10.0 mg. 【0071】 In one embodiment, the method or use is a) Administering a dose of approximately 5.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) The dose is increased to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0072】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) The dose is increased to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0073】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, the dose may be increased to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose administered to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) The dose is increased to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0074】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) The dose is increased to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0075】 In alternative preferred embodiments of this disclosure, the maximum increased dose of the compound, or a pharmaceutically acceptable salt thereof, is about 12.0 mg. 【0076】 In one embodiment, the method or use is a) Administering a dose of approximately 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) The dose is increased to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0077】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0078】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, the dose may be increased to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose administered to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0079】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0080】 In alternative preferred embodiments of this disclosure, the maximum increased dose of the compound, or a pharmaceutically acceptable salt thereof, is about 13.0 mg. 【0081】 In one embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0082】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0083】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose is increased to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0084】 In alternative preferred embodiments of this disclosure, the maximum increased dose of the compound, or a pharmaceutically acceptable salt thereof, is about 14.0 mg. 【0085】 In one embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 11.0 mg or 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 14.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0086】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Optionally, increase the dose to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) The dose is increased to approximately 14.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0087】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) The dose is increased to about 14.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0088】 In alternative preferred embodiments of this disclosure, the maximum increased dose of the compound, or a pharmaceutically acceptable salt thereof, is about 15.0 mg. 【0089】 In one embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Optionally, increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 15.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0090】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Optionally, increase the dose to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) The dose is increased to approximately 15.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0091】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) The dose is increased to about 15.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0092】 In alternative preferred embodiments of this disclosure, the maximum increased dose of the compound, or a pharmaceutically acceptable salt thereof, is about 16.0 mg. 【0093】 In one embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, the dose may be increased to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administered once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 9.0 or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0094】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Increase the dose to approximately 12.0 mg or 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dose to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0095】 In another embodiment, the method or use is (a) Administering approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) The dose is increased to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. 【0096】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0097】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0098】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0099】 In another embodiment, the method or use is (a) Administering approximately 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0100】 In another embodiment, the method or use is (a) Administering approximately 2.0 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) The dose is increased to approximately 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose is administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0101】 In one embodiment, the method or use includes administering each dose once a week for at least about two weeks. In one embodiment, the method or use includes administering each dose once a week for at least about four weeks. In one embodiment, the method or use includes administering each dose once a week for at least about eight weeks. 【0102】 In one preferred embodiment, the method or use comprises administering a dose once per week for at least about two weeks and administering a maximum dose once per week for at least about four weeks. In another preferred embodiment, the method or use comprises administering a dose once per week for at least about four weeks and administering a maximum dose once per week for at least about four weeks. In yet another preferred embodiment, the method or use comprises administering a dose once per week for at least about four weeks and administering a maximum dose once per week for at least about eight weeks. 【0103】 In one embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction in the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 10% of the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 15% of the patient's body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a reduction of at least about 20% of the patient's body weight. 【0104】 In one embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's HbA1c. In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's LDL cholesterol and / or triglycerides. In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, does not result in unacceptable tolerability. 【0105】 In one embodiment, the patient is overweight. In another embodiment, the patient is obese. In yet another embodiment, the patient has type 2 diabetes. 【0106】 In another aspect, the present invention provides a method for providing chronic weight management, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides in patients who require chronic weight management, improved blood glucose control, and / or reduction of LDL cholesterol or triglycerides, the method being (1) Administer the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, once weekly in gradually increasing doses, to patients in need for at least two weeks. (2) Thereafter, administer a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, once a week in an amount of more than 6 mg to about 16 mg, for at least about two weeks. 【0107】 In some embodiments, methods are provided herein for the prevention and / or treatment of a condition selected from 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 in patients, for weight reduction, reduction of food intake, and / or induction of satisfaction, the methods being provided herein. (1) Administer the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, once weekly in gradually increasing doses, to patients in need for at least two weeks. (2) Thereafter, administer a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, once a week in an amount of more than 6 mg to about 16 mg, for at least about two weeks. 【0108】 Another aspect of this disclosure provides a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an increasing dose for at least two weeks. (2) Subsequently, a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, in an amount of more than 6 mg to about 16 mg once a week is administered for at least two weeks. 【0109】 In another embodiment, a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention and / or treatment of a condition selected from type 2 diabetes mellitus, 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 kidney disease in patients, for use in weight reduction, for use in reducing food intake, and / or for use in inducing satiety. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an increasing dose for at least two weeks. (2) Subsequently, a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, in an amount of more than 6 mg to about 16 mg once a week is administered for at least two weeks. 【0110】 Further aspects of this disclosure provide the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an increasing dose for at least two weeks. (2) Subsequently, a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, in an amount of more than 6 mg to about 16 mg once a week is administered for at least two weeks. 【0111】 In another embodiment, the use of the compound of Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the prevention and / or treatment of a condition selected from 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 kidney disease in a patient, for weight reduction, reduction of food intake, and / or induction of satisfaction, is provided. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an increasing dose for at least two weeks. (2) Subsequently, a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, in an amount of more than 6 mg to about 16 mg once a week is administered for at least two weeks. 【0112】 In further aspects of this disclosure, the once-weekly maintenance dose is approximately 6.25 mg to 16.0 mg, approximately 6.5 mg to 16.0 mg, approximately 8.0 mg to 16.0 mg, approximately 10 mg to 16.0 mg, approximately 11.0 mg to 16 mg, approximately 12.0 mg to 16.0 mg, approximately 13.0 mg to 16.0 mg, or approximately 14.0 mg to 16.0 mg. 【0113】 In further aspects of this disclosure, the weekly maintenance dose may be approximately 6.25 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 11.0 mg, 12.0 mg, 13.0 mg, 14.0 mg, 15.0 mg, or 16.0 mg. 【0114】 In further aspects of this disclosure, the once-weekly maintenance dose is approximately 8.0 mg to approximately 16.0 mg. In yet further aspects of this disclosure, the once-weekly maintenance dose is approximately 8.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0115】 In further embodiments of this disclosure, the once-weekly maintenance dose is approximately 10.0 mg to approximately 16.0 mg. In further embodiments of this disclosure, the once-weekly maintenance dose is approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. 【0116】 In further embodiments of this disclosure, the method or use includes administering a maintenance dose once weekly for at least about four weeks. In further embodiments of this disclosure, the method or use includes administering a maintenance dose once weekly for at least about six weeks. In further embodiments of this disclosure, the method or use includes administering a maintenance dose once weekly for at least about eight weeks. 【0117】 In further embodiments of this disclosure, the once-weekly escalating dose is approximately 1.0 mg to approximately 6.0 mg. In further embodiments of this disclosure, the once-weekly escalating dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg. 【0118】 In further aspects of this disclosure, a series of once-weekly escalating doses are administered to the patient in steps (1) and (2). 【0119】 In a preferred embodiment of the Disclosure, the first once-weekly escalating dose is approximately 1.0 mg to approximately 6.0 mg. In a further embodiment of the Disclosure, the first once-weekly escalating dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg. In a preferred embodiment of the Disclosure, the once-weekly escalating dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, or approximately 3.0 mg. 【0120】 In a more preferred embodiment of this disclosure, the first and each subsequent once-weekly escalating dose are increased in increments of approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, or any combination thereof, and each once-weekly escalating dose is administered for at least approximately two weeks. 【0121】 In a more preferred embodiment of this disclosure, the final or maximum escalating dose is higher than the maintenance dose. For example, weekly escalating doses of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, are administered to a patient for three weeks, each time. After three weeks at the maximum escalating dose of 10 mg, the maintenance dose is reduced to 8 mg. 【0122】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 6.5 mg. 【0123】 Preferably, the method or use is a) Administering a gradually increasing dose of approximately 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least 2 weeks, at least about 3 weeks, or at least about 4 weeks. b) Administering a maintenance dose of approximately 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0124】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Optionally, increase the dose to approximately 4.5 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) administering a maintenance dose of approximately 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0125】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Increase the dose escalate to approximately 4.0 mg or 5.