Methods of using GCG / GLP1 core agonists 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 Sequence Listing) This disclosure has been filed together with a sequence listing in ST.26 XML format. The sequence listing is provided as a file entitled "30324_WO_SeqListing" created on May 18, 2023, and is 3.1 kilobytes (kb) in size. The sequence listing information in ST.26 XML format is hereby incorporated by reference in its entirety into this specification.

[0002] (Field of the Invention) This disclosure relates to a method of using an incretin analog or a pharmaceutically acceptable salt thereof that is active at each of the glucagon (Gcg) receptor and the glucagon-like peptide-1 (GLP1) receptor, its medical use, and a pharmaceutical composition comprising the same. In particular, diabetes (especially type 2 diabetes mellitus (T2DM)) and / or its symptoms, obesity, hypertension, cardiovascular diseases, specifically, MACE (including death, myocardial infarction, stroke, hospitalization for heart failure, and revascularization including percutaneous coronary intervention and coronary artery bypass graft) and atherosclerosis, chronic kidney disease, diabetic kidney disease, osteoarthritis, polycystic ovary syndrome, dyslipidemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty acid liver disease (NAFLD), obstructive sleep apnea, etc. The present invention relates to a method of using a specific dose of an incretin analog and a composition containing a specific dose of an incretin analog for treating conditions, diseases, and disorders, and its medical use.

Background Art

[0003] Over the past few decades, the prevalence of diabetes, a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, has been continuously increasing. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes. In T2DM, the combined effects of impaired insulin secretion and insulin resistance are associated with elevated blood glucose levels.

[0004] Uncontrolled diabetes can cause one or more conditions that affect the morbidity and mortality of such individuals. One of the main risk factors for T2DM is obesity, and many (about 90%) of the individuals with T2DM are overweight or obese. It has been demonstrated that a reduction in body fat accumulation will result in an improvement in obesity-related comorbidities.

[0005] Current standard treatments for T2DM, obesity, and obesity-related metabolic disorders include diet and exercise, as well as treatment with 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 blood glucose control goals (see, for example, Casagrande et al. (2013) Diabetes Care 36:2271-2279), and there remains a "gap" between the efficacy of GLP-1 analogs and the efficacy of bariatric surgery. To fill this gap, researchers have pursued a "co-agonist" strategy by combining GLP-1 with related hormones and related peptides from the proglucagon family, including GIP and Gcg itself (see Sanchez-Garrido MA et al., Diabetologia (2017) 60(10):1851-61).

[0006] There are multiple GLP-1 / Gcg core agonists 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 of Hope D C D et al., Frontiers in Endocrinology (Lausanne), 2021 Sep 8;12:735019). Some of these GLP-1 / Gcg core agonists have been shown to have promising weight loss, glucose effects, or both in these early-phase clinical results. However, some reports suggest that the weight loss and / or glucose-lowering effects of these core agonists may plateau such that higher doses do not result in improved efficacy and thus limit the achievable weight loss and / or glucose improvement, and furthermore, tolerability may be limited at higher doses by adverse gastrointestinal events. See, for example, Ji et al., The Lancet, EClinicalMedicine 39 (2021) 101088, Nahra et al., Diabetes Care. 2021;44:1433-42, Alba et al., Clinical Obesity, 2021 Apr;11(2):e12432), Ambery et al., British Journal of Clinical Pharmacology, 2018 Oct;84(10):2325-2335.

[0007] Accordingly, there is a need for more effective doses and dosing regimens for GLP-1 / GCG core agonists that can provide high weight loss and / or improved glucose control in individuals in need of such treatment while also preserving the overall acceptable benefit / risk profile for the individual.

Summary of the Invention

Means for Solving the Problems

[0008] The present invention reports dosages and dosing regimens of GLP-1 / Gcg core agonists that result in unexpectedly improved weight loss, improved body composition, robust glycemic control, lipid reduction, and / or insulin sensitization, while reducing the beta cell insulin secretion workload, and at the same time exhibit only mild or moderate adverse events.

[0009] In one aspect, the present invention provides a method for providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides in a patient in need thereof, the method comprising: (1) a once-weekly dose of a compound of the following formula: 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 wherein Xaa2 is Aib, the Lys at position 20 is chemically modified by the linkage of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 CO2H, the C-terminal amino acid is amidated (SEQ ID NO: 1), a compound, or a pharmaceutically acceptable salt thereof, administering to a patient in need thereof for at least about 2 weeks, (2) then increasing the dose to greater than about 6 mg to about 16 mg and administering the increased dose to the patient once weekly for at least about 2 weeks.

[0010] In some embodiments, provided herein are methods 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 greater than about 6 mg to about 16 mg and administering the increased dose to the patient once weekly 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 greater 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 at a once-weekly dose, 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.

[0013] In a further aspect of the present disclosure, there is provided the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides, (1) The compound of SEQ ID NO: 1 at a once-weekly dose, 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.

[0014] In some embodiments, there is provided the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease, for weight loss, for reducing food intake, and / or for inducing satiety, (1) The compound of SEQ ID NO: 1 at a once-weekly dose, 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.

[0015] In a further aspect of the present disclosure, the increased once-weekly dose is from about 6.25 mg to about 16.0 mg, from about 6.5 mg to about 16.0 mg, from about 8.0 mg to about 16.0 mg, from about 10 mg to about 16.0 mg, from about 11.0 mg to about 16 mg, from about 12.0 mg to about 16.0 mg, from about 13.0 mg to about 16.0 mg, or from about 14.0 mg to about 16.0.

[0016] In a further aspect of the present disclosure, the increased once-weekly dosage is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg. In some embodiments, the increased once-weekly dosage is about 6.5 mg. In some embodiments, the increased once-weekly dosage is about 7.0 mg. In some embodiments, the increased once-weekly dosage is about 8.0 mg. In some embodiments, the increased once-weekly dosage is about 9.0 mg. In some embodiments, the increased once-weekly dosage is about 10.0 mg. In some embodiments, the increased once-weekly dosage is about 11.0 mg. In some embodiments, the increased once-weekly dosage is about 12.0 mg. In some embodiments, the increased once-weekly dosage is about 13.0 mg. In some embodiments, the increased once-weekly dosage is about 14.0 mg. In some embodiments, the increased once-weekly dosage is about 15.0 mg. In some embodiments, the increased once-weekly dosage is about 16.0 mg.

[0017] In a preferred aspect of the present disclosure, the increased once-weekly dosage is from about 8.0 mg to about 16.0 mg. In yet a further aspect of the present disclosure, the increased once-weekly dosage is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0018] In another preferred aspect of the present disclosure, the increased once-weekly dosage is from about 10.0 mg to about 16.0 mg. In yet a further aspect of the present disclosure, the increased once-weekly dosage is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0019] In one aspect of the present disclosure, the once-weekly dose in step (1) is from about 1.0 mg to about 6.0 mg. In a further aspect of the present disclosure, the once-weekly dose for about one week is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg.

[0020] In a further aspect of the present disclosure, a plurality of different once-weekly doses are administered to the patient in steps (1) and (2).

[0021] In one aspect of the present disclosure, the patient is administered a first or initial once-weekly dose of from about 1.0 mg to about 6.0 mg. Thus, in some embodiments, the first once-weekly dose is from about 1.0 mg to about 6.0 mg. In a further aspect of the present 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 a preferred aspect of the present 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 about 3.0 mg.

[0022] In one aspect of the present disclosure, the first dose and each subsequent increased dose are increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and each dose is administered for at least about two weeks. Thus, the first dose is selected from about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, and about 6.5 mg, and each subsequent dose is increased 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 relative to the previously administered dose. In a preferred aspect, the first dose is selected from about 1.5 mg, about 2.0 mg, and about 3.0 mg, and each subsequent dose is increased in increments 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 the present disclosure, the dose can be decreased after administering the maximum or highest dose for that patient. For example, the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof at a once-weekly dose of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg is administered to the patient for 3 weeks each. After 3 weeks at the maximum dose of 10 mg, the dose is reduced to 8 mg.

[0024] In another aspect of the present disclosure, the method or use includes administering a once-weekly dose for at least about 4 weeks. In a further aspect of the present disclosure, the method or use includes administering a once-weekly dose for at least about 6 weeks. In a further aspect of the present disclosure, the method or use includes administering a once-weekly dose for at least about 8 weeks.

[0025] In one preferred embodiment, the method or use comprises administering a once-weekly dose for at least about 2 weeks and administering a maximum once-weekly dose for at least about 4 weeks. In another preferred embodiment, the method or use comprises administering a once-weekly dose for at least about 4 weeks and administering a maximum once-weekly dose for at least about 4 weeks. In another preferred embodiment, the method or use comprises administering a once-weekly dose for at least about 4 weeks and administering a maximum once-weekly dose for at least about 8 weeks.

[0026] 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 body weight. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease of at least about 10% 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 decrease of at least about 15% 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 decrease of at least about 20% in 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 a decrease in triglycerides. In another embodiment, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, does not result in unacceptable intolerance.

[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 another embodiment, the patient has type 2 diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0030]

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Mode for Carrying Out the Invention

[0031] Overview Several peptides derived from preproglucagon, and their analogs, 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 diverse physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the control of food intake.