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) a maintenance dose of approximately 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, or at least approximately 8 weeks. 【0126】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 8.0 mg. 【0127】 Preferably, the method or use is a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) Administering a maintenance dose of approximately 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0128】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Administering a maintenance dose of approximately 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0129】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Increase the dose escalate to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Administering a maintenance dose of approximately 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0130】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 9.0 mg. 【0131】 Preferably, the method or use is a) Administering a gradually increasing dose of approximately 4.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) Administering a maintenance dose of approximately 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0132】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose escalates to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose escalates once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. 【0133】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Increase the dose escalate to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) The dose escalates to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and the dose escalates to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. 【0134】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) a maintenance dose of approximately 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0135】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 10.0 mg. 【0136】 Preferably, the method or use is a) Administering a gradually increasing dose of approximately 5.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. b) Administering a maintenance dose of approximately 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0137】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) administering a maintenance dose of approximately 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0138】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Increase the dose escalate to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) administering a maintenance dose of approximately 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0139】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) a maintenance dose of approximately 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0140】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 12.0 mg. 【0141】 Preferably, the method or use is a) A step of administering a gradually increasing dose of approximately 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks, b) Administering a maintenance dose of approximately 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0142】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) administering an increasing dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 10.0 mg once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Administering a maintenance dose of approximately 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0143】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Increase the dose escalate to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose escalate to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Administering a maintenance dose of approximately 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0144】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) a maintenance dose of approximately 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0145】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 13.0 mg. 【0146】 Preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Administering a maintenance dose of approximately 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0147】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose escalation to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer this dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Administering a maintenance dose of approximately 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0148】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) administering a maintenance dose of approximately 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0149】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 14.0 mg. 【0150】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 11.0 mg or 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Administering a maintenance dose of approximately 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0151】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose escalation to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer this dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Optionally, increase the dose escalation to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) Administering a maintenance dose of approximately 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0152】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately two weeks. (e) administering a maintenance dose of approximately 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0153】 In alternative preferred embodiments of this disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 15.0 mg. 【0154】 Preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 5.0 mg or 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Increase the dose escalate to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Optionally, increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Administering a maintenance dose of approximately 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0155】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose escalation to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer this dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Optionally, increase the dose escalation to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) A maintenance dose of approximately 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, administered once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0156】 Alternatively, preferably, the method or use is (a) Administering a compound of increasing dose of about 3.0 mg, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the increasing dose to a compound of about 6.0 mg, or a pharmaceutically acceptable salt thereof, and administering the increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increasing the increasing dose to a compound of about 9.0 mg or about 10.0 mg, or a pharmaceutically acceptable salt thereof, and administering the increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Optionally, increasing the increasing dose to a compound of about 12.0 mg or about 13.0 mg, or a pharmaceutically acceptable salt thereof, and administering the increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Administering a maintenance dose of a compound of about 15.0 mg, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and including. 【0157】 In an alternative preferred embodiment of the present disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 16.0 mg. 【0158】 Preferably, the method or use is (a) Administering a compound of increasing dose of about 1.5 mg, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the increasing dose to a compound of about 3.0 mg, or a pharmaceutically acceptable salt thereof, and administering the increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increasing the increasing dose to a compound of about 5.0 mg or about 6.0 mg, or a pharmaceutically acceptable salt thereof, and administering the increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Optionally, increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose increase once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose escalation to approximately 9.0 or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose escalation once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0159】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks, at least approximately three weeks, or at least approximately four weeks. (b) Optionally, increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, administering the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) Optionally, increase the dose escalation to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer this dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (f) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (g) Optionally, increase the dose escalation to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalation to the patient once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (h) Administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once weekly for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0160】 Alternatively, preferably, the method or use is (a) Administering a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (b) Increase the dose escalate to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (c) Increase the dose escalate to approximately 9.0 mg or 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (d) Increase the dose escalate to approximately 12.0 mg or 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose escalate once a week for at least approximately 2 weeks, at least approximately 3 weeks, or at least approximately 4 weeks. (e) administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, or at least approximately 8 weeks. 【0161】 Alternatively, preferably, the method or use is (a) Administer a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about two weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) Administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks. 【0162】 Alternatively, preferably, the method or use is (a) Administer a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about two weeks. (b) Increase the dose to approximately 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (g) Administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks. 【0163】 Alternatively, preferably, the method or use is (a) Administer a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about two weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) Administering a maintenance dose of approximately 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least approximately two weeks. 【0164】 Alternatively, preferably, the method or use is (a) Administer a gradually increasing dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about two weeks. (b) Increase the dose to approximately 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (c) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (d) Increase the escalating dose to about 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (e) Increase the escalating dose to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (f) Administer a maintenance dose of about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, and. 【0165】 Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, and (b) Increase the escalating dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (c) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (d) Increase the escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (e) Increase the escalating dose to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, and (f) Administer a maintenance dose of about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, and. 【0166】 More preferably, the method or use comprises administering each escalating dose once a week for at least about 2 weeks and administering the maintenance dose once a week for at least about 4 weeks. 【0167】 More preferably, the method or use comprises administering each escalating dose once a week for at least about four weeks, and administering a maintenance dose once a week for at least about four weeks. 【0168】 More preferably, the method or use comprises administering each escalating dose once a week for at least about 4 weeks, and administering a maintenance dose once a week for at least about 8 weeks. 【0169】 Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing GLP-1 / Gcg coagonists, pharmaceutical compositions, and methods, but preferred methods and materials are described herein. 【0170】 Furthermore, the use of the indefinite article "a" or "an" to refer to an element does not rule out the possibility of multiple elements existing unless the context explicitly requires that there be one or only one element. Therefore, the indefinite article "a" or "an" usually means "at least one." 【0171】 definition As used herein, “about” means within a statistically significant range of a value, such as concentration, length, molecular weight, pH, sequence identity, time frame, temperature, or volume. Such a value or range may be within a scale typically 20%, more typically 10%, and even more typically 5% of a given value or range. The permissible variation encompassed by “about” depends on the particular system in the study and will be readily apparent to those skilled in the art. 【0172】 As used herein, and with respect to one or more GLP-1 receptors or Gcg receptors, “active,” “activates,” “activates,” etc., means the ability of a compound such as a GLP-1 / Gcg coagonist described herein to bind to the receptor and induce a response at the receptor, as can be measured using assays known in the art. 【0173】 As used herein, “amino acid” means a molecule characterized by containing one or more amine groups and one or more carboxylic acid groups from a chemical standpoint, and which may contain other functional groups. As is known in the art, there is a set of 20 amino acids designated as standard amino acids, which are used as building blocks of most peptides / polypeptides / proteins produced by all living organisms. 【0174】 As used herein, “analog” means a compound such as a synthetic peptide or polypeptide that activates a target receptor and induces at least one in vivo or in vitro effect induced by a native receptor agonist. 【0175】 As used herein, “dose” or “dose(s)” means the amount of GLP-1 / Gcg coagonist for a once-weekly dose administered to an individual in a specific amount at a particular time. As used in relation to terms such as dose, medication, and dose(s), “adjustment” means any amount of reduction or increase to the dose administered in the previous week. As used in relation to terms such as dose, medication, and dose(s), “regimen” means a set of guidelines for determining and administering one or more doses and / or adjustments thereof. 【0176】 As used herein, “effective dose” means an amount, concentration, or dosage of one or more of the GLP-1 / Gcg coagonists herein, or a pharmaceutically acceptable salt thereof, which, after single or multiple dose administration to an individual in need, provides the desired effect in such individual under diagnosis or treatment (i.e., it may produce a clinically measurable difference in the individual’s condition, such as, for example, a reduction in blood glucose, a reduction in HbA1c, a reduction in body weight or body fat, and / or a change in body composition). The effective dose can be readily determined by those skilled in the art by the use of known techniques and by observing the results obtained under similar circumstances. When determining the effective dose for an individual, a number of factors are taken into consideration, including, but are not limited to, the species of mammal, its size, age, and overall health status, the specific disease or disorder involved, the degree, involvement, or severity of the disease or disorder, the individual’s response, the GLP-1 / Gcg coagonist administered, the mode of administration, the bioavailability characteristics of the administered preparation, the dose regimen selected, the use of concomitant medications, and other relevant circumstances. 【0177】 As used herein, “fasting blood glucose” means the blood glucose level from a blood sample taken after an individual has fasted for at least approximately 8 hours. 【0178】 As used herein, “glycemic control” means an individual’s HbA1c level or a reduction thereof. Similarly, “improving” glycemic control and / or “improved” glycemic control means a reduction in HbA1c. Furthermore, “requiring further glycemic control” means the need for a reduction in HbA1c. 【0179】 As used herein, “hemoglobin A1c” or “HbA1c” means the level of glycated hemoglobin that occurs when hemoglobin binds to glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in individuals with diabetes, and a decrease in HbA1c levels generally indicates an improvement in glycemic control. In the context of this disclosure, the doses, regimens, and methods described herein result in a decrease in HbA1c. In certain cases, the decrease in HbA1c is compared to the HbA1c level resulting from existing treatment with the same or even different GLP-1 / Gcg coagonists, including other GLP-1 / Gcg coagonists. 【0180】 As used herein, “incretin analog” means a compound that has structural similarities to OXM, GLP-1, and GCG, and in particular human OXM, human GLP-1, and human GCG, but has several differences. The incretin analogs herein include amino acid sequences that result in compounds having affinity for the GLP-1 and GCG receptors and activity in each of them (i.e., dual-receptor agonist activity). Exemplary incretin analogs for use herein, as well as the sequences of human OXM, GLP-1, and GCG, are described in International Patent Application Publication No. 2016 / 209707(A1). Of particular use herein is the GLP-1 / Gcg coagonist described in Example 2 of International Patent Application Publication No. 2016 / 209707(A1), which has the following sequence: 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 In the equation, Xaa2 is Aib, The Lys at position 20 is connected to the epsilon-amino group of the Lys side chain and ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 It is chemically modified by conjugation with CO2H, The C-terminal amino acid is amidated (SEQ ID NO: 1), Alternatively, a pharmaceutically acceptable salt thereof containing any protein that is the subject of a regulatory submission seeking approval of a GLP-1 / Gcg coagonist product, regardless of whether the party seeking approval of the product actually identifies the incretin analog as a GLP-1 / Gcg coagonist or uses some other terminology, and depending on the overall or partial data concerning this incretin analog submitted to the regulatory authority by Eli Lilly and Company. 【0181】 As used herein, “individuals in need of it” means mammals, such as humans, that have an abnormality, disease, disorder, or symptom in need of treatment or therapy, including, for example, those listed herein. Specifically, the preferred individual to be treated is a human. 【0182】 In certain embodiments as used herein, “titrate dose” or “escalation dose” means a dose less than the best desired effective dose for the patient. Where used herein, this disclosure intends that the “titrate dose” or “escalation dose” may be the best desired effective dose, or a “maintenance dose” if such a dose is observed to be the desired effective dose for the patient, and such a dose is administered chronically for a period of at least two weeks. Alternatively, in certain embodiments as used herein, “titrate dose” or “escalation dose” means a dose higher than the maintenance dose for the patient. This aspect of the disclosure is particularly useful when the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered, for example, to reduce weight, to treat obesity, or to manage weight. Significant weight loss may be achieved at the highest dose, and weight loss may be maintained at lower doses. 【0183】 As used herein, “maintenance dose” means both the dose that is the best desired effective dose for the patient, and the maintenance dose that may become an escalating dose if such a maintenance dose is less than the best desired effective dose. That is, if for a particular patient the “approximately 8 mg” maintenance dose intended by this disclosure is not the best desired effective dose, then that 8 mg maintenance dose may, in retrospect, become a titration or escalating dose as the dose for that particular patient that will increase until it reaches the next best dose intended by this disclosure, for example, 10 mg or 12 mg in at least approximately two weeks. This disclosure intends that patients who reach a maintenance dose of approximately 12 mg to approximately 16 mg may need to reduce their dose to a lower maintenance dose, as determined by a physician or other healthcare provider. 【0184】 As used herein, “expected once-weekly maintenance dose” means the dose of a therapeutic agent, such as a GLP-1 / Gcg coagonist, suitable for once-weekly administration, that is expected to be required to provide glycemic control or weight management in a given individual, based on factors including, but not limited to, the individual’s fasting glucose, HbA1c, the frequency and severity of hypoglycemia and other adverse events, and / or body weight (BW). 【0185】 As used herein, “obese” or “obese” means, with respect to an individual, 30 kg / m². 2 This refers to individuals with a BMI of the above. 【0186】 As used herein, "overweight" means 27 kg / m² for an individual. 2 That's all, except for 30 kg / m 2 This refers to individuals with a BMI below a certain level. 【0187】 As used herein, “to treat,” “to treat,” and “to treat” mean to suppress, delay, halt, or reverse the progression or severity of an existing condition, disease, disorder, or symptom. 【0188】 As used herein, with reference to an incretin analog, “dual receptor agonist activity” means an incretin analog having activity at each of the GLP-1 and GCG receptors, in particular an analog having balanced and sufficient activity at each receptor to provide the benefits of receptor agonism while avoiding the undesirable side effects associated with excessive activity of that receptor. Furthermore, incretin analogs having dual receptor agonist activity have long-lasting effects at each of the GLP-1 and GCG receptors, which advantageously allows for administration at low frequencies of once daily, three times a week, twice a week, or once a week. 【0189】 As used herein, “weight management” means weight reduction and / or changes in body fat composition, as well as maintenance of weight and / or body fat composition. 【0190】 composition The compositions herein include, for example, a GLP-1 / Gcg coagonist having the structure of SEQ ID NO: 1. GLP-1 / Gcg coagonists can be produced synthetically (see, for example, International Patent Application Publication No. 2016 / 209707(A1)). Formulations for GLP-1 / Gcg coagonists that may be used herein are disclosed in International Patent Application No. PCT / US2021 / 064592. 【0191】 In some cases, the compositions of this specification are formulated to contain a dose of GLP-1 / Gcg coagonist ranging from about 1.5 mg to about 16.0 mg. In other cases, the dose of GLP-1 / Gcg coagonist may 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 of this specification may be administered intravenously (IV), intramuscularly (IM), or subcutaneously (SC), particularly SC. The composition may be provided lyophilized and then reconstituted, or as a solution formulation administered using a pre-filled disposable pen, a reusable pen, or an auto-pen syringe. Alternatively, the composition may be administered using a multi-use vial or pump device. In some examples, the device is an auto-injector, such as the one described in U.S. Patent No. 8,734,394. 【0192】 Therefore, the compositions herein may be provided in pre-filled syringes / multi-use vials. Such pre-filled syringes / multi-use vials may be useful for administering approximately 0.5 mL to approximately 2.0 mL of the composition per patient per dose. The dose of the composition may be administered using a dosing schedule determined by a clinician, physician, or other trained healthcare professional. 【0193】 Alternatively, the composition can be prepared for use in cartridges and thus differ from the above composition by including a preservative. 【0194】 Alternatively, the composition may be prepared as part of a product containing the composition, which may be a multi-use vial, a reusable pen-type syringe, a pre-filled disposable pen, an auto-injector, or a pump. 【0195】 Considering the above, the compositions herein relate to acceptable shelf-life stability, stability in use, and acceptable injection site experience. 【0196】 Treatment methods and medical use The GLP-1 / Gcg coagonist drug regimens described herein are suitable for providing chronic weight management. The GLP-1 / Gcg coagonist drug regimens described herein are also suitable for improving glycemic control (e.g., measured by glucose levels, HbA1c, and / or fructosamine). The GLP-1 / Gcg coagonist drug regimens described herein are also suitable for reducing LDL cholesterol and / or triglycerides. 【0197】 The GLP-1 / Gcg coagonist regimens described herein may be suitable for the prevention or treatment of several conditions, including, but not limited to, the prevention or treatment of type 2 diabetes, hyperglycemia, non-insulin-dependent diabetes, obesity, weight and / or food intake, dyslipidemia, non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), atherosclerosis, obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, and diabetic nephropathy. They may also be suitable for inducing satiety, reducing fasting plasma glucose, reducing postprandial blood glucose 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 the person receiving treatment. 【0198】 In addition, the GLP-1 / Gcg coagonist regimens described herein may be suitable for the following: treatment of obesity, appetite control, reduction of calorie intake, reduction of food intake, appetite suppression, induction of anorexia, treatment of impaired glucose tolerance, treatment of postprandial hyperglycemia, treatment of hyperglycemic states, reduction of triglycerides, reduction of cholesterol, treatment of impaired glucose tolerance, treatment of prediabetes (blood glucose levels higher than normal but not yet high enough to be diagnosed as diabetes), treatment of type 1 diabetes (e.g., in combination with insulin), reduction of the risk of cardiovascular events due to impaired glucose tolerance, reduction of the risk of cerebrovascular events due to impaired glucose tolerance, delay of diabetes progression, improvement of diabetes, delay of diabetes onset, induction of beta cell preservation and restoration of beta cell function, restoration of euglycemic state, provision of euglycemic control, treatment of gestational diabetes, treatment or prevention of nephropathy, treatment or prevention of cardiovascular diseases (e.g., heart failure, atherosclerosis, and acute coronary syndrome), and treatment or prevention of metabolic syndromes. 【0199】 In preferred embodiments, the GLP-1 / Gcg coagonist regimens described herein are suitable for: providing chronic weight management, improving glycemic control, reducing LDL cholesterol and / or triglycerides, reducing body weight, reducing food intake, and / or inducing satiety. In some preferred embodiments, the GLP-1 / Gcg coagonist regimens described herein are suitable for preventing or treating conditions selected from 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, or chronic kidney disease. 