[0032] Gcg is a 29 - amino - acid peptide corresponding to amino acids 53 - 81 of preproglucagon. OXM is a 37 - amino - acid peptide and is composed of the complete 29 - amino - acid sequence of Gcg with an octapeptide carboxy - terminal extension (amino acids 82 - 89 of preproglucagon, also called "intervening peptide 1" or IP - 1). Gcg binds to the Gcg receptor on hepatocytes and helps maintain blood glucose levels by releasing glucose (stored in the form of glycogen) from the liver through glycogenolysis. As these stores are depleted, Gcg stimulates the liver to synthesize additional glucose through gluconeogenesis. This glucose is released into the bloodstream and prevents the onset of hypoglycemia.

[0033] GLP - 1 has different biological activities compared to Gcg. Its actions include stimulation of insulin synthesis and secretion, inhibition of Gcg secretion, and inhibition of food intake. GLP - 1 has been shown to reduce 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 favorable effects on body weight, have no risk of hypoglycemia, and are effective in glycemic control. However, due to dose - dependent gastrointestinal side effects, weight loss is moderate.

[0034] OXM activates both the Gcg receptor and the GLP-1 receptor and has slightly higher potency for the Gcg receptor than for the GLP-1 receptor. It has less potency for each of those respective receptors than native Gcg and GLP-1. Human Gcg can also activate both receptors but has a stronger preference for the Gcg receptor than for 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 OXM analogs (GLP-1 / Gcg coregonists) that can be used to treat diabetes, obesity, obesity-related comorbidities, and other medical conditions. Of particular interest herein is the fatty acid acylated long-acting OXM analog (GLP-1 / Gcg coregonist) (SEQ ID NO: 1), the OXM analog (GLP-1 / Gcg coregonist) described in Example 2 of this specification.

[0035] Unfortunately, many individuals with diabetes are unable to reach their HbA1c goals and struggle with weight management, so there is a need for new therapies and dosing regimens that can provide additional glycemic control and / or weight loss. As noted above, simply increasing the dose of a therapeutic agent may not necessarily achieve an increase in efficacy, as it can plateau at a certain dose level where it is effective. Furthermore, increasing the dose of a therapeutic agent may, in some cases, achieve an increase in efficacy, but increasing the dose of a therapeutic agent, specifically one that is active at each of the GLP-1 and GCG receptors, also has a greater risk of side effects, particularly gastrointestinal side effects.

[0036] The present invention described herein overcomes these problems and surprisingly provides substantially improved weight loss, improved body composition, robust blood glucose control, lipid lowering, and / or insulin sensitization, while reducing the beta cell insulin secretion workload, and at the same time provides dosages and dosing regimens that exhibit only mild or moderate adverse events.

[0037] As described herein, unexpectedly high weight losses (-19.4 and -20.6%) were achieved in two separate cohorts receiving dosages greater than about 6 mg to greater than about 16 mg, compared to the placebo - receiving cohort, in a 20 - week study. Such magnitudes of weight loss in such a short time have not been previously reported for any GLP - 1 / Gcg co - agonist.

[0038] Specifically, and surprisingly, the dosages 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 fat-free body mass percentage. Surprisingly, the dosages and regimens described herein have also been found to achieve glycemic control, as evidenced, for example, by substantial reduction of HbA1c, fasting glucose, and glucose excursions in a Mixed Meal Tolerance Test (MMTT). Surprisingly, the dosages 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 excursions in MMTT, and reduced HOMA-IR. Surprisingly, the dosages and regimens described herein have also been found to achieve reduced appetite, as evidenced, for example, by reduced hunger and increased satiety. Surprisingly, the dosages and regimens described herein have also been found to achieve improved lipid profiles, as evidenced, for example, by reduced fasting and sMMTT total cholesterol, triglycerides, LDL cholesterol, and increased HDL cholesterol. Surprisingly, the dosages and regimens described herein have also been found to achieve Gcg-R target engagement, as evidenced by reduced fasting and sMMTT glucagon levels.

[0039] Multiple aspects of dosing regimens and methods of use of GLP-1 / Gcg coagonists suitable for once-weekly dosing are described herein. In certain examples, the regimens and methods described herein include determination and administration of an initial dose of such a GLP-1 / Gcg coagonist. In other aspects, the regimens and methods described herein include determination and administration of a maximum or top dose, including how and when to adjust the dose.

[0040] In one aspect, the present invention provides a method for providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides in a patient in need thereof, the method comprising: (1) a once-weekly dose of a compound of the following formula, 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 wherein Xaa2 is Aib, the Lys at position 20 is chemically modified by the linkage of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 CO2H, the C-terminal amino acid is amidated (SEQ ID NO: 1), a compound, or a pharmaceutically acceptable salt thereof, administering to a patient in need thereof for at least about 2 weeks, (2) then increasing the dose to greater than about 6 mg to about 16 mg and administering the increased dose to the patient once a week for at least about 2 weeks.

[0041] In another aspect, a method is provided herein 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease i 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 compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, once a week 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.

[0042] In another aspect of the present disclosure, there is provided a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides. (1) A compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least about 2 weeks. (2) Thereafter, the once-a-week dose is increased to more than about 6 mg to about 16 mg and administered for at least about 2 weeks.

[0043] In another aspect, there is provided a 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease, for use in weight loss, for use in reducing food intake, and / or for use in inducing satiety. (1) A compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered once a week for at least about 2 weeks. (2) Thereafter, the once-a-week dose is increased to more than about 6 mg to about 16 mg and administered for at least about 2 weeks.

[0044] In a further aspect of the present disclosure, there is provided the use of a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1 at a once-weekly dose, 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.

[0045] In another aspect, provided is the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease in a patient, weight reduction, reduction of food intake, and / or induction of satiety, (1) The compound of SEQ ID NO: 1 at a once-weekly dose, 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.

[0046] In a further aspect of the present disclosure, the increased once-weekly dose is from about 6.25 mg to about 16.0 mg, from about 6.5 mg to about 16.0 mg, from about 8.0 mg to about 16.0 mg, from about 10 mg to about 16.0 mg, from about 11.0 mg to about 16 mg, from about 12.0 mg to about 16.0 mg, from about 13.0 mg to about 16.0 mg, or from about 14.0 mg to about 16.0.

[0047] In a further aspect of the present disclosure, the increased once-weekly dosage is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg. In some embodiments, the increased once-weekly dosage is about 6.5 mg. In some embodiments, the increased once-weekly dosage is about 7.0 mg. In some embodiments, the increased once-weekly dosage is about 8.0 mg. In some embodiments, the increased once-weekly dosage is about 9.0 mg. In some embodiments, the increased once-weekly dosage is about 10.0 mg. In some embodiments, the increased once-weekly dosage is about 11.0 mg. In some embodiments, the increased once-weekly dosage is about 12.0 mg. In some embodiments, the increased once-weekly dosage is about 13.0 mg. In some embodiments, the increased once-weekly dosage is about 14.0 mg. In some embodiments, the increased once-weekly dosage is about 15.0 mg. In some embodiments, the increased once-weekly dosage is about 16.0 mg.

[0048] In a preferred aspect of the present disclosure, the increased once-weekly dosage is from about 8.0 mg to about 16.0 mg. In a still further aspect of the present disclosure, the increased once-weekly dosage is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0049] In another preferred aspect of the present disclosure, the increased once-weekly dosage is from about 10.0 mg to about 16.0 mg. In a still further aspect of the present disclosure, the increased once-weekly dosage is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0050] In one aspect of the present disclosure, the once-weekly dose in step (1) is from about 1.0 mg to about 6.0 mg. In a further aspect of the present disclosure, the once-weekly dose for about one week is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg.

[0051] In a further aspect of the present disclosure, a plurality of different once-weekly doses are administered to the patient in steps (1) and (2).

[0052] In one aspect of the present disclosure, the patient is administered a first or initial once-weekly dose of from about 1.0 mg to about 6.0 mg. Thus, in some embodiments, the first once-weekly dose is from about 1.0 mg to about 6.0 mg. In a further aspect of the present 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 a preferred aspect of the present 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 about 3.0 mg.

[0053] In one aspect of the present disclosure, the first dose and each subsequent increased dose are increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and each dose is administered for at least about two weeks. Thus, the first dose is selected from about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, and about 6.5 mg, and each subsequent dose is increased 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 relative to the previously administered dose.

[0054] In a preferred aspect, the first dose is selected from about 1.5 mg, about 2.0 mg, and about 3.0 mg, and each subsequent dose is increased in increments 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. For example, a patient is 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, a patient is 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 10.0 mg (an increment of 4.0 mg relative to the previous dose of 6.0 mg), a subsequent dose of 13.0 mg (an increment of 3.0 mg relative to the previous dose of 10.0 mg), and a subsequent dose of 16.0 mg (an increment of 3.0 mg relative to the previous dose of 13.0 mg).

[0055] In another aspect of the disclosure, the dosage can be reduced after administering the maximum or highest dosage for that patient. For example, a compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof at a once-weekly dosage of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg is administered to the patient for 3 weeks each. After 3 weeks at the maximum dosage of 10 mg, the dosage is reduced to 8 mg.