【0200】 The following non-limiting embodiments are provided for illustrative purposes only, not limiting purposes. [Examples] 【0201】 Example 1: Clinical Study overview This study is a Phase 1, single-center, patient- and investigator-blinded, placebo-controlled, randomized, non-crossover, repeated dose escalation study in patients with T2DM to investigate the safety, tolerability, pharmacokinetics, and disease progression of GLP-1 / glucagon coagonist peptide (compound 1) of Sequence ID No. 1 administered as multiple SC injections QW over 12 weeks in cohort 1 and 16 weeks in cohort 2. 【0202】 Test group The principal investigator enrolled participants with T2DM in this trial for at least six months prior to screening. 【0203】 inclusion The following patients were deemed eligible to participate in the study. - Otherwise, they are generally healthy and do not have any known potential secondary conditions of diabetes. - Patients with screening-time glycated hemoglobin (HbA1c) levels of 7.0% or higher and 10.5% or lower, who were treated with diet and exercise alone or a stable dose of metformin for at least 3 months prior to screening / visit 1. 【0204】 exclusion The following patients were deemed ineligible to participate in the study. - Has type 1 diabetes or adult latent autoimmune diabetes. - Having poorly controlled diabetes mellitus, defined as an episode of ketoacidosis or hyperosmolar state requiring hospitalization within the six months prior to screening. - Have you had an episode of severe hypoglycemia, or have a history of asymptomatic hypoglycemia or poor recognition of hypoglycemic symptoms? 【0205】 treatment Two planned dose regimens of Compound 1 will be investigated in this study via once-weekly administration by SC injection. The study will be patient and investigator blinded. To maintain blinding for Compound 1 and placebo, all study site personnel will be blinded to treatment assignments, with the exception of pharmacy staff preparing and dispensing the study drugs. Blinding for Compound 1 and placebo will be maintained throughout the conduct of the study until all data have been evaluated to an acceptable level of quality and locked. 【0206】 The first medication regimen (also known as Cohort 1) has a duration of 12 weeks and requires dose increments of 1.5 mg, starting with 1.5 mg. - 1.5 mg QW of compound 1 for 4 weeks. - Compound 1 at 3.0 mg QW for 4 weeks, and - Compound 1 at 4.5 mg QW for 4 weeks. 【0207】 The second medication regimen (also known as Cohort 2) has a duration of 16 weeks and requires dose increments of 2 mg, starting with 2 mg. - 2 mg QW of compound 1 for 3 weeks. - 4 mg QW of compound 1 for 3 weeks. - 6 mg QW compound 1 for 3 weeks - Compound 1 at 8 mg QW for 3 weeks, - Compound 1 at 10mg QW for 4 weeks. 【0208】 Regarding the second medication regimen, the dose to 10 mg Qw can only be advanced if the patient first tolerates the titration steps of 3 doses of 4 mg QW, 3 doses of 6 mg QW, and then 3 doses of 8 mg QW. 【0209】 For each drug regimen, compound 1 is administered intravenously to the patient's abdomen after an overnight fast of at least 8 hours. 【0210】 Of the 82 patients screened for the trial after obtaining informed consent, 24 were randomly assigned to receive at least one dose of the trial intervention. A total of 23 patients completed the trial, as shown in Figure 1. 【0211】 Dosage change Dose levels or increments, sampling schedules, and length of stay in clinical research units (CRUs) may be adjusted in consideration of safety, tolerability, or pharmacokinetic (PK) data that emerge during the study. Specifically, dose increments within the cohort may be reduced (but not increased), or lower doses may be administered accordingly. 【0212】 The actual doses, increments, and / or duration of treatment within each cohort at each dose level may be adjusted in consideration of the resulting safety, tolerability, or PK data. Due to the nature of this repeated dose-escalation study with dose titration, the data are It will be continuously evaluated until the MTD is determined or the termination criteria are met. 【0213】 Safety data will be the primary criterion for dose escalation titration. Dose escalation titration within a cohort cannot be performed without prior discussion and consent between the principal investigator and the designated clinical pharmacologist. To support the dose within a cohort, all safety and available pharmacokinetic (PK) and pharmacodynamic (PD) data from one week prior to the dose will be used. To support the dose between cohorts 1 and 2, all safety and available PK and PD data up to week 11 will be used. PD data will likely be used. 【0214】 After reviewing these data, dose escalation titrations within the cohort to the next dose level will be performed by the principal investigator and sponsor. Half of the patients in any cohort, If dose titration is not tolerated, the dose increment may be halved, and dose escalation titrations will be performed every two weeks. 【0215】 If any of the following discontinuation criteria occur in either cohort, the current level of medication and further dose-escalation titrations in both cohorts will be discontinued. - Two clinically significant events (CSEs) are reported that occur under one treatment (unless they are due to the expected pharmacological effects of compound 1 [e.g., hypoglycemia]) or are considered to be potentially related to compound 1, or - More than 40% of subjects at the dose level experienced symptomatic hypoglycemic episodes with blood glucose levels ≤2.8 mmol / L (corresponding to plasma glucose [PG] levels of 50 mg / dL, ≤3.1 mmol / L [56 mg / dL]), and these events were considered to be related to the administration of compound 1, or - Two or more subjects taking the active drug develop persistent (>1 week) symptoms suggestive of acute pancreatitis. - Two or more subjects in the same cohort, regardless of whether they belong to the same organ-specific subgroup, who have a “severe” non-serious adverse reaction likely related to the study drug. 【0216】 If any of these three scenarios occur, medication will be interrupted and will only be resumed with the approval of the responsible physician or a suitable designated person. 【0217】 Test evaluation The relevant test procedures and their timings are summarized below. 【0218】 body weight 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. 【0219】 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. 【0220】 To the greatest extent possible, the same scale should be used for all weight measurements throughout the study, and the scale should not be moved or recalibrated. Subjects should be weighed in light clothing at approximately the same time each morning, before medication (day 1 only), after an overnight fast, and, if possible, after defecation and urination. During the treatment period, weight should be measured twice at each scheduled occasion, with subjects stepping off the scale between measurements. The average of the two weight measurements should be recorded in the source data. 【0221】 Waist circumference For Cohort 1, waist circumference is measured at baseline, as well as on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. 【0222】 For Cohort 2, waist circumference was measured at baseline, as well as on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, and 109. 【0223】 Waist circumference is measured at the midpoint between the lowest palpable rib and the top of the iliac crest. The patient should stand with their feet together, arms at their sides, and weight evenly distributed, and should be lightly dressed. The patient should be relaxed, and the measurement should be taken at the end of a normal exhalation. During screening, baseline, treatment period, and follow-up, waist circumference will be measured twice at each scheduled opportunity. The average of the two measurements will be recorded in the source material. 【0224】 Pharmacokinetics (PK) To determine the plasma concentration of compound 1, approximately 3 mL of venous blood samples are taken. Up to two additional samples may be taken at any point during the study, if approved and agreed upon by both the principal investigator and the sponsor. The actual date and time (24-hour format) of each sample, as well as the date and time of each dose of compound 1, are recorded. 【0225】 Drug concentration information that could allow for the deblinding of the study will not be reported to the research facility or the blinded personnel until the study is deblinded. 【0226】 For Cohort 1, PK sampling was performed 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). 【0227】 For Cohort 2, PK sampling was performed on day 1 (12 hours after administration of compound 1), day 2 (48 hours after administration of compound 1), day 72 (times 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). 【0228】 HbA1c For Cohort 1, HbA1c levels are determined at baseline, as well as on days 1, 29, 57, and 78. For Cohort 2, HbA1c is measured at baseline, as well as on days 1, 22, 43, 64, 85, and 106. 【0229】 Pharmacodynamics (PD) Fasting plasma samples for glucose and insulin are investigated as secondary PD markers. Exploratory PD may include, but is not limited to, plasma glucagon, C-peptide, natural OXM, lipid panels (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), beta-cell function, and homeostatic model assessment (HOMA) indices. 【0230】 Plasma concentrations of at least glucose, glucagon, insulin, C-peptide, and natural OXM are assayed using validated analytical methods. 【0231】 Samples are identified by a patient number (which is coded) and stored for up to one year after the last patient visit for the test. 【0232】 For Cohort 1, PD sampling was performed at baseline, as well as on days 1, 3 (48 hours after administration of compound 1), 8, 22, 29, 50, 57, 78, and 80. 【0233】 For Cohort 2, PD sampling was performed at baseline, as well as on days 1, 3 (48 hours after administration of compound 1), 8, 22, 43, 64, 85, 106, and 108. 【0234】 Mixed food challenge test (MMTT) For Cohort 1, the MMTT will be performed at baseline and on day 80. For Cohort 2, the MMTT will be performed at baseline and on day 108. 【0235】 Patients are provided with breakfast for the MMTT. Upon waking, patients are intoxicated with water to mitigate any issues related to blood sampling. Patients are provided with an individualized breakfast for the MMTT. The total calorie content is approximately 30% of the estimated daily calorie requirement for body weight. The macronutrient composition of the meal aims to provide approximately 50% of calories from carbohydrates, 30% from fat, and 20% from protein. Patients are fasted for at least 8 hours (except water) before each test meal and consume each meal within approximately 20 minutes. The test meals for each patient are kept consistent in terms of calorie and nutrient content throughout all MMTT assessments in the study. 【0236】 For both parts of the study, patients are not permitted to take in water (except for fluids provided with meals) for approximately 3 hours after the MMTT until the BOD POD® measurement. 【0237】 While residing in the CRU, patients may refrain from consuming any food or calorie-rich beverages other than those provided by the CRU. When not residing in the CRU, patients may resume a normal diet. Record the actual time of meal initiation and completion, total calories, and the percentage of food consumed during the Meal-Minute Time Test (MMTT). 【0238】 appetite analysis To investigate the effects of compound 1 on food intake and appetite perception, participants will be asked to assess their appetite perception using a 100mm visual analogue scale (VAS) for parameters of hunger, satiety, satisfaction, and expected food intake in a fasted state during hospitalization and scheduled outpatient visits. The VAS is a validated tool for assessing appetite perception parameters (Flint et al., Int J Obes Relat Metab Disord., 2000;24(1):38-48). The VAS will be presented as a 10cm (100mm) line fixed by linguistic descriptors, typically "very much" and "not at all." Participants will be asked to assess their subjective sensations using four 100mm scales combined with similar questions as follows: - "How hungry do you feel?" - "How satisfied do you feel?" - "How full do you feel?" - "How much do you think you were able to eat?" The overall appetite score is calculated as the average of four individual scores: satisfaction + fullness + (100 - expected food intake) + (100 - hunger) / 4 (van Can et al., Int J Obes (Lond). 2014;38(6):784-793). A higher overall appetite score indicates less appetite, while a lower score indicates more appetite. 【0239】 For Cohort 1, satisfaction VAS (post-fasting) was completed at baseline, as well as on days 1, 29, 57, 78, and 80. 【0240】 For Cohort 1, satisfaction VAS (post-fasting) was completed at baseline, as well as on days 1, 22, 43, 64, 85, 106, and 108. 【0241】 When the satisfaction VAS rating matches the MMTT, it is performed before the meal and 1 and 4 hours after the MMTT. 【0242】 gastric emptying Acetaminophen is a well-established marker for the rate and extent of gastric emptying. It is rapidly absorbed from the duodenum after release from the stomach. Delays in gastric emptying are reflected in the alteration of the acetaminophen concentration-time profile, specifically by decreasing its Cmax and increasing the time to the observed maximum drug concentration (tmax) without altering the extent of absorption (total drug amount). An oral solution dose of approximately 1 g of acetaminophen is considered sufficient for bioanalytical detection and is administered as shown below for cohorts 1 and 2. Approximately 2 mL of venous blood samples are taken from each patient to determine the plasma concentration of acetaminophen. The concentration of acetaminophen is assayed using a validated LC / MS method. Bioanalytical samples taken to measure acetaminophen concentration are retained for up to 2 years after the last patient visit for the study. 【0243】 For Cohort 1, gastric emptying is assessed at baseline, as well as on days 2 and 79. 【0244】 For Cohort 2, gastric emptying is assessed at baseline, as well as on days 2 and 107. 【0245】 Adverse event (AE) The principal investigator is responsible for monitoring the safety of patients participating in this trial. The principal investigator is responsible for providing appropriate medical care to patients during the trial. The principal investigator will document the review of each laboratory safety report. The principal investigator remains responsible for providing appropriate medical options, including: 【0246】 An adverse event (AE) that is serious or otherwise medically significant is one that is thought to be related to compound 1 or the study, or that causes the patient to discontinue compound 1 before the study is completed. The patient will be followed up until the event resolves, stabilizes on appropriate diagnostic assessment, or is reasonably explained. The frequency of follow-up assessments for AEs is at the discretion of the principal investigator. 【0247】 The principal investigator shall record all relevant AE and SAE information. After obtaining patient consent, the study site staff shall record the occurrence and nature of each patient's pre-existing condition, including clinically significant signs and symptoms of the disease being treated in the study. In addition, the site staff shall record any changes in the condition, as well as the occurrence and nature of any AEs. 【0248】 The principal investigator shall interpret and document, taking into account the disease, concomitant therapies, or pathology, whether there is a reasonable possibility that the adverse event (AE) is related to the investigational treatment or procedure. 【0249】 "Reasonable possibility" means that there is a potential causal relationship between compound 1, the test apparatus, and / or the test procedure and the AE. The planned surgery should not be reported as an AE unless the underlying medical condition worsens during the course of the study. 【0250】 A serious adverse event (SAE) is any AE from this trial that results in one of the following: - death - Initial or long-term hospitalization - A life-threatening experience (i.e., an imminent risk of death) - Persistent or significant impairment / inability - Congenital abnormalities / birth defects - A significant medical event that is not immediately life-threatening, or may result in death or hospitalization, but could endanger the patient or require intervention to prevent one of the other outcomes listed in the definition above. 【0251】 Record all adverse events (AEs) that occur after signing the ICF and evaluate them for severity. 【0252】 Laboratory Test For Cohort 1, samples for the clinical laboratory study were collected at baseline, as well as on days 1, 15, 29, 43, 57, and 78. 【0253】 For Cohort 2, samples for the clinical laboratory study were collected at baseline, as well as on days 1, 22, 43, 64, 85, and 106. 【0254】 result Demographic and other baseline characteristics Table 1 shows the baseline characteristics of patients with type 2 diabetes. A total of 24 patients, 21 men and 3 women, aged between 40 and 68 years, participated in this study. 【0255】 [Table 1] 【0256】 Combination therapy and post-intervention therapy Table 2 summarizes the current diabetes treatments being studied. 【0257】 [Table 2] Abbreviation: n = number of patients. 【0258】 body weight Figure 2 shows the mean change in body weight from baseline. The mean change in body weight from baseline ranged from -2.30 kg to -11.24 kg for compound 1, compared to -0.35 kg to -2.03 kg for placebo. During the multi-dose treatment period with compound 1, a mean decrease in body weight was observed in all treatment groups at each time point evaluated. The trend of weight loss appeared to be dose-dependent, and the mean change in body weight from baseline was observed at the end of the treatment period as follows. - Placebo: -0.34kg on day 78 - Cohort 1: -2.88kg on day 78 - Cohort 2: -10.73kg on day 109. 【0259】 In Cohort 2, which started on Day 50 and continued until Day 162 (i.e., 54 days after the last dose of the test drug), there was a consistent statistically significant decrease in body weight from baseline compared to placebo. 【0260】 Abdominal circumference The mean change in abdominal circumference from baseline is shown in Figure 3. A decrease in mean abdominal circumference was observed in Cohort 1 and Cohort 2 during the multiple-dose treatment period with Compound 1. As shown in Table 3, a decrease in fat mass and an increase in fat-free body mass were also observed in both Cohort 1 and Cohort 2. 【0261】 【Table 3】 【0262】 Pharmacokinetics A total of 355 PK concentrations of Compound 1 from 18 patients are used for population PK modeling. All available PK data are used for model development. Table 4a lists the final PK base model parameter estimates for Compound 1 and the corresponding between-subject variability. 【0263】 【Table 4】 Abbreviation: SEE = standard error of the estimate 【0264】 Model predicted mean (CV%) maximum steady state concentration (C max,ss )、mean (CV%) steady state concentration - time curve area under the curve [AUC(0 - 168) ss , and estimated half-life (t 1 / 2 ) for Compound 1 at 4.5 mg QW and 10 mg QW are listed in Table 4b below. 【0265】 【Table 5】 Abbreviation: AUC(0 - 168) ss= Area under the steady-state concentration-time curve over the weekly medication interval, C max,ss = maximum steady-state concentration, CV% = coefficient of variation, t 1 / 2 = Emission half-life 【0266】 Glucose control - HbA1c Table 4 shows the change in HbA1c from baseline. During 12–16 weeks of medication, mean HbA1c levels decreased from baseline in all treatment groups, including placebo, starting from day 29 (week 5). A statistically significant decrease in mean HbA1c from baseline was observed in both Cohort 1 and Cohort 2 treatment groups compared to placebo, starting at day 57 and continuing until day 134. 【0267】 On average, HbA1c levels remained reduced from baseline at day 106 (i.e., 28 days after the last dose in study intervention cohort 1) for all treatment groups. 【0268】 [Table 6] Abbreviations: HbA1c = Glycated hemoglobin, NC = Not calculated. a-2nd day average absolute value * p-value < 0.05 【0269】 Glucose control - Fasting glucose At baseline, fasting glucose measurements were similar between the treatment and placebo groups. Over the duration of treatment with multiple doses of compound 1, mean fasting glucose levels decreased from baseline in all treatment groups, as shown in Figure 4. When compared to placebo, the greatest decrease from baseline was observed in Cohort 2 at the end of the treatment period on day 106 (week 16). 【0270】 Insulin sensitivity - Fasting insulin At baseline, fasting insulin levels were similar in the low-dose cohort and the placebo group. However, baseline fasting insulin levels were significantly lower in the high-dose cohort. Figure 5 shows a pattern consistent with improved insulin sensitivity, with an increase in fasting insulin levels observed in cohort 1, compared to a moderate decrease in fasting insulin levels in cohort 2. 【0271】 Insulin-sensitive fasting C-peptide Figure 6 shows the change from baseline in fasting c-peptide levels. At baseline, fasting c-peptide measurements were similar between the treatment and placebo groups. Over the duration of treatment with multiple doses of compound 1, mean fasting c-peptide levels increased from baseline in all treatment groups except the placebo group. However, mean fasting c-peptide levels decreased from baseline starting at day 106 in cohort 2 and continued until day 108, a pattern consistent with improved insulin sensitivity. 【0272】 Mixed food challenge test Table 6 shows the changes from baseline in AUC (0-3 hours) of C-peptide, glucagon, glucose, insulin, and oxytomodulin during MMTT. 【0273】 [Table 7] Abbreviation: AUC(0~3h) = Area under the concentration-time curve from 0 to 3 hours after dose. a-2nd day average absolute value For cohort 1, the date was 80 days; for cohort 2, the date was 108 days. 【0274】 Table 7 shows the changes from baseline in beta cell function and insulin sensitivity parameters derived from MMTT. 【0275】 [Table 8] Abbreviations: HOMA2-B = Evaluation of homeostasis model of beta cell function, HOMA2-IR = Evaluation of homeostasis model of insulin resistance, ISI-M = Matsuda index, 1st PH ISI-S = Phase 1 Stumvoll index, 2nd PH ISI-S = Phase 2 Stumvoll index a -2nd day average absolute value b. Day 80 for Cohort 1, and Day 108 for Cohort 2. 【0276】 (i) Glucose AUC (0-3) hours Over the duration of treatment with multiple doses of compound 1, the mean AUC (0–3 hours) of glucose, as determined by MMTT, decreased from baseline in all treatment groups. When compared to placebo, the greatest decrease from baseline was observed in Cohort 2 at the end of the treatment period on day 108 (week 16). (ii) Insulin and C-peptide AUC (0-3 hours) Over a 12-week treatment period with multiple doses of compound 1, the mean AUC(0–3 hours) of C-peptide and insulin, as determined by MMTT, increased from mean baseline levels in Cohort 1. When compared to placebo, Cohort 1 showed the greatest increase from baseline in mean AUC(0–3 hours) for C-peptide at the end of the treatment period on day 80 (week 12). Over a 16-week course of treatment with multiple doses of compound 1, the mean AUC (0–3 hours) of C-peptide and insulin, as determined by MMTT, decreased from mean baseline levels in cohort 2. (iii) Beta cell function Over the duration of treatment with multiple doses of compound 1, the mean HOMA2-B index increased from baseline in both treatment groups. The greatest increase in mean HOMA2-B was observed in cohort 1 at day 80 (week 12). (iv) Glucagon AUC (0-3 hours) Over the duration of treatment with multiple doses of compound 1, the mean AUC (0–3 hours) of glucagon, as determined by MMTT, decreased from baseline in all treatment groups. When compared to placebo, the greatest decrease from baseline was observed in Cohort 2 at the end of the treatment period on day 108 (week 16). (v) Insulin sensitivity parameters Over the duration of treatment with multiple doses of compound 1, the mean HOMA2-IR index decreased from baseline and the mean Matsuda insulin sensitivity index increased in all treatment groups. In Cohort 1, glucose, insulin, and c-peptide excursions increased during sMMTT, similar to the patterns observed in GLP-1R monoagonist and insulin secretagogue therapy. 【0277】 Lipids - Cholesterol, HDL, LDL, and triglycerides As shown in Figure 7a, mean fasting cholesterol levels decreased from baseline in both treatment groups over the course of the treatment period. Similarly, as shown in Figure 7b, compound 1 cohort 2 dose substantially reduced sMMTT total cholesterol levels. 【0278】 As shown in Figures 7c and 7d, mean fasting HDL and LDL levels decreased from baseline in Cohort 2 over the course of the treatment period. Similarly, as shown in Figures 7e and 7f, the Compound 1 Cohort 2 dose substantially reduced sMMTT LDL cholesterol levels and sMMTT HDL cholesterol levels. 【0279】 As shown in Figure 7g, mean fasting triglyceride levels decreased from baseline in both treatment groups over the course of the treatment period. Similarly, as shown in Figure 7h, compound 1 cohort 2 dose substantially reduced sMMTT triglyceride levels. 【0280】 gastric emptying The PK parameters of acetaminophen were compared among treatment groups to determine the rate and extent of gastric emptying. The primary analysis of acetaminophen Cmax and Tmax is shown in Table 8. The PK profiles of acetaminophen before and day 1 with compound 1 were similar among treatment groups. Within the treatment groups, the Cmax of acetaminophen was similar. max Cmax decreased from day 1 during 12 weeks of multiple dosing with compound 1. Cmax for acetaminophen was lowest on day 2 in both treatment groups. However, baseline Cmax for acetaminophen decreased. max The change increased on day 107. The central t of acetaminophen max The effects were comparable between treatment groups and over time. 【0281】 [Table 9] Abbreviation:C max = Observed maximum drug concentration, NC = Not calculated, t max = Time to reach the observed maximum drug concentration. 【0282】 appetite analysis A summary of appetite perception data across all time points is shown in Figure 8. The VAS appetite assessment showed reduced hunger, increased satisfaction, and decreased overall appetite (higher overall score) in the higher-dose cohort. (i) Overall appetite score During multiple doses with compound 1, the overall appetite score generally increases from baseline in all treatment groups, including placebo, over a 12-week or 16-week treatment period. (ii) feeling of hunger; Over the course of treatment with multiple doses of compound 1, hunger scores decreased from baseline for most of the time points assessed in both treatment groups, including placebo. (iii) Satisfaction During the treatment period with multiple doses of compound 1, satisfaction scores decreased from baseline in both treatment groups. In the placebo group, patient satisfaction scores increased from baseline at day 80. (iv) feeling of fullness Over the course of treatment with multiple doses of compound 1, satiety scores increased from baseline in both treatment groups. In the placebo group, patients' satiety scores decreased from baseline at day 80. The greatest increase from baseline in satiety scores was observed in Cohort 1. 