[0056] In another aspect of the disclosure, the method or use includes administering a once-weekly dosage for at least about 4 weeks. In a further aspect of the disclosure, the method or use includes administering a once-weekly dosage for at least about 6 weeks. In a further aspect of the disclosure, the method or use includes administering a once-weekly dosage for at least about 8 weeks. Different once-weekly dosages can be administered for different periods. For example, the first dosage and subsequent increased dosages are administered for about 4 weeks, and the maximum increased dosage is administered for at least about 8 weeks. In another example, the first dosage is administered for 2 weeks, each subsequent increased dosage is administered for about 2 or 4 weeks, and the maximum increased dosage is administered for at least about 8 weeks.

[0057] In a preferred aspect of the disclosure, the maximum increased once-weekly dosage 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 dosage of about 3.0 mg of the compound 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 dosage 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 a first dosage of about 1.5 mg of the compound 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) Increase the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Optionally, increase the dosage to about 4.5 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0060] In another embodiment, the method or use is (a) Administer about 2.0 mg of a first dosage of the compound, 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) Increase the dosage to about 4.0 mg or about 5.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.5 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 4 weeks, or at least about 8 weeks, including.

[0061] In an alternative preferred embodiment of the present disclosure, the maximum increased once-weekly dosage of the compound, or a pharmaceutically acceptable salt thereof, is about 8.0 mg.

[0062] In one embodiment, the method or use is a) Administer about 4.0 mg of a dosage of the compound, 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 dosage to about 8.0 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, comprising.

[0063] In another embodiment, the method or use is (a) administering a first dosage of about 1.5 mg of the compound, 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; (b) increasing the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) increasing the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (d) increasing the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, comprising.

[0064] In another embodiment, the method or use is (a) administering a first dosage of about 2.0 mg of the compound, 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; (b) increasing the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) increasing the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (d) increasing the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage 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, comprising.

[0065] In an alternative preferred embodiment of the present 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 about 4.5 mg of the compound, 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 dose to about 9.0 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.

[0067] In another embodiment, the method or use is (a) administering a first dose of about 1.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; and (b) increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the 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 dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; and (d) increasing the dose to about 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks.

[0068] In another embodiment, the method or use is (a) administering a first dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; and (b) Increase the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0069] In another embodiment, the method or use is (a) Administer about 3.0 mg of a first dosage of the compound, 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) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0070] In an alternative preferred embodiment of the present disclosure, the maximum increased once-weekly dosage of the compound, or a pharmaceutically acceptable salt thereof, is about 10.0 mg.

[0071] In one embodiment, the method or use is a) Administer about 5.0 mg of the dosage of the compound, 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 dosage 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, and including this.

[0072] In another embodiment, the method or use is (a) administering a first dosage of about 1.5 mg of the compound, 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 dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) increasing the dosage to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) increasing the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) increasing the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage 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 this.

[0073] In another embodiment, the method or use is (a) administering a first dosage of about 2.0 mg of the compound, 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 dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient 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 dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0074] In another embodiment, the method or use is (a) Administer a first dosage of about 3.0 mg of the compound, 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) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0075] In an alternative preferred embodiment of the present disclosure, the maximum increased dosage of the compound, or a pharmaceutically acceptable salt thereof, is about 12.0 mg.

[0076] In one embodiment, the method or use is a) Administer a dosage of about 6.0 mg of the compound, 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 dosage to about 12.0 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, comprising.

[0077] In another embodiment, the method or use is (a) administering a first dosage of about 1.5 mg of the compound, 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; (b) increasing the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) increasing the dosage to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (d) increasing the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (e) optionally, increasing the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (f) increasing the dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dosage 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, comprising.

[0078] In another embodiment, the method or use is (a) administering a first dosage of about 2.0 mg of the compound, 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; (b) Increase the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient 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 dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 include.

[0079] In another embodiment, the method or use is (a) Administer about 3.0 mg of a first dosage of the compound, 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) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 include.

[0080] In an alternative preferred embodiment of the present 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 a first dose of about 1.5 mg of the compound, 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; (b) increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) increasing the dose to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (d) optionally, increasing the dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (e) increasing the dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (f) increasing the dose to about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose 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 comprises.

[0082] In another embodiment, the method or use is (a) administering a first dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (b) optionally, increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) Increase the dosage to about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Optionally, increase the dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) Increase the dosage to about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage 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 the like.

[0083] In another embodiment, the method or use is (a) Administer a first dosage of about 3.0 mg of the compound 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, (b) Increase the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the dosage to about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage 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 the like.

[0084] In an alternative preferred embodiment of the present 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 a first dose of about 1.5 mg of the compound, 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; (b) increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (c) increasing the dose to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (d) increasing the dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (e) optionally, 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 2 weeks, at least about 3 weeks, or at least about 4 weeks; (f) increasing the dose to about 11.0 mg or about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks; (g) increasing the dose to about 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose 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.

[0086] In another embodiment, the method or use is (a) Administering a first dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Optionally, increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the 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 dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increasing the dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, increasing the dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increasing the dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) Optionally, increasing the dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (h) Increasing the dose to about 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose 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.

[0087] In another embodiment, the method or use is (a) Administering a first dose of about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 includes.

[0088] In an alternative preferred embodiment of the present disclosure, the maximum increased dosage of the compound, or a pharmaceutically acceptable salt thereof, is about 15.0 mg.

[0089] In one embodiment, the method or use is (a) Administer a first dosage of about 1.5 mg of the compound, 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) Increase the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Optionally, increase the dosage to about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) Increase the dosage to about 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0090] In another embodiment, the method or use is (a) Administer about 2.0 mg of a first dosage of the compound, 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, (b) Optionally, increase the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Optionally, increase the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) Optionally, increase the dosage to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (h) Increase the dosage to about 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 includes.

[0091] In another embodiment, the method or use is (a) Administer a first dosage of about 3.0 mg of the compound, 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, (b) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Optionally, increase the dosage to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Increase the dosage to about 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 includes.

[0092] In an alternative preferred embodiment of the present disclosure, the maximum increased dosage 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 a first dose of about 1.5 mg of the compound, 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 dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the 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 dose to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the 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 dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, increasing the dose to about 9.0 or 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increasing the dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) 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 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and including.

[0094] In another embodiment, the method or use is (a) Administering a first dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Optionally, increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, increase the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) Increase the dosage to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (h) Increase the dosage to about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 includes.

[0095] In another embodiment, the method or use is (a) Administer a first dosage of about 3.0 mg of the compound, 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) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0096] In another embodiment, the method or use is (a) Administer a first dosage of about 1.5 mg of the compound, 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) Increase the dosage to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the dosage to about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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, including.

[0097] In another embodiment, the method or use is (a) Administering a first dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the 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 dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increasing the dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) 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 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increasing the dose to about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) 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 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and including.

[0098] In another embodiment, the method or use is (a) Administering a first dose of about 1.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage 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 dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the dosage to about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) Increase the dosage to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage 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

[0099] In another embodiment, the method or use is (a) Administer about 1.5 mg of a first dosage of the compound 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) Increase the dosage to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the dosage to about 9.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the dosage to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Increase the dosage to about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 include.

[0100] In another embodiment, the method or use is (a) Administer a first dosage of about 2.0 mg of the compound, 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, (b) Increase the dosage to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the dosage to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the dosage to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Increase the dosage to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Increase the dosage to about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the dosage 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 include.

[0101] In one aspect, the method or use comprises administering each dose once a week for at least about two weeks. In one aspect, the method or use comprises administering each dose once a week for at least about four weeks. In one aspect, the method or use comprises administering each dose once a week for at least about eight weeks.

[0102] In one preferred aspect, the method or use comprises administering the once-a-week dose for at least about two weeks and administering the maximum once-a-week dose for at least about four weeks. In another preferred aspect, the method or use comprises administering the once-a-week dose for at least about four weeks and administering the maximum once-a-week dose for at least about four weeks. In another preferred aspect, the method or use comprises administering the once-a-week dose for at least about four weeks and administering the maximum once-a-week dose for at least about eight weeks.

[0103] In one aspect, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease 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 decrease in the patient's body weight of at least about 10%. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's body weight of at least about 15%. In some embodiments, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, results in a decrease in the patient's body weight of at least about 20%.

[0104] In one aspect, 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 one aspect, 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 a decrease in triglycerides. In one aspect, administration of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, does not result in unacceptable intolerance.

[0105] In one aspect, the patient is overweight. In another aspect, the patient is obese. In another aspect, the patient has type 2 diabetes.

[0106] In another aspect, the present invention provides a method for providing chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides in patients in need thereof, the method comprising: (1) administering to a patient in need thereof a gradually increasing dose, once a week, of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for at least about two weeks; (2) thereafter, administering a maintenance dose of said compound, or a pharmaceutically acceptable salt thereof, of greater than about 6 mg to about 16 mg once a week 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, insulin-independent diabetes, obesity, dyslipidemia, non-alcoholic fatty 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, weight loss, reduction of food intake, and / or induction of satiety, the method comprising: (1) administering to a patient in need thereof a gradually increasing dose, once a week, of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for at least about two weeks; (2) thereafter, administering a maintenance dose of said compound, or a pharmaceutically acceptable salt thereof, of greater than about 6 mg to about 16 mg once a week for at least about two weeks.

[0108] In another aspect of the present disclosure, there is provided a compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in chronic weight management, improving glycemic control, and / or reducing LDL cholesterol or triglycerides, (1) wherein a gradually increasing dose, once a week, of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered for at least about two weeks, (2) Thereafter, the compound of formula (I) or a pharmaceutically acceptable salt thereof at a maintenance dose of more than about 6 mg to about 16 mg once a week is administered for at least about 2 weeks.