【0283】 Pharmacodynamic evaluation of differences when doses are gradually increased. Fasting glucose Patients in Cohort 1 had a mean baseline fasting plasma glucose of 10.78 mmol / L. As the dose of compound 1 was escalated to 4.5 mg, the mean fasting glucose decreased to 6.52 mmol / L on day 80, representing a reduction of approximately 40%. 【0284】 Patients in Cohort 2 had a mean baseline fasting glucose of 10.46 mmol / L. As the dose of compound 1 was gradually increased to 10.0 mg, the mean fasting glucose decreased to 5.91 mmol / L on day 108, representing an approximate reduction of 43%. 【0285】 Fasting insulin Patients in Cohort 1 had a mean fasting baseline plasma insulin level of 9.648 mIU / L. As the dose of compound 1 was escalated to 4.5 mg, the mean fasting insulin level increased to 13.362 mIU / L on day 78 and to 14.046 mIU / L on day 80, representing an approximate increase of 38–46% from baseline. 【0286】 Patients in Cohort 2 had a mean fasting baseline insulin level of 5.892 mIU / L. As the dose of Compound 1 was escalated to 6.0 mg, the mean fasting insulin level increased to 6.73 mIU / L, representing an approximate 14% increase from baseline. As the dose of Compound 1 was escalated to 8.0 mg, the mean fasting insulin level was 6.589 mIU / L, an approximate 12% increase from baseline. As the dose of Compound 1 was escalated 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, representing an approximate 20% decrease in fasting insulin from baseline. These data suggest that at doses of Compound 1 above 8.0 mg, fasting plasma glucose can be reduced without increasing fasting insulin levels, which is consistent with a reduction in insulin resistance. 【0287】 C-peptide Patients in Cohort 1 had a mean fasting baseline plasma C-peptide level of 667 pmol / L. As the dose of compound 1 was escalated to 4.5 mg, the mean fasting C-peptide level increased to 820.2 pmol / L on day 78 and to 874.9 pmol / L on day 80, representing an approximate increase of 22–31% from baseline. 【0288】 Patients in Cohort 2 had a mean fasting baseline C-peptide level of 532.8 pmol / L. As the dose of compound 1 was escalated to 6.0 mg, the mean fasting C-peptide level increased to 596.6 pmol / L, representing an approximate 12% increase from baseline. As the dose of compound 1 was escalated to 8.0 mg, the mean fasting C-peptide level increased only slightly from baseline to 541.7 pmol / L (approximately 2%). As the dose of compound 1 was escalated 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, representing an approximate 18% decrease from baseline. This data indicates that at doses of compound 1 exceeding 8.0 mg, fasting plasma glucose can be reduced without increasing fasting C-peptide secretion from pancreatic beta cells, which is consistent with reducing the workload on pancreatic beta cells. 【0289】 Glucagon on an empty stomach Patients in Cohort 1 had a mean fasting baseline plasma glucagon level of 14.79 pmol / L. As the dose of compound 1 was escalated to 4.5 mg, the mean fasting glucagon level decreased to 6.65 pmol / L on day 78 and to 8.19 pmol / L on day 80, representing an approximate decrease of 45–55% from baseline. 【0290】 Patients in Cohort 2 had a mean fasting baseline glucagon level of 9.83 pmol / L. As the dose of Compound 1 was escalated to 6.0 mg, the mean fasting glucagon level decreased to 3.65 pmol / L, representing an approximate 63% reduction from baseline. As the dose of Compound 1 was escalated to 8.0 mg, the mean fasting glucagon level decreased to 2 pmol / L from baseline at day 80. As the dose of Compound 1 was escalated to 10.0 mg, the mean fasting glucagon level decreased to 1.98 pmol / L from baseline at day 106 and to 1.93 pmol / L from baseline at day 108. These data demonstrate that fasting plasma glucagon can be reduced by approximately 80% at doses of Compound 1 above 6.0 mg. 【0291】 Fasting total cholesterol Patients in Cohort 1 had a mean fasting total cholesterol level of 5.065 mmol / L. As the dose of compound 1 was gradually increased to 4.5 mg, the mean fasting total cholesterol level decreased to 4.275 mmol / L on day 78 and to 4.461 mmol / L on day 80, representing an approximate decrease of 12–16% from baseline. 【0292】 Patients in Cohort 2 had a mean fasting baseline total cholesterol level of 4.971 mmol / L. As the dose of Compound 1 was escalated to 6.0 mg, the mean fasting total cholesterol level decreased to 3.673 mmol / L on day 64, representing an approximate 26% reduction from baseline. As the dose of Compound 1 was escalated to 8.0 mg, the mean fasting total cholesterol level decreased to 3.614 mmol / L from baseline on day 85 (approximately 27%). As the dose of Compound 1 was escalated to 10.0 mg, the mean total cholesterol level decreased to 3.454 mmol / L on day 106 and 3.441 mmol / L on day 108, representing an approximate 31% reduction in fasting total cholesterol level from baseline. These data demonstrate that fasting total cholesterol levels can be reduced by more than 30% at doses of Compound 1 above 8.0 mg. 【0293】 Fasting LDL cholesterol Patients in Cohort 1 had a mean fasting LDL cholesterol level of 2.852 mmol / L. As the dose of compound 1 was gradually increased to 4.5 mg, the mean fasting LDL cholesterol level decreased to 2.56 mmol / L on day 78 and day 80, representing an approximate 10% reduction from baseline. 【0294】 Patients in Cohort 2 had a mean fasting baseline LDL cholesterol level of 2.796 mmol / L. As the dose of Compound 1 was gradually increased to 6.0 mg, the mean fasting LDL cholesterol level decreased to 1.997 mmol / L on day 64, representing an approximate 29% reduction from baseline. As the dose of Compound 1 was gradually increased to 8.0 mg, the mean fasting LDL cholesterol level decreased to 1.954 mmol / L from baseline on day 85 (approximately 30%). As the dose of Compound 1 was gradually increased to 10.0 mg, the mean fasting LDL cholesterol level decreased to 1.859 mmol / L on day 106 and 1.849 mmol / L on day 108, representing an approximate 33–34% reduction from baseline. These data demonstrate that fasting LDL cholesterol levels can be reduced by more than 30% at doses of Compound 1 of 8.0 mg or higher. 【0295】 Fasting triglycerides Patients in Cohort 1 had a mean fasting triglyceride level of 2.938 mmol / L. As the dose of compound 1 was escalated to 4.5 mg, the mean fasting triglyceride level decreased to 1.456 mmol / L on day 78 and to 2.084 mmol / L on day 80, representing an approximate reduction of 29–50% from baseline. 【0296】 Patients in Cohort 2 had a mean fasting baseline triglyceride level of 1.867 mmol / L. As the dose of compound 1 was escalated to 6.0 mg, the mean fasting triglyceride level decreased to 1.055 mmol / L on day 64, representing an approximate 43% decrease from baseline. As the dose of compound 1 was escalated to 8.0 mg, the mean fasting triglyceride level decreased to 0.855 mmol / L from baseline on day 85 (approximately 54%). As the dose of compound 1 was escalated to 10.0 mg, the mean fasting triglyceride level decreased to 0.86 mmol / L on day 106 and to 0.985 mmol / L on day 108, representing an approximate 47–54% decrease from baseline. This data indicates that fasting triglyceride levels can be reduced by more than 50% at doses of compound 1 exceeding 6.0 mg. 【0297】 body weight In Cohort 1, patients had a mean baseline weight of 97.19 kg. The dose of LY was gradually increased to 4.5 mg, and the mean weight decreased to 94.0 kg on day 78, representing a mean change of -3.03% from baseline. 【0298】 Patients in Cohort 2 had a mean baseline weight of 94.9 kg. As the dose of compound 1 was escalated to 4.0 mg, the mean body weight decreased to 90.38 kg on day 43, with a mean percentage change of -4.04% from baseline. As the dose of compound 1 was escalated to 6.0 mg, the mean body weight decreased to 87.69 kg on day 64, with a mean percentage change of -7.07% from baseline. As the dose of compound 1 was escalated to 8.0 mg, the mean body weight decreased to 85.88 kg on day 85, with a mean percentage change of -9.05% from baseline. As the dose of compound 1 was escalated to 10 mg, the mean body weight decreased to 82.55 kg on day 109, with a mean percentage change of -12.71% from baseline. 【0299】 Body weight remained reduced from baseline after 16 weeks of Compound 1 dose administration. On day 134, the mean body weight of the Compound 1 group in Cohort 2 was 84.05 kg, a mean percentage change from baseline of -11.14%. On day 162, the mean body weight of the Compound 1 group in Cohort 2 was 88.96 kg, a mean percentage change from baseline of -6.56%. These results indicate that doses of Compound 1 greater than 6 mg can result in a body weight reduction of more than 9%. Furthermore, doses of Compound 1 greater than 10 mg can reduce body weight by more than 12%. 【0300】 Waist circumference In Cohort 1, patients had a mean baseline waist circumference of 108.66 cm. The LY dose was gradually increased to 4.5 mg, and the mean waist circumference decreased to 105.66 cm on day 78, a reduction of approximately 3% from baseline. 【0301】 Patients in Cohort 2 had a mean baseline waist circumference of 106.93 cm. As the dose of compound 1 was escalated to 4.0 mg, the mean waist circumference decreased to 103.38 cm on day 43, a reduction of approximately 3% from baseline. As the dose of compound 1 was escalated to 6.0 mg, the mean waist circumference decreased to 101.31 cm on day 64, a reduction of approximately 5% from baseline. As the dose of compound 1 was escalated to 8.0 mg, the mean waist circumference decreased to 98.58 cm on day 85, a reduction of approximately 8% from baseline. As the dose of compound 1 was escalated to 10 mg, the mean waist circumference decreased to 96.56 cm on day 109, a reduction of approximately 10% from baseline. 【0302】 Waist circumference remained reduced from baseline after 16 weeks of LY dose administration. At day 134, the mean waist circumference in the compound 1 group in the second cohort was 97.59 cm, a reduction of approximately 9% from baseline. At day 162, the mean waist circumference in the compound 1 group in the second cohort was 102.79 cm, a reduction of approximately 4% from baseline. These data suggest that compound 1 doses greater than 6.0 mg can result in improvements in body composition with waist circumference reductions of more than 5%. 【0303】 Fasting insulin resistance Patients in Cohort 1 had a mean fasting insulin resistance HOMA-IR index of 4.704. As the dose of compound 1 was escalated to 4.5 mg, the mean HOMA-IR index decreased to 4.289 on day 78 and to 4.271 on day 80, representing an approximate 9% reduction from baseline. 【0304】 Patients in Cohort 2 had a mean fasting insulin resistance HOMA-IR index of 2.7. As the dose of compound 1 was escalated to 6.0 mg, the mean HOMA-IR index decreased to 2.158 at day 64, representing an approximate 20% reduction from baseline. As the dose of compound 1 was escalated to 8.0 mg, the mean HOMA-IR index decreased to 1.976 at day 85 from baseline (approximately 27%). As the dose of compound 1 was escalated to 10.0 mg, the mean HOMA-IR index decreased to 1.325 at day 108, representing an approximate 51% reduction in HOMA-IR from baseline. These data indicate that fasting insulin resistance can be reduced by more than 25% at compound 1 doses above 6.0 mg. At compound 1 doses above 10 mg, the fasting insulin resistance index can be reduced by 50%. 【0305】 Pancreatic beta cells in a fasted state Patients in Cohort 1 had a mean fasting pancreatic beta-cell HOMA-B index of 15.791 insulin secretion. As the dose of compound 1 was escalated to 4.5 mg, the mean HOMA-B index increased to 38.762 at day 80, representing an approximate increase of 145% from baseline. 【0306】 Patients in Cohort 2 had a mean fasting pancreatic beta-cell HOMA-B index of 9.108 for insulin secretion. As the dose of compound 1 was escalated to 6.0 mg, the mean HOMA-B index increased to 16.072 from baseline at day 64, representing an approximate increase of 76%. As the dose of compound 1 was escalated to 8.0 mg, the mean HOMA-B index increased to 16.689 from baseline at day 85 (approximately 83%). As the dose of compound 1 was escalated to 10.0 mg, the mean HOMA-B index increased to 12.077 from baseline at day 108, representing an approximate increase of 33% from baseline in HOMA-B. These data suggest that at compound 1 doses above 8.0 mg, the increase in fasting HOMA-B index for insulin secretion was attenuated, consistent with the reduced requirement for insulin secretion in a situation of improved fasting insulin sensitivity and reduced fasting glucose levels. 【0307】 MMTT-Glucose Levels Patients in Cohort 1 had a baseline mean area under the curve for glucose levels from 0 to 3 hours during the mixed food challenge test, and 43.06h * The concentration was mmol / L. As the dose of compound 1 was gradually increased to mg, the mean area under the curve for glucose levels from 0 to 3 hours was 25.76 h on day 80. * It decreased to mmol / L, resulting in an approximate 40% reduction from baseline. 【0308】 In Cohort 2, patients averaged 38.27 hours. * The baseline mean area under the curve for glucose levels during a mixed diet challenge test with mmol / L is shown for 0–3 hours. As the dose of compound 1 is gradually increased to 10.0 mg, the area under the curve for glucose levels during 0–3 hours is 25.76 h on day 108.* The level decreased to mmol / L, resulting in an approximate 38% reduction in food-stimulated glucose levels from baseline. 【0309】 MMTT - Insulin Levels Patients in Cohort 1 had a baseline mean area under the curve for insulin levels from 0 to 3 hours during the mixed food challenge test, with an area under 125.233h * The level was mIU / L. As the dose of compound 1 was gradually increased to 4.5 mg, the mean area under the curve for insulin levels from 0 to 3 hours was 189.435 h on day 80. * The level increased to mIU / L, representing an approximate increase of 51% from baseline. 【0310】 In Cohort 2, patients averaged 77.692 hours. * The baseline mean area under the curve for insulin levels during a mixed food challenge test at mIU / L is shown for 0-3 hours. As the dose of compound 1 is escalated to 10.0 mg, the area under the curve for insulin levels during 0-3 hours is 69.847 h on day 108. * The insulin level decreased to mIU / L, resulting in an approximate 10% reduction in food-stimulated insulin levels from baseline. This data indicates that doses of compound 1 up to 4.5 mg stimulate insulin secretion from baseline in response to a mixed meal. Doses of compound 1 greater than 4.5 mg up to 10 mg do not stimulate insulin secretion from baseline in response to a mixed meal, and are consistent with reducing pancreatic beta-cell workload while also lowering glucose levels. 【0311】 MMTT-C-peptide Patients in Cohort 1 had a baseline mean area under the curve for C-peptide levels from 0 to 3 hours during the mixed food challenge test, with an area of ​​4391.4h * The concentration was pmol / L. As the dose of compound 1 was gradually increased to 4.5 mg, the mean area under the curve for C-peptide levels from 0 to 3 hours was 5850.1 h on day 80. * It increased to pmol / L, resulting in an approximate increase of 33% from baseline. 【0312】 In Cohort 2, the patient count was 3604.1h. * The baseline mean area under the curve for C-peptide levels during a pmol / L mixed diet challenge test is shown for 0-3 hours. As the dose of compound 1 is gradually increased to 10.0 mg, the area under the curve for C-peptide levels for 0-3 hours is 3147.4 h on day 108. * The levels decreased to pmol / L, resulting in an approximate 13% reduction in food-stimulated C-peptide levels from baseline. This data indicates that doses of compound 1 up to 4.5 mg stimulate insulin secretion in proinsulin processing from baseline in response to mixed meals. Doses of compound 1 greater than 4.5 mg up to 10 mg do not stimulate insulin secretion in proinsulin processing from baseline in response to mixed meals, and are consistent with reducing pancreatic beta-cell workload while also lowering glucose levels. 【0313】 MMTT-glucagon In Cohort 1, patients averaged 64.98 hours. * The mean area under the curve for glucagon levels during a pmol / L mixed diet challenge test is shown for 0–3 hours from baseline. As the dose of compound 1 is gradually increased to 4.5 mg, the mean area under the curve for glucagon levels during 0–3 hours is 27.93 h on day 80. * It decreased to pmol / L, resulting in an approximate 57% reduction from baseline. 【0314】 In Cohort 2, patients averaged 39.89 hours. * The baseline mean area under the curve for glucagon levels during a pmol / L mixed diet challenge test is shown for 0–3 hours. As the dose of compound 1 is gradually increased to 10.0 mg, the area under the curve for glucagon levels for 0–3 hours is 7.61 h on day 108. *The levels decreased to pmol / L, resulting in an approximate 81% reduction in food-stimulated glucagon levels from baseline. This data indicates that doses of compound 1 up to 4.5 mg reduce glucagon secretion by more than 50% from baseline in response to mixed meals. Doses of compound 1 up to 10 mg reduce glucagon secretion by more than 80% from baseline in response to mixed meals. 【0315】 MMTT-Matsuda Insulin Sensitivity Index (ISI-M) Patients in Cohort 1 had a baseline Matsuda insulin sensitivity index (ISI-M) of 3.568, calculated from mixed-food challenge parameters. As the dose of compound 1 was escalated to 4.5 mg, the mean Matsuda index was 3.567 at day 80, indicating no change from baseline. 【0316】 Patients in Cohort 2 had a baseline Matsuda insulin sensitivity index (ISI-M) calculated from mixed-food challenge parameters of 4.616. As the dose of compound 1 was escalated to 10.0 mg, the Matsuda index increased to 10.7 on day 108, an increase of approximately 132% from baseline, indicating increased insulin sensitivity. This data suggests that doses of compound 1 up to 4.5 mg do not improve insulin sensitivity in response to mixed food. Doses of compound 1 up to 10 mg significantly increase insulin sensitivity from baseline in response to mixed food. 【0317】 Adverse events No deaths occurred during this trial. Throughout the trial, a total of 17 patients (94.4%) who received compound 1 reported TEAEs, as summarized in Table 9, compared to 6 patients (100%) who received placebo. The majority of TEAEs reported during the trial were mild in severity (88.5%). Overall, the most frequently reported TEAE by participants receiving LY3305677 was gastrointestinal disorder. • Nausea 7 (38.9%) ·Vomiting 5 (27.8%), • Burping 4 (22.2%) • Diarrhea 4 (22.2%) • Abdominal pain 1 (5.6%), and ·Constipation 2 (11.1%). 【0318】 [Table 10] Abbreviation: N = Number of patients 【0319】 During this trial, one SAE was reported in one patient treated with the trial intervention, as shown in Table 10. 【0320】 [Table 11] Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, SAE = Serious adverse event. Derived based on the first dose of the study drug administered on day 1. 【0321】 Example 2: Clinical Trial overview This trial is designed to evaluate the safety, tolerability, disease progression (PD), and drug action (PK) of higher doses of compound 1 in individuals with obesity. The multiple ascending dose (MAD) trial will target individuals with obesity (i.e., women or men aged 18–70 years, 27 kg / m²). 2 ~50kg / m 2 This is a randomized, physician-blinded, placebo-controlled, repeated dose-escalation, single or multi-center trial conducted within a BMI range. Participants should have a stable body weight for at least three months prior to the start of the trial. 【0322】 treatment The dosage of compound 1 will be evaluated in two cohorts over 20 weeks with weekly administration. Each cohort will include 12 patients, with 9 receiving compound 1 and 3 receiving a placebo. 【0323】 The dosage for Cohort 1 is as follows: - 1.5 mg of compound 1 for 2 weeks. - 3.0 mg of compound 1 for 2 weeks - 6.0 mg of compound 1 for 4 weeks - 8.0 mg of compound 1 for 4 weeks - 12.0 mg of compound 1 for 4 weeks, and - 16.0 mg of compound 1 for 4 weeks. 【0324】 The dosage for Cohort 2 is as follows: - 2.0 mg of compound 1 for 3 weeks. - 4.0 mg of compound 1 for 3 weeks - 6.0 mg of compound 1 for 3 weeks. - 8.0 mg of compound 1 for 3 weeks - 10.0 mg of compound 1 for 2 weeks. - 13.0 mg of compound 1 for 2 weeks, and - 16.0 mg of compound 1 for 4 weeks. 【0325】 evaluation Blood samples were collected regularly from day 1 to day 138 to determine the plasma concentration of compound 1 over increasing doses in individuals with obesity. 【0326】 HbA1c, C-peptide, glucagon, serum glucose, and insulin were measured at multiple time points in a fasted state over doses from day 1 to day 138, and for mixed meal challenge tests (MMTT), at baseline before the first dose and during week 20, using methods known in the art for each analyte. The mean absolute and percentage changes in fasting glucose, insulin, C-peptide, and glucagon were calculated for compound 1 and placebo groups within each cohort and compared to baseline at multiple time points from day 1 to day 138. 【0327】 The parameters obtained from fasting samples and MMTT for evaluating insulin resistance and pancreatic β-cell function include the following: - Homeostasis Model Assessment (HOMA)-B, - HOMA-IR, and - Insulin sensitivity (Matsuda index). 【0328】 Insulin sensitivity (Matsuda index) is calculated according to the following formula. 【0329】 【number】 In the formula, glucose is expressed in mg / dL units, and insulin is expressed in μU / mL units. 【0330】 Mean parameters for several indices related to glycemic control, pancreatic beta-cell function, and insulin sensitivity at day 138 will be derived from fasting and MMTT measurements for compound 1 and placebo groups within each cohort and compared to baseline. 【0331】 Satisfaction VAS scores are measured in a fasted state at multiple time points across doses from day 1 to day 138. Appetite perception is assessed using VAS for parameters such as hunger, satiety, satisfaction, and expected food intake, and an overall appetite score is calculated. 【0332】 Body weight and waist circumference are measured at frequent intervals over the dose period from day 1 to day 138, and during the long-term follow-up period after the end of medication. The mean absolute and percentage change in body weight are calculated for compound 1 and placebo groups within each cohort and compared to baseline at multiple time points from day 1 to day 138 and throughout the long-term follow-up period after the end of medication. The mean absolute and percentage change in waist circumference are calculated for compound 1 and placebo groups within each cohort and compared to baseline at multiple time points from day 1 to day 138 and throughout the long-term follow-up period after the end of medication. The weight loss described in Example 1 is from the T2D patient population, but greater weight loss is typical in the obese patient population. Multipliers of 1.6 to 1.8 may be applied to the percentage of weight loss shifting from the T2D population to the obese population. 【0333】 Lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, are measured in a fasted state at multiple time points across doses from day 1 to day 138. The mean absolute and percentage change in fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, are calculated for compound 1 and the placebo group within each cohort and compared to baseline at multiple time points from day 1 to day 138. 【0334】 Vital signs, including heart rate, pulse rate, systolic blood pressure, and diastolic blood pressure, should be monitored at frequent intervals throughout the dose from day 1 to day 138. 【0335】 Safety parameters evaluated during the study included AEs (with particular interest in GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examination / medical assessment, vital signs and ECG, blood weight, injection site reactions, hypersensitivity reactions, and glucose monitoring (with particular attention to hypoglycemia). 【0336】 body weight During the multi-dose period of compound 1, mean weight loss was observed in all treatment groups at each time point evaluated. The trend of weight loss was dose-dependent, and the mean percentage change in weight from baseline was observed at the end of the treatment period as follows: - Placebo: +0.5% on day 138 (week 20) - Cohort 1: -19.4% on day 138 (week 20) - Cohort 2: -20.6% on day 138 (week 20) 【0337】 The weight loss data at various time points in the two cohorts are as follows: Day 85 / 12 weeks (4 weeks after 8mg): Placebo +0.2%, Cohort 1 -10.7%, Cohort 2 -11.7% Day 99 / 14 weeks (Cohort 2, 2 weeks after 10mg): Placebo +0.07%, Cohort 2 -13.4% Day 113 / 16 weeks (Cohort 1: 4 weeks after 12mg, Cohort 2: 2 weeks after 13mg): Placebo +0.7%, Cohort 1 -15.4%, Cohort 2 -16.2% Day 138 / 20 weeks (4 weeks after 16mg): Placebo +0.5%, Cohort 1 -19.4%, Cohort 2 -20.6%. 【0338】 Waist circumference During the period of multiple dose administration of compound 1, a decrease in mean waist circumference was observed in both cohort 1 and cohort 2. Day 85 / 12 weeks (4 weeks after 8mg): Placebo +0.04%, Cohort 1 -5.2%, Cohort 2 -7.6% Day 99 / 14 weeks (Cohort 2, 2 weeks after 10mg): Placebo +1.0%, Cohort 2 -6.8% Day 113 / 16 weeks (Cohort 1: 4 weeks after 12mg, Cohort 2: 2 weeks after 13mg): Placebo +1.3%, Cohort 1 -6.3%, Cohort 2 -12.6% Day 138 / 20 weeks (4 weeks after 16mg): Placebo +0.4%, Cohort 1 -11.5%, Cohort 2 -16.6% Adverse events No deaths occurred during this study. No serious adverse events were observed. The most common adverse events observed under mazdutide treatment were gastrointestinal (nausea, vomiting, diarrhea), consistent with GLP-1 receptor agonists. The incidence of nausea, vomiting, and diarrhea was similar across high doses of 10–16 mg, and was mild to moderate in severity. 【0339】 Example 3: Clinical Trial overview This exam is This study is designed to further evaluate the efficacy and safety of compound 1 in a population of obese or overweight individuals. The study will include obese or overweight individuals without diabetes (i.e., those who were obese before randomization and weighed 30 kg / m² at screening). 2 Having a BMI of the above or higher, or being overweight before randomization, and having a BMI of 27 kg / m² at the time of screening. 2 30 kg / m 2 This is a randomized, investigator-blinded, placebo-controlled trial conducted in women or men aged 18–75 years who have a BMI less than 100 and have one or more weight-related comorbidities such as hypertension, dyslipidemia, cardiovascular disease, osteoarthritis, or obstructive sleep apnea, but do not have T2DM. Participants should have a stable weight for at least three months prior to the start of the trial. 【0340】 treatment Multiple doses of compound 1 will be evaluated over 48 weeks in cohorts receiving either compound 1 or placebo. Each cohort will consist of approximately 60 individuals. 