[0109] In another aspect, there is provided 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease in a patient, 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, at a gradually increasing dose once a week is administered for at least about 2 weeks. (2) Thereafter, the compound of formula (I) or a pharmaceutically acceptable salt thereof at a maintenance dose of more than about 6 mg to about 16 mg once a week is administered for at least about 2 weeks.

[0110] In a further aspect of the disclosure, there is provided the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for chronic weight management, improvement of glycemic control, and / or reduction of LDL cholesterol or triglycerides. (1) The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, at a gradually increasing dose once a week is administered for at least about 2 weeks. (2) Thereafter, the compound of formula (I) or a pharmaceutically acceptable salt thereof at a maintenance dose of more than about 6 mg to about 16 mg once a week is administered for at least about 2 weeks.

[0111] In another aspect, provided is the use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, or diabetic kidney disease in a patient, for weight reduction, for reducing food intake, and / or for inducing a sense of satisfaction. (1) A compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, at a gradually increasing dose once a week, is administered for at least about 2 weeks. (2) Thereafter, a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, of more than about 6 mg to about 16 mg once a week is administered for at least about 2 weeks.

[0112] In a further aspect of the present disclosure, the once-a-week maintenance dose is about 6.25 mg to about 16.0 mg, about 6.5 mg to about 16.0 mg, about 8.0 mg to about 16.0 mg, about 10 mg to about 16.0 mg, about 11.0 mg to about 16 mg, about 12.0 mg to about 16.0 mg, about 13.0 mg to about 16.0 mg, or about 14.0 mg to about 16.0 mg.

[0113] In a further aspect of the present disclosure, the once-a-week maintenance dose is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or 16.0 mg.

[0114] In a further aspect of the present disclosure, the once-a-week maintenance dose is about 8.0 mg to about 16.0 mg. In yet a further aspect of the present disclosure, the once-a-week maintenance dose is about 8.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0115] In yet a further aspect of the present disclosure, the once-weekly maintenance dose is from about 10.0 mg to about 16.0 mg. In yet a further aspect of the present disclosure, the once-weekly maintenance dose is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

[0116] In yet a further aspect of the present disclosure, the method or use comprises administering the once-weekly maintenance dose for at least about 4 weeks. In yet a further aspect of the present disclosure, the method or use comprises administering the once-weekly maintenance dose for at least about 6 weeks. In yet a further aspect of the present disclosure, the method or use comprises administering the once-weekly maintenance dose for at least about 8 weeks.

[0117] In yet a further aspect of the present disclosure, the once-weekly escalating dose is from about 1.0 mg to about 6.0 mg. In yet a further aspect of the present disclosure, the once-weekly escalating dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg.

[0118] In yet a further aspect of the present disclosure, a plurality of once-weekly escalating doses are administered to the patient in steps (1) and (2).

[0119] In a preferred aspect of the present disclosure, the first once-weekly escalating dose is from about 1.0 mg to about 6.0 mg. In a further aspect of the present disclosure, the first once-weekly escalating dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg. In a preferred aspect of the present disclosure, the once-weekly escalating dose is about 1.0 mg, about 1.5 mg, about 2.0 mg, or about 3.0 mg.

[0120] In a further preferred embodiment of the present disclosure, the first and each subsequent once-weekly escalating dose is increased in increments of about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, or any combination thereof, and each once-weekly escalating dose is administered for at least about two weeks.

[0121] In a further preferred embodiment of the present disclosure, the final or maximum escalating dose is higher than the maintenance dose. For example, the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof at once-weekly escalating doses of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 10.0 mg is administered to a patient for 3 weeks each. After 3 weeks at the maximum escalating dose of 10 mg, the maintenance dose is reduced to 8 mg.

[0122] In an alternative preferred embodiment of the present 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 compound of about 3.0 mg escalating dose, 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; and b) administering a compound of about 6.5 mg maintenance dose, 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.

[0124] Alternatively preferably, the method or use is (a) administering a compound of about 1.5 mg escalating dose, 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 escalating dose to a compound of about 3.0 mg, or a pharmaceutically acceptable salt thereof, and administering the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks. (c) Optionally, increase the escalating dose to about 4.5 mg of the compound or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) administering a maintenance dose of about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and comprising.

[0125] Alternatively or preferably, the method or use is (a) administering 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, at least about 3 weeks, or at least about 4 weeks, and (b) increasing the escalating dose to about 4.0 mg or about 5.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) administering a maintenance dose of about 6.5 mg of the compound or a pharmaceutically acceptable salt thereof once a week for at least about 2 weeks, at least about 4 weeks, or at least about 8 weeks, and comprising.

[0126] In an alternative preferred embodiment of the present 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 an escalating dose of about 4.0 mg of the compound 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) administering a maintenance dose of about 8.0 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, and comprising.

[0128] Alternatively or preferably, the method or use is (a) Administering a compound, or a pharmaceutically acceptable salt thereof, in a gradually increasing dose of about 1.5 mg once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) increasing the gradually increasing dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) administering a maintenance dose of about 8.0 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, and

[0129] Alternatively or preferably, the method or use is (a) Administering a compound, or a pharmaceutically acceptable salt thereof, in a gradually increasing dose of about 2.0 mg once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) increasing the gradually increasing dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) administering a maintenance dose of about 8.0 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, and

[0130] In an alternative preferred embodiment of the present 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 compound in a gradually increasing dose of about 4.5 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) Administering a compound in a maintenance dose of about 10.0 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, comprising.

[0132] Alternatively or preferably, the method or use is (a) Administering a compound in a gradually 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 gradually increasing dose to a compound of about 3.0 mg, or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to a compound of about 6.0 mg, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increasing the gradually increasing dose to a compound of about 9.0 mg, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, comprising.

[0133] Alternatively or preferably, the method or use is (a) Administering a compound in a gradually increasing dose of about 2.0 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 gradually increasing dose to a compound of about 4.0 mg, or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to a compound of about 6.0 mg, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the escalating dose to about 9.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks.

[0134] Alternatively, preferably, the method or use (a) Administer an escalating dose of about 3.0 mg of the compound, 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, (b) 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, at least about 3 weeks, or at least about 4 weeks, (c) Administer a maintenance dose of about 9.0 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.

[0135] In an alternative preferred embodiment of the present disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 10.0 mg.

[0136] Preferably, the method or use a) Administer an escalating dose of about 5.0 mg of the compound, 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, b) Administer a maintenance dose of 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.

[0137] Alternatively, preferably, the method or use (a) Administer an escalating dose of about 1.5 mg of the compound, 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, (b) Increase the escalating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the escalating dose to about 5.0 mg or 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, at least about 3 weeks, or at least about 4 weeks, (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, at least about 3 weeks, or at least about 4 weeks, (e) Administer a maintenance dose of 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, and include.

[0138] Alternatively, 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, at least about 3 weeks, or at least about 4 weeks, (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, at least about 3 weeks, or at least about 4 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 to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Increase the escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Administer a maintenance dose of 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, and include.

[0139] 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, (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, (c) administering a maintenance dose of about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and comprising.

[0140] In an alternative preferred embodiment of the present 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) administering a compound of increasing dose of about 6.0 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, b) administering a maintenance dose of about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and comprising.

[0142] Alternatively 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, (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, (c) Increase the escalating dose to about 5.0 mg or 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, at least about 3 weeks, or at least about 4 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, at least about 3 weeks, or at least about 4 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, at least about 3 weeks, or at least about 4 weeks, and (f) Administer about 12.0 mg of the maintenance dose 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, including.

[0143] Alternatively or preferably, the method or use is (a) Administer about 2.0 mg of the escalating dose of the compound, 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) 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, at least about 3 weeks, or at least about 4 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 to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 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 to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 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 to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Administering a maintenance dose of about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, is included.

[0144] Alternatively or preferably, the method or use is (a) Administering a titrating dose of about 3.0 mg of the compound, 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, (b) Increasing the titrating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increasing the titrating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Administering a maintenance dose of about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, is included.

[0145] In an alternative preferred embodiment of the present 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 titrating dose of about 1.5 mg of the compound, 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, (b) Increasing the titrating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the escalating dose to about 5.0 mg or 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, at least about 3 weeks, or at least about 4 weeks, and (d) Optionally, 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, at least about 3 weeks, or at least about 4 weeks, and (e) Increase the escalating dose to about 9.0 mg or 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, at least about 3 weeks, or at least about 4 weeks, and (f) Administer a maintenance dose of about 13.0 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, including.

[0147] 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, at least about 3 weeks, or at least about 4 weeks, and (b) Optionally, increase the escalating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) 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, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, increase the escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) Administer a maintenance dose of about 13.0 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, and the method includes.

[0148] Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 3.0 mg of the compound, 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, (b) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increase the escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Administer a maintenance dose of about 13.0 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, and the method includes.

[0149] In an alternative preferred embodiment of the present disclosure, the maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, is 14.0 mg.

[0150] Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 1.5 mg of the compound, 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, (b) Increase the escalating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the escalating dose to about 5.0 mg or 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, at least about 3 weeks, or at least about 4 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, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, 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, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the escalating dose to about 11.0 mg or 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, at least about 3 weeks, or at least about 4 weeks, and (g) Administer a maintenance dose of about 14.0 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, and includes.

[0151] 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, at least about 3 weeks, or at least about 4 weeks, and (b) Optionally, increase the escalating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) 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, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (e) Optionally, increase the escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) Optionally, increase the escalating dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (h) Administering a maintenance dose of about 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and including.

[0152] Alternatively or preferably, the method or use is (a) Administering an escalating dose of about 3.0 mg of the compound, 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 escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the escalating 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 escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the escalating 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 dose to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the dose once a week for at least about 2 weeks, and (e) Administering a maintenance dose of about 14.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, is included.

[0153] In an alternative preferred embodiment of the present 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 titrating dose of about 1.5 mg of the compound, 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, (b) Increasing the titrating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) Increasing the titrating dose to about 5.0 mg or about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) Optionally, increasing the titrating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Increasing the titrating dose to about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) Optionally, increasing the titrating dose to about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the titrating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) Administering a maintenance dose of about 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, is included.

[0155] Alternatively or preferably, the method or use is (a) administering a gradually increasing dose of about 2.0 mg of the compound, 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, (b) optionally increasing the gradually increasing dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) increasing the gradually increasing dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (d) increasing the gradually increasing dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) optionally increasing the gradually increasing dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (f) increasing the gradually increasing dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) optionally increasing the gradually increasing dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (h) administering a maintenance dose of about 15.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, and comprises.

[0156] Alternatively or preferably, the method or use is (a) Administering a compound or a pharmaceutically acceptable salt thereof in a gradually increasing dose of about 3.0 mg once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the gradually increasing dose to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to about 9.0 mg or about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to about 12.0 mg or about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the gradually 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 about 15.0 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, comprising.

[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 or a pharmaceutically acceptable salt thereof in a gradually increasing dose of about 1.5 mg once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (b) Increasing the gradually increasing dose to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the gradually 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 gradually increasing dose to about 5.0 mg or about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the gradually 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 escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalation once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Optionally, increase the escalating dose to about 9.0 or 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, at least about 3 weeks, or at least about 4 weeks, (f) Increase the escalating dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (g) 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, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, including.

[0159] 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, at least about 3 weeks, or at least about 4 weeks, (b) Optionally, increase the escalating dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (c) 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, at least about 3 weeks, or at least about 4 weeks, (d) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, (e) Optionally, increase the escalating dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (f) Increase the escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (g) Optionally, increase the escalating dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (h) 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, at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks, including.

[0160] Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 3.0 mg of the compound, 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) Increase the escalating dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (c) Increase the escalating dose to about 9.0 mg or about 10.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient once a week for at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks, and (d) Increase the escalating dose to about 12.0 mg or about 13.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administer the escalating dose to the patient 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 about 16.0 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, including.

[0161] Alternatively or preferably, the method or use is (a) Administering a gradually increasing dose of about 1.5 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, (b) Increasing the gradually increasing dose to about 3.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (c) Increasing the gradually increasing dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (d) Increasing the gradually increasing dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (e) Increasing the gradually increasing dose to about 12.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (f) Administering a maintenance dose of about 16.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, including.

[0162] Alternatively or preferably, the method or use is (a) Administering a gradually increasing dose of about 2.0 mg of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, (b) Increasing the gradually increasing dose to about 4.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (c) Increasing the gradually increasing dose to about 6.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (d) Increasing the gradually increasing dose to about 8.0 mg of the compound, or a pharmaceutically acceptable salt thereof, and administering the gradually increasing dose once a week for at least about 2 weeks, (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) Increase the escalating dose to about 13.0 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 (g) Administer about 16.0 mg of a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, and

[0163] Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 1.5 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 3.0 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 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 (e) Increase the escalating dose to about 13.0 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 about 16.0 mg of a maintenance dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks, and

[0164] Alternatively or preferably, the method or use is (a) Administer an escalating dose of about 1.5 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 3.0 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 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 about 16.0 mg of the maintenance dose 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 comprises (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 about 16.0 mg of the maintenance dose 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] Even more preferably, the method or use comprises administering each escalating dose once a week for at least about 4 weeks and administering the maintenance dose once a week for at least about 4 weeks.

[0168] Even more preferably, the method or use comprises administering each escalating dose once a week for at least about 4 weeks and administering the 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 meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of GLP-1 / Gcg core agonists, pharmaceutical compositions, and methods, but the preferred methods and materials are described herein.

[0170] Furthermore, references to an element by the indefinite article "a" or "an" do not exclude the possibility of there being more than one element, unless the context clearly requires that there be one and only one element. Thus, the indefinite article "a" or "an" typically means "at least one".

[0171] Definitions As used herein, "about" means within a statistically significant range of a value, such as, for example, a concentration, length, molecular weight, pH, sequence identity, time frame, temperature, or volume as described. Such a value or range can be within a scale typically within 20% of a given value or range, more typically within 10% of a given value or range, and even more typically within 5% of a given value or range. The allowable variation encompassed by "about" depends on the particular system in the study and can be readily understood by one of ordinary skill in the art.

[0172] As used herein, with respect to one or more of the GLP-1 receptor or the Gcg receptor, "active", "activate", "activation", etc. mean 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 measured using assays known in the art.

[0173] As used herein, "amino acid" means, from a chemical perspective, a molecule characterized by containing one or more amine groups and one or more carboxylic acid groups, and may contain other functional groups. As is known in the art, there is a set of 20 amino acids designated as standard amino acids and used as components of most peptides / polypeptides / proteins produced by any organism.

[0174] As used herein, "analog (or analogue)" 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 "doses" means the amount of a GLP-1 / Gcg coagonist for once-weekly dosing administered to an individual in an individual amount at a specific time point. When used in connection with terms such as dose, dosing, doses, etc., "adjustment" means any amount of decrease or increase relative to the dose administered the previous week. When used in connection with terms such as dose, dosing, doses, etc., "regimen" means a series of guidelines for determining and administering one or more doses and / or adjustments thereto.

[0176] As used herein, "effective amount" means an amount, concentration, or dosage of one or more of the GLP-1 / Gcg core agonists herein, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such individual under diagnosis or treatment (i.e., can result in a clinically measurable difference in the condition of the individual, such as, for example, reduction of blood glucose, reduction of HbA1c, reduction of body weight or body fat, and / or change in body composition). An effective amount can be readily determined by one of ordinary skill in the art by use of known techniques and by observing results obtained in similar circumstances. In determining the effective amount for an individual, numerous factors are considered including, but not limited to, mammalian species, its size, age, and general health, the particular disease or disorder involved, the degree, involvement, or severity of the disease or disorder, the individual's response, the GLP-1 / Gcg core agonist administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dosage 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 about 8 hours.

[0178] As used herein, "glycemic control" means the level or reduction of an individual's HbA1c. Similarly, "improving" glycemic control and / or "improved" glycemic control means a decrease in HbA1c. Further, "requiring further glycemic control" means a need for a decrease in HbA1c.

[0179] As used herein, "hemoglobin A1c" or "HbA1c" refers to the level of glycated hemoglobin that occurs when hemoglobin binds to glucose in the blood. HbA1c levels are a commonly used measure of blood glucose control in individuals with diabetes, and a decrease in HbA1c levels generally indicates improved blood glucose control. In the context of the present disclosure, the dosages, regimens, and methods herein result in a decrease in HbA1c. In certain examples, the decrease in HbA1c is relative to the HbA1c levels resulting from existing treatments 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 having structural similarity to each of OXM, GLP-1, and GCG, particularly human OXM, human GLP-1, and human GCG, but having a plurality of differences. The incretin analogs herein include amino acid sequences that result in compounds having affinity for GLP-1 and GCG receptors and activity at 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). Particularly useful 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 wherein Xaa2 is Aib, the Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 CO2H, The C-terminal amino acid is amidated (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof, comprising any protein that is the subject of a regulatory submission for approval of a GLP-1 / Gcg coagonist product, whether or not the party seeking approval of the product has actually identified the incretin analog as a GLP-1 / Gcg coagonist or used some other term, and that depends in whole or in part on data regarding this incretin analog submitted to a regulatory authority by Eli Lilly and Company.

[0181] As used herein, "an individual in need thereof" means a mammal, such as a human, having an abnormality, disease, disorder, or condition that requires treatment or therapy, including, for example, those listed herein. Specifically, the preferred individual to be treated is a human.

[0182] In certain aspects used herein, "titration dose" or "ramping dose" means a dose that is less than the highest desired effective dose for a patient. As used herein, the present disclosure contemplates that a "titration dose" or "ramping dose" may become a "maintenance dose" when the highest desired effective dose, or such a dose is observed to be the desired effective dose for a patient, and such a dose is administered chronically for a period exceeding at least two weeks. Alternatively, in certain aspects used herein, "titration dose" or "ramping dose" means a dose that is higher than the maintenance dose for a patient. This aspect of the present disclosure is particularly useful when the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, is administered, for example, to reduce body weight, treat obesity, or manage body weight. Substantial weight loss can be achieved at the highest dose, and weight loss can be maintained at lower doses.

[0183] As used herein, "maintenance dose" means both the dose that is the highest desired effective dose for a patient and, if such maintenance dose is less than the highest desired effective dose, a maintenance dose that can be a titrated dose, i.e., for a particular patient, if the "about 8 mg" maintenance dose contemplated by the present disclosure is not the highest desired effective dose, that 8 mg maintenance dose will, in hindsight, be a titrated or escalated dose as the dose for that particular patient that will increase until it reaches the next highest dose contemplated by the present disclosure, e.g., 10 mg for at least about two weeks or 12 mg for at least about two weeks. The present disclosure contemplates that patients who reach a maintenance dose of about 12 mg to about 16 mg may need to have their dosage reduced to a lower maintenance dose as determined by a physician or other healthcare provider.

[0184] As used herein, "predicted once-weekly maintenance dose" means the dose of a therapeutic agent, such as a GLP-1 / Gcg coagonist, suitable for once-weekly dosing that is predicted 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, frequency and severity of hypoglycemia and other AEs, and / or BW.

[0185] As used herein, "obese" or "obesity" means, with respect to an individual, an individual having a BMI of 30 kg / m 2 or greater.

[0186] As used herein, "overweight" means, with respect to an individual, an individual having a BMI of 27 kg / m 2 or greater but less than 30 kg / m 2 or less.

[0187] As used herein, "treating", "treatment", "to treat", etc. mean suppressing, delaying, halting, or reversing 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, particularly an analog having balanced and sufficient activity at each receptor to provide the advantages of receptor agonism while avoiding undesirable side effects associated with overactivity of those receptors. Further, an incretin analog having dual receptor agonist activity has a long-lasting action at each of the GLP-1 and GCG receptors, which advantageously enables dosing at a low frequency 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 change 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. The GLP-1 / Gcg coagonist can be produced synthetically (see, e.g., International Patent Application Publication No. 2016 / 209707 (A1)). Formulations for GLP-1 / Gcg coagonists that can be used herein are disclosed in International Patent Application No. PCT / US2021 / 064592.

[0191] In some examples, the compositions herein are formulated to contain a GLP-1 / Gcg core agonist in a dose of from about 1.5 mg to about 16.0 mg. In other examples, the dose of the GLP-1 / Gcg core agonist can be about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 6.0 mg, about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 10.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg. The compositions herein can be administered intravenously (IV), intramuscularly (IM), or subcutaneously (SC), particularly SC. The composition may be lyophilized and then reconstituted for delivery, or provided as a solution formulation for administration using a prefilled disposable pen, a reusable pen, or an auto-injector pen. Alternatively, the composition can be administered using a multi-dose vial or a pump device. In some examples, the device is an auto-injector device as described in U.S. Patent No. 8,734,394.

[0192] Accordingly, the compositions herein may be provided in prefilled syringes / multi-dose vials. Such prefilled syringes / multi-dose vials may be useful for administering from about 0.5 mL to about 2.0 mL of the composition per dose per patient. The dose of the composition can be administered using a dosing schedule determined by a clinician, physician, or other trained medical professional.

[0193] Alternatively, the composition can be prepared for use in a cartridge and will thus differ from the above compositions by including a preservative.

[0194] Alternatively, the composition can be prepared as part of a product that contains the composition, and the product can be a multi-dose vial, a reusable pen injector, a prefilled disposable pen, an auto-injector, or a pump.

[0195] In view of the above, the compositions of the present specification are related to acceptable storage life stability, in-use stability, and acceptable injection site experience.

[0196] Methods of treatment and medical uses The dosing regimens of the GLP-1 / Gcg core agonists described herein are suitable for providing chronic weight management. The dosing regimens of the GLP-1 / Gcg core agonists described herein are also suitable for improving glycemic control (e.g., as measured by glucose level, HbA1c, and / or fructosamine). The dosing regimens of the GLP-1 / Gcg core agonists described herein are also suitable for reducing LDL cholesterol and / or triglycerides.

[0197] The dosing regimens of the GLP-1 / Gcg core agonists described herein may be suitable for the prevention or treatment of type 2 diabetes, the prevention or treatment of hyperglycemia, the prevention of insulin-independent diabetes, the prevention or treatment of obesity, the reduction of body weight and / or food intake, the prevention or treatment of dyslipidemia, the prevention or treatment of non-alcoholic fatty liver disease (NAFLD), the prevention or treatment of non-alcoholic steatohepatitis (NASH), atherosclerosis, obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, chronic kidney disease, and the prevention or treatment of diabetic kidney disease, including but not limited to these. It is also 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 subject being treated.

[0198] In addition, the dosing regimens of the GLP-1 / Gcg core agonists described herein are as follows: treatment of obesity, control of appetite, reduction of calorie intake, reduction of food intake, suppression of appetite, 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 that are 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 the progression of diabetes, improvement of diabetes, delay of the onset of diabetes, induction of beta-cell preservation and restoration of beta-cell function, restoration of normoglycemia, provision of normoglycemic 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), treatment or prevention of metabolic syndrome.

[0199] In preferred embodiments, the dosing regimens of the GLP-1 / Gcg core agonists described herein are as follows: 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 dosing regimens of the GLP-1 / Gcg core agonists described herein are suitable for preventing 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 events (MACE), obstructive sleep apnea, osteoarthritis, polycystic ovary syndrome, or chronic kidney disease.

[0200] The following non-limiting examples are provided for illustrative purposes only and not for purposes of limitation.

Example

[0201] Example 1: Clinical Study Overview This trial is a Phase 1, single-site, patient and investigator blinded, placebo-controlled, randomized, non-cross-over, repeated dose escalation study with titration in each cohort in patients with T2DM to investigate the safety, tolerability, PK, and PD of the GLP-1 / glucagon core agonist peptide (Compound 1) of SEQ ID NO:1 administered as multiple SC injections QW for 12 weeks in Cohort 1 and 16 weeks in Cohort 2.

[0202] Study Population The investigator registered participants with T2DM in this trial for at least 6 months prior to screening.

[0203] Inclusion The following patients were considered eligible to participate in the trial. - Otherwise generally healthy and without known secondary diseases with a potential for diabetes. - Having a glycated hemoglobin (HbA1c) value at screening of 7.0% or more and 10.5% or less and treated with diet and exercise alone or stable-dose metformin for at least 3 months prior to Screening / Visit 1.

[0204] Exclusion The following patients were considered ineligible to participate in the trial. - Having type 1 diabetes or latent autoimmune diabetes in adults. - Having poorly controlled diabetes defined as an episode of ketoacidosis or hyperosmolar state requiring hospitalization within 6 months prior to screening. - Having had an episode of severe hypoglycemia or having a history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms.

[0205] Treatment Two planned dosing regimens of Compound 1 are investigated in this study via once-weekly administration by SC injection in Week 1. The study is patient- and responsible physician-blinded. To maintain the blinding of the study for Compound 1 and placebo, all study site staff except the pharmacy staff who prepare and dispense the investigational drug are blinded to the treatment assignment. The blinding of Compound 1 and placebo is maintained throughout the conduct of the study until all data are evaluated to an acceptable level of quality and locked.

[0206] The first dosing regimen (also referred to as Cohort 1) has a duration of 12 weeks and requires dose increments of 1.5 mg starting from 1.5 mg. - Compound 1 at 1.5 mg QW 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 dosing regimen (also referred to as Cohort 2) has a duration of 16 weeks and requires dose increments of 2 mg starting from 2 mg. - Compound 1 at 2 mg QW for 3 weeks, - Compound 1 at 4 mg QW for 3 weeks, - Compound 1 at 6 mg QW for 3 weeks, - Compound 1 at 8 mg QW for 3 weeks, and - Compound 1 at 10 mg QW for 4 weeks.

[0208] For the second dosing regimen, the dose to 10 mg Qw can only proceed if the patient first tolerates the titration steps of 3 doses at 4 mg QW, 3 doses at 6 mg QW, and then 3 doses at 8 mg QW.

[0209] For each dosing regimen, Compound 1 is administered SC to the patient's abdomen after an overnight fast of at least 8 hours.

[0210] Informed consent was obtained, and of the 82 patients screened in the trial, 24 were randomly assigned and received at least one dose of the study intervention. As shown in Figure 1, a total of 23 patients completed the trial.

[0211] Dose modification The dose level or increment, sampling schedule, and length of stay in the clinical research unit (CRU) can be adjusted in consideration of the safety, tolerability, or PK data that emerge during the trial. Specifically, accordingly, the dose increment within a cohort can be reduced (but not increased), or lower doses can be administered.

[0212] The actual dose, increment, and / or dosing period within each cohort at each dose level can be adjusted in consideration of the emerging safety, tolerability, or PK data. Due to the nature of the repeated dose escalation trial involving dose titration, the data will be continuously evaluated until the MTD is determined or the stopping criteria are met.

[0213] Safety data will be the main criterion for dose escalation titration. Dose escalation titration within a cohort cannot be carried out without prior discussion and agreement between the responsible physician and the designated clinical pharmacologist. All safety and available pharmacokinetic (PK) and pharmacodynamic (PD) data one week prior to the dose will be used to support the dose within a cohort. All safety and available PK and PD data up to week 11 will be used to support the dose between cohorts 1 and 2.

[0214] After consideration of these data, dose escalation titration within a cohort to the next dose level will be carried out by the principal investigator and the sponsor of the clinical trial. Half of the patients in any cohort If unable to tolerate dose titration, the dose increment can be halved, and dose escalation titration will be carried out every two weeks.

[0215] In any cohort, if any of the following stopping criteria occur, dosing at the current level and further dose escalation titration within both cohorts will be discontinued. - One SAE occurred under one treatment (unless it is due to the expected pharmacology of Compound 1 [e.g., hypoglycemia]) or two clinically significant events (CSEs) that may be related to Compound 1 are reported, or - More than 40% of the subjects at a dose level experience symptomatic hypoglycemic episodes with plasma glucose levels ≤ 2.8 mmol / L (50 mg / dL, corresponding to plasma glucose [PG] levels ≤ 3.1 mmol / L [56 mg / dL]), and these events are 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 with "severe" non-serious adverse reactions probably related to the investigational drug, regardless of whether they are within the same major organ classification.

[0216] If any of these three scenarios occur, dosing will be interrupted and will only be resumed if approved by the responsible physician or a suitable designee.

[0217] Study evaluation The relevant study procedures and their timings are summarized below.

[0218] Body weight For Cohort 1, body weight is 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 is 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] Throughout the trial, use the same scale for all weight measurements and do not move or recalibrate the scale if possible. Subjects are weighed lightly, at approximately the same time in the morning, before dosing (on Day 1 only), after an overnight fast, and after defecation and urination if possible. During the treatment period, weight is measured twice at each scheduled opportunity, and the subject steps off the scale between measurements. The average of the two weight measurements is recorded in the source document.

[0221] Abdominal circumference For Cohort 1, abdominal circumference is measured at baseline and on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

[0222] For Cohort 2, abdominal circumference is measured at baseline and on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, and 109.

[0223] Abdominal circumference is measured at the midpoint between the lower edge of the most palpable rib and the upper part of the iliac crest. The patient should stand with feet closed, arms at the sides, weight evenly distributed, and lightly clothed. The patient should be relaxed, and the measurement should be taken at the end of normal exhalation. During screening, baseline, the treatment period, and follow-up, abdominal circumference will be measured twice at each scheduled opportunity. The average of the two measurements will be recorded in the source document.

[0224] Pharmacokinetics (PK) To determine the plasma concentration of Compound 1, approximately 3 mL of venous blood samples are taken. If agreed upon between both the responsible physician and the sponsor, up to two additional samples may be taken at additional time points during the trial. The actual date and time (24-hour time) of each sampling, as well as the date and time of each dose of Compound 1, are recorded.

[0225] Drug concentration information that could unblind the study is not reported to the investigational site or the blinded personnel until the study is unblinded.

[0226] For cohort 1, PK sampling is 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 is performed on day 1 (12 hours after administration of compound 1), day 2, (48 hours after administration of compound 1), 72 (hours after administration of compound 1), day 8, day 22, day 24 (48 hours after administration of compound 1), day 36, day 43, day 45 (48 hours after administration of compound 1), day 64, day 66 (48 hours after administration of compound 1), day 85, day 87 (48 hours after administration of compound 1), day 92, day 99, day 106 (12 hours after administration of compound 1), day 107 (24 hours after administration of compound 1), day 108 (48 hours after administration of compound 1), and day 109 (72 hours after administration of compound 1).

[0228] HbA1c For cohort 1, HbA1c levels are determined at baseline, and on day 1, day 29, day 57, and day 78. For cohort 2, HbA1c is measured at baseline, and on day 1, day 22, day 43, day 64, day 85, and day 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, native OXM, lipid panel (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), beta-cell function, and homeostatic model assessment (HOMA) index.

[0230] The plasma concentrations of at least glucose, glucagon, insulin, C-peptide, and native OXM are assayed using validated analytical methods.

[0231] Samples are identified by patient number (coded) and stored for up to 1 year after the last patient visit for the study.

[0232] For cohort 1, PD sampling is performed at baseline, and on days 1, 3 (48 hours after dosing of compound 1), 8, 22, 29, 50, 57, 78, and 80.

[0233] For cohort 2, PD sampling is performed at baseline, and on days 1, 3 (48 hours after dosing of compound 1), 8, 22, 43, 64, 85, 106, and 108.

[0234] Mixed meal tolerance test (MMTT) For cohort 1, MMTT is performed at baseline and day 80. For cohort 2, MMTT is performed at baseline and day 108.

[0235] Patients are provided with breakfast for the MMTT. Upon waking, patients hydrate by consuming water to reduce 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 main nutrient composition of the meal is targeted to provide approximately 50% of calories from carbohydrates, 30% of calories from fat, and 20% of calories from protein. Patients are fasted (except for water) for at least 8 hours prior to each test meal and consume each meal within approximately 20 minutes. The test meals for each patient are consistent with respect to calorie and nutrient content over all MMTT evaluations in the study.

[0236] For both parts of the study, patients are not permitted to consume water (except for fluids provided with meals) until approximately 3 hours after the MMTT until BOD POD® measurement.

[0237] While residing in the CRU, patients may not consume any food or caloric beverages other than those provided by the CRU. When not residing in the CRU, patients may resume their regular diet. Record the actual times of meal start and completion, total calories, and the amount (%) of the meal consumed in the MMTT.

[0238] Appetite Analysis To investigate the effect of Compound 1 on food intake and appetite sensation, subjects were asked to evaluate their appetite sensation using a 100-mm visual analogue scale (VAS) for parameters of hunger, fullness, satisfaction, and expected food intake in the fasting state during hospitalization and at scheduled outpatient visits. The VAS is a validated tool for evaluating appetite sensation parameters (Flint et al., Int J Obes Relat Metab Disord., 2000;24(1):38-48). The VAS is presented as a 10-cm (100-mm) line fixed by verbal descriptors, usually "extremely" and "not at all". Subjects were required to evaluate their subjective sensations on four 100-mm scales combined with questions similar to the following. - "How hungry do you feel?" - "How satisfied do you feel?" - "How full do you feel?" - "How much do you think you could eat?" The overall appetite score is calculated as the average of the 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, and a lower score indicates more appetite.

[0239] For cohort 1, the satisfaction VAS (post-fasting) is completed at baseline, and on days 1, 29, 57, 78, and 80.

[0240] For cohort 1, the satisfaction VAS (post-fasting) is completed at baseline, and on days 1, 22, 43, 64, 85, 106, and 108.

[0241] When the satisfaction VAS assessment coincides with the MMTT, it is performed before eating and 1 hour 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. Delayed gastric emptying is reflected in modifications to the acetaminophen concentration-time profile, specifically decreasing its Cmax and increasing the time to the observed maximum drug concentration (tmax) without modifying the extent of absorption (total amount of drug). 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. For determination of the plasma concentration of acetaminophen, approximately 2 mL of venous blood samples are taken from each. The concentration of acetaminophen is assayed using a validated LC / MS method. Bioanalytical samples taken for measuring acetaminophen concentration are retained for up to 2 years after the last patient visit for the study.

[0243] For cohort 1, gastric emptying is evaluated at baseline, and on days 2 and 79.

[0244] For cohort 2, gastric emptying is evaluated at baseline, and on days 2 and 107.

[0245] Adverse event (AE) The responsible physician is responsible for monitoring the safety of patients participating in this trial. The responsible physician is responsible for the appropriate medical care of patients during the trial. The responsible physician documents the review of each laboratory safety report. The responsible physician still has the following responsibilities through appropriate medical options.

[0246] An AE that is severe or otherwise medically important, is considered related to compound 1 or the trial, or leads to discontinuation of compound 1 in a patient before completion of the trial. The patient is followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up evaluation of the AE is left to the discretion of the responsible physician.

[0247] The responsible physician records all relevant AE and SAE information. After obtaining consent from the patient, the trial facility staff records the occurrence and nature of each patient's existing condition, including clinically significant signs and symptoms of the disease under treatment in the trial. Additionally, the facility staff records any change in condition, as well as the occurrence and nature of any AE.

[0248] The responsible physician interprets and documents whether an AE has a reasonable possibility of being related to the investigational treatment or procedure, taking into account the disease, concomitant therapy, or pathology.

[0249] "Reasonable possibility" means that there is a potential causal relationship between Compound 1, the test device, and / or the test procedure and the AE. A planned surgery should not be reported as an AE unless the underlying medical condition has deteriorated during the course of the trial.

[0250] A Serious Adverse Event (SAE) is any AE from this trial that results in one of the following. - Death - Initial or prolonged hospitalization - Life-threatening experience (i.e., imminent risk of death) - Persistent or significant disability / incapacity - Congenital anomaly / birth defect - An important medical event that is not immediately life-threatening but may result in death or hospitalization, may place the patient at risk, or may require intervention to prevent one of the other outcomes listed in the above definition.

[0251] Record all AEs that occur after signing the ICF and evaluate them against the severity criteria.

[0252] Laboratory Tests For cohort 1, samples for clinical laboratory tests are taken at baseline and on days 1, 15, 29, 43, 57, and 78.

[0253] For cohort 2, samples for the clinical laboratory tests are taken at baseline and on days 1, 22, 43, 64, 85, and 106.

[0254] Results Demographics and other baseline characteristics The baseline characteristics of the patients with type 2 diabetes are shown in Table 1. A total of 24 patients, 21 males and 3 females, aged between 40 and 68 years, participated in this study.

[0255] [Table 1]

[0256] Combination and post-intervention therapies The current diabetes treatments during the study are summarized in Table 2.

[0257] [Table 2] Abbreviation: n = number of patients.

[0258] Body weight The average change in body weight from baseline is shown in Figure 2. The average change in body weight from baseline was in the range of -2.30 kg to -11.24 kg for Compound 1, while it was in the range of -0.35 kg to -2.03 kg for placebo. During the dosing period of multiple doses of Compound 1, a decrease in average body weight was observed in all treatment groups at each time point evaluated. The trend of body weight loss seems to be dose-dependent, and the average change in body weight from baseline was observed at the end of the treatment period as follows. - Placebo: -0.34 kg on day 78 - Cohort 1: -2.88 kg on day 78 - Cohort 2: -10.73 kg 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 dosing period of multiple doses of Compound 1. As shown in Table 3, a decrease in fat mass and an increase in fat-free body weight 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 of Compound 1 and the corresponding between-subject variability.

[0263]

Table 4

[0264] Model predicted mean (CV%) maximum steady-state concentration (C max,ss ) and mean (CV%) steady-state concentration-time curve under the area [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

[0266] Glucose control - HbA1c The change in HbA1c from baseline is shown in Table 4. During the 12 - 16 weeks of dosing, the mean HbA1c level decreased from baseline in all treatment groups, including placebo, after day 29 (week 5). A statistically significant decrease from baseline in the mean HbA1c was observed in the treatment groups of both Cohort 1 and Cohort 2, starting on day 57 and continuing until day 134, when compared to placebo.

[0267] Based on the mean, the HbA1c level remained decreased from baseline for all treatment groups on day 106 (i.e., 28 days after the last dose in Test Intervention Cohort 1).

[0268]

Table 6

[0269] Glucose control - fasting glucose At baseline, fasting glucose measurements were similar between the treatment and placebo groups. Over the dosing period with multiple doses of Compound 1, the mean fasting glucose level 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 106 - day (16 - week) treatment period.

[0270] Insulin sensitivity - fasting insulin At baseline, fasting insulin measurements are similar for the low-dose cohort and the placebo group. However, the baseline fasting insulin level of the high-dose cohort is much lower. Figure 5 shows an increase in fasting insulin level observed in cohort 1, while a moderate decrease in fasting insulin level is observed in cohort 2, indicating a pattern consistent with improved insulin sensitivity.

[0271] Insulin sensitivity - fasting C-peptide Changes from baseline in fasting c-peptide levels are shown in Figure 6. At baseline, fasting c-peptide measurements are similar between the treatment and placebo groups. Over the dosing period 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 on day 106 in cohort 2 and continued until day 108, which is a pattern consistent with improved insulin sensitivity.

[0272] Mixed meal tolerance test Table 6 shows changes from baseline in the AUC(0 - 3 hours) of C-peptide, glucagon, glucose, insulin, and oxyntomodulin during the MMTT.

[0273]

Table 7

[0274] Table 7 shows changes from baseline in beta cell function and insulin sensitivity parameters derived from the MMTT.

[0275]

Table 8

[0276] (i) Glucose AUC(0 - 3) hours Over the dosing period with multiple doses of Compound 1, the mean AUC(0 - 3 hours) of glucose, determined by MMTT, decreased from baseline in all treatment groups. When compared to placebo, in cohort 2, the greatest decrease from baseline was observed at the end of the 108-day (16-week) treatment period. (ii) Insulin and C-peptide AUC(0 - 3 hours) Over the 12-week dosing period with multiple doses of Compound 1, the mean AUC(0 - 3 hours) of C-peptide and insulin, determined by MMTT, increased from the mean baseline level in cohort 1. When compared to placebo, in cohort 1, the greatest increase from baseline in the mean AUC(0 - 3 hours) of C-peptide was observed at the end of the 80-day (12-week) treatment period. Over the 16-week dosing period with multiple doses of Compound 1, the mean AUC(0 - 3 hours) of C-peptide and insulin, determined by MMTT, decreased from the mean baseline level in cohort 2. (iii) Beta cell function Over the dosing period 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 (12 weeks). (iv) Glucagon AUC(0 - 3 hours) Over the dosing period 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 at the end of the treatment period on Day 108 (Week 16) in Cohort 2. (v) Insulin sensitivity parameters Over the dosing period with multiple doses of Compound 1, the mean HOMA2-IR index decreased from baseline and the mean Matsuda insulin sensitivity index value increased from baseline in all treatment groups. In Cohort 1, glucose, insulin, and c-peptide excursions increased during sMMTT and were similar to the patterns seen with GLP-1R monoagonist and insulin secretagogue therapies.

[0277] Lipids - cholesterol, HDL, LDL, and triglycerides As shown in Figure 7a, the mean fasting cholesterol level decreased from baseline in both treatment groups over the course of the dosing period. Similarly, as shown in Figure 7b, the Compound 1 Cohort 2 dose substantially reduced the sMMTT total cholesterol level.

[0278] As shown in Figures 7c and 7d, the mean fasting HDL and LDL levels decreased from baseline in Cohort 2 over the course of the dosing period. Similarly, as shown in Figures 7e and 7f, the Compound 1 Cohort 2 dose substantially reduces the sMMTT LDL cholesterol level and the sMMTT HDL cholesterol level.

[0279] As shown in Figure 7g, the mean fasting triglyceride level decreased from baseline in both treatment groups over the course of the dosing period. Similarly, as shown in Figure 7h, the Compound 1 Cohort 2 dose substantially reduces the sMMTT triglyceride level.

[0280] Gastric emptying The PK parameters of acetaminophen were compared between treatment groups to determine the rate and extent of gastric emptying. A primary analysis of acetaminophen Cmax and Tmax is provided in Table 8. The PK profile of acetaminophen on day -1, prior to dosing with Compound 1, was similar between treatment groups. Within the treatment groups, the C max of acetaminophen decreased from day -1 during 12 weeks of multiple dosing with Compound 1. The Cmax of acetaminophen was lowest on day 2 in both treatment groups. However, the change in baseline C max of acetaminophen increased on day 107. The median t max of acetaminophen was equivalent between treatment groups and over time.

[0281] [Table 9] Abbreviations: C max = observed maximum drug concentration, NC = not calculated, t max = time to observed maximum drug concentration.

[0282] Appetite analysis A summary of appetite sensation data across all time points is shown in Figure 8. The VAS appetite assessment showed a reduction in hunger, an increase in satiety, and a decrease in overall appetite (higher overall score) in the higher dose cohort. (i) Overall appetite score During multiple dosing with Compound 1, the overall appetite score generally increased from baseline in all treatment groups, including placebo, over the 12 - or 16 - week dosing period. (ii) Hunger Over the dosing period with multiple doses of Compound 1, the hunger score decreased from baseline at most of the time points evaluated in both treatment groups, including placebo. (iii) Satiety Over the dosing period with multiple doses of Compound 1, the satiety score decreased from baseline in both treatment groups. The satiety score of patients in the placebo group increased from baseline on day 80. (iv) Satiety Over the dosing period with multiple doses of Compound 1, the satiety scores increased from baseline in both treatment groups. The satiety scores of patients in the placebo group decreased from baseline on day 80. The largest increase from baseline in the satiety scores was observed in Cohort 1.

[0283] Pharmacodynamic evaluation of differences when the dose is increased gradually Fasting glucose Patients in Cohort 1 had a mean baseline fasting plasma glucose of 10.78 mmol / L. When the dose of Compound 1 was increased gradually to 4.5 mg, the mean fasting glucose decreased to 6.52 mmol / L on day 80, resulting in an approximate reduction of 40%.

[0284] Patients in Cohort 2 had a mean baseline fasting glucose of 10.46 mmol / L. When the dose of Compound 1 was increased gradually to 10.0 mg, the mean fasting glucose decreased to 5.91 mmol / L on day 108, resulting in an approximate reduction of 43%.

[0285] Fasting insulin Patients in Cohort 1 had a mean baseline fasting plasma insulin level of 9.648 mIU / L. When the dose of Compound 1 was increased gradually 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, resulting in an approximate increase of 38 - 46% from baseline.

[0286] Patients in Cohort 2 have a mean fasting baseline insulin level of 5.892 mIU / L. As the dose of Compound 1 is gradually increased to 6.0 mg, the mean fasting insulin level increases to 6.73 mIU / L, resulting in an approximate increase of 14% from the baseline. As the dose of Compound 1 is gradually increased to 8.0 mg, the mean fasting insulin level is 6.589 mIU / L, an approximate increase of 12% from the baseline. As the dose of Compound 1 is gradually increased to 10.0 mg, the mean fasting insulin level decreases to 5.355 mIU / L on day 106 and 4.74 mIU / L on day 108, resulting in an approximate decrease of fasting insulin of 20% from the baseline. This data indicates that at doses of Compound 1 above 8.0 mg, fasting plasma glucose can be reduced without increasing the fasting insulin level, consistent with a reduction in insulin resistance.

[0287] C-Peptide Patients in Cohort 1 have a mean fasting baseline plasma C-peptide level of 667 pmol / L. As the dose of Compound 1 is gradually increased to 4.5 mg, the mean fasting C-peptide level increases to 820.2 pmol / L on day 78 and 874.9 pmol / L on day 80, resulting in an approximate increase of 22 - 31% from the baseline.

[0288] Patients in cohort 2 have a mean fasting baseline C-peptide level of 532.8 pmol / L. As the dose of compound 1 is gradually increased to 6.0 mg, the mean fasting C-peptide level increases to 596.6 pmol / L, resulting in an approximate increase of 12% from baseline. As