【0341】 Compound 1 is administered to multiple cohorts from week 1 to week 20 or week 32, and different maintenance or maximum doses are achieved between week 21 or week 32 (or the earliest week in which the dose is first achieved) and week 48. The starting dose of the dose regimen may vary by cohort, for example, 1.5 mg, 2.0 mg, or 3.0 mg. The time interval between dose steps may vary within and across cohorts, and may include dose increases after intervals of 2, 3, or 4 weeks. The magnitude of the dose increase may vary within and across cohorts, with dose increases of 1.5 mg, 2.0 mg, 3.0 mg, 4.0 mg, or 5.0 mg occurring over dose steps to achieve the specified dose. 【0342】 In this study, the first medication regimen (Cohort 1) is as follows: - 1.5 mg QW of compound 1 for 4 weeks. - Compound 1 at 3.0 mg QW for 28 weeks, - Compound 1 at 6 mg QW for 16 weeks. 【0343】 The second medication regimen (Cohort 2) is as follows: - 1.5 mg QW of compound 1 for 4 weeks. - 3 mg QW of compound 1 for 4 weeks. - 6 mg QW of compound 1 for 4 weeks. - Compound 1 at 8 mg QW for 4 weeks, - Compound 1 at 10 mg QW for 32 weeks. 【0344】 The third medication regimen (Cohort 3) is as follows: - 1.5 mg QW of compound 1 for 4 weeks. - 3 mg QW of compound 1 for 4 weeks. - 6 mg QW of compound 1 for 4 weeks. - Compound 1 at 9 mg QW for 4 weeks - Compound 1 of 12 mg QW for 4 weeks, and - Compound 1 at 16 mg QW for 28 weeks 【0345】 Three cohorts were administered compound 1: one cohort received 1.5 mg at weeks 1–4, 3.0 mg at weeks 5–32, and 6.0 mg at weeks 33–48; the second cohort received 1.5 mg at weeks 1–4, 3.0 mg at weeks 5–8, 6.0 mg at weeks 9–12, 8.0 mg at weeks 13–16, and 10.0 mg at weeks 17–48; and the third cohort received 1.5 mg at weeks 1–4, 3.0 mg at weeks 5–8, 6.0 mg at weeks 9–12, 9.0 mg at weeks 13–16, 12.0 mg at weeks 17–20, and 16.0 mg at weeks 21–48. 【0346】 evaluation Approximately 40 individuals per cohort will be evaluated at baseline and at 48 weeks for changes from baseline in multiple body composition measurements, including changes in hepatic fat, abdominal subcutaneous adipose tissue, and visceral adipose tissue, as determined by magnetic resonance imaging. Individuals will also be evaluated for changes in NAFLD, characterized by ≥10% hepatic fat, as determined by magnetic resonance imaging. 【0347】 Blood samples were collected regularly from week 1 to week 48 to determine the plasma concentration of compound 1 over increasing doses in obese individuals. 【0348】 HbA1c, C-peptide, glucagon, serum glucose, and insulin were measured in a fasted state at multiple time points from week 1 to week 48 across the dose. The mean absolute values ​​and percentage changes in fasting glucose, insulin, C-peptide, and glucagon were calculated at weeks 32 and 48 and compared to baseline week 1 prior to dose for each compound 1 and placebo cohort. The mean absolute values ​​and percentage changes in fasting glucose, insulin, C-peptide, and glucagon were calculated for each compound 1 and cohort and compared to placebo at weeks 32 and 48. 【0349】 Parameters derived from fasting samples to assess insulin resistance and pancreatic β-cell function include Homeostasis Model Assessment (HOMA)-B and HOMA-IR. Mean HOMA index parameters related to glycemic control, pancreatic β-cell function, and insulin sensitivity will be derived from fasting measurements for one cohort of each compound and compared to placebo at weeks 32 and 48. 【0350】 Satisfaction VAS scores are measured in a fasted state at multiple time points from week 1 to week 48 across the dose range. Appetite perception is assessed using VAS for parameters such as hunger, satiety, satisfaction, and expected food intake, and an overall appetite score is calculated. 【0351】 Body weight and waist circumference will be measured at frequent intervals from week 1 to week 48 over the course of the dose, and during the long-term follow-up period after the end of medication. Mean absolute and percentage change in body weight will be calculated at weeks 32 and 48 and compared to baseline one week prior to dose for each compound 1 cohort and placebo cohort. Mean absolute and percentage change in waist circumference will be calculated at weeks 32 and 48 and compared to baseline one week prior to dose for each compound 1 cohort and placebo cohort. Mean absolute and percentage change in waist circumference will be calculated for each compound 1 cohort and compared to placebo at weeks 32 and 48. 【0352】 Lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, are measured in a fasted state at multiple time points from week 1 to week 48 across doses. The mean absolute and percentage change in fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, are calculated at weeks 32 and 52 and compared to baseline week 1 prior to dose for each compound 1 cohort and placebo cohort. The mean absolute and percentage change in fasting lipid profiles, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, are calculated for each compound 1 cohort and compared to placebo at weeks 32 and 48. 【0353】 Vital signs, including heart rate, pulse rate, systolic blood pressure, and diastolic blood pressure, should be monitored at frequent intervals from week 1 to week 48 across the dosage period. 【0354】 Safety parameters to be evaluated during the study include AEs (with particular interest in GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examination / medical assessment, 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 blood glucose control, pancreatic beta-cell function, and insulin sensitivity), derived from fasting measurements at weeks 32 and 48 for each compound 1 and placebo cohort, and compared to baseline one week prior to dose.

Claims

[Claim 1] A pharmaceutical composition for reducing weight, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides, used in a method for reducing weight, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides in a patient who requires weight reduction, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides, The method described above is (1) Administer to the patient, once a week, a compound comprising the amino acid sequence shown in SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for at least about two weeks. (2) A pharmaceutical composition comprising: (2) thereafter increasing the dose to more 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. [Claim 2] The pharmaceutical composition according to claim 1, wherein the increased dose once a week is selected from the group consisting of approximately 6.25 mg to approximately 16.0 mg of the compound, approximately 6.5 mg to approximately 16.0 mg, approximately 8.0 mg to approximately 16.0 mg, approximately 10 mg to approximately 16.0 mg, approximately 11.0 mg to approximately 16 mg, approximately 12.0 mg to approximately 16.0 mg, approximately 13.0 mg to approximately 16.0 mg, or approximately 14.0 mg to approximately 16.0 mg. [Claim 3] The pharmaceutical composition according to claim 1, wherein the once-weekly increased dose is approximately 6.25 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. [Claim 4] The pharmaceutical composition according to claim 2, wherein the increased weekly dose is approximately 8 mg to approximately 16.0 mg. [Claim 5] The pharmaceutical composition according to claim 4, wherein the once-weekly increased dose is approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. [Claim 6] The pharmaceutical composition according to claim 2, wherein the increased weekly dose is approximately 10 mg to approximately 16.0 mg. [Claim 7] The pharmaceutical composition according to claim 6, wherein the once-weekly increased dose is approximately 10.0 mg, approximately 11.0 mg, approximately 12.0 mg, approximately 13.0 mg, approximately 14.0 mg, approximately 15.0 mg, or approximately 16.0 mg. [Claim 8] The pharmaceutical composition according to claim 1, wherein a number of different once-weekly doses are administered to the patient in steps (1) and (2). [Claim 9] The pharmaceutical composition according to claim 8, wherein the first once-weekly dose is approximately 1.0 mg to approximately 6.0 mg. [Claim 10] The pharmaceutical composition according to claim 9, wherein the first once-weekly dose is approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 3.5 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg. [Claim 11] The pharmaceutical composition according to claim 10, wherein the first once-weekly dose is approximately 1.5 mg, approximately 2.0 mg, or approximately 3.0 mg. [Claim 12] The pharmaceutical composition according to claim 9, wherein the first once-weekly dose and each subsequent increased once-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 each dose is administered for at least about two weeks. [Claim 13] The pharmaceutical composition according to claim 12, wherein the first once-weekly dose is about 1.5 mg, about 2.0 mg, or about 3.0 mg, and 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. [Claim 14] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 1.5 mg once a week for at least approximately two weeks, (b) Increase the dose to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 15] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 2.0 mg once a week for at least approximately two weeks. (b) Increase the dose to about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 16] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 1.5 mg once a week for at least approximately two weeks, (b) Increase the dose to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 17] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 2.0 mg once a week for at least approximately two weeks. (b) Increase the dose to about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (f) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (g) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 18] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 1.5 mg once a week for at least approximately two weeks, (b) Increase the dose to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to approximately 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (e) Increase the dose to approximately 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 19] (a) Administering a first dose of the compound, or a pharmaceutically acceptable salt thereof, at a dose of approximately 1.5 mg once a week for at least approximately two weeks, (b) Increase the dose to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (c) Increase the dose to approximately 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (d) Increase the dose to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least about two weeks. (e) Increase the dose to approximately 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dose once a week for at least approximately two weeks. (f) The pharmaceutical composition according to claim 1, comprising increasing the dose to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about two weeks. [Claim 20] The pharmaceutical composition according to claim 1, comprising administering a dose once a week for at least about four weeks. [Claim 21] The pharmaceutical composition according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is administered subcutaneously. [Claim 22] The pharmaceutical composition according to claim 1, wherein the administration of a compound comprising the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, results in a reduction in the patient's weight. [Claim 23] The pharmaceutical composition according to claim 1, wherein the administration of a compound comprising the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, results in a reduction in the patient's HbA1c. [Claim 24] The pharmaceutical composition according to claim 1, wherein the administration of a compound comprising the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, results in a reduction of the patient's LDL cholesterol and / or triglycerides. [Claim 25] The pharmaceutical composition according to claim 1, wherein the administration of a compound comprising the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, does not result in unacceptable tolerability. [Claim 26] The pharmaceutical composition according to claim 1, wherein the patient is overweight. [Claim 27] The pharmaceutical composition according to claim 1, wherein the patient is obese. [Claim 28] The pharmaceutical composition according to claim 1, wherein the patient has type 2 diabetes. [Claim 29] A pharmaceutical composition comprising the compound of Sequence ID No. 1 or a pharmaceutically acceptable salt thereof, for the purpose of providing weight reduction, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides, (1) A compound consisting of the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least about two weeks. (2) A pharmaceutical composition wherein the once-weekly dose is subsequently increased to more than approximately 6 mg to approximately 16 mg and administered for at least approximately two weeks. [Claim 30] A pharmaceutical agent comprising the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof, for the purpose of reducing body weight, improving blood glucose control, and / or reducing LDL cholesterol or triglycerides, (1) A compound consisting of the amino acid sequence shown in Sequence ID No. 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least about two weeks. (2) A pharmaceutical drug in which the once-weekly dose is subsequently increased to more than approximately 6 mg to approximately 16 mg and administered for at least approximately two weeks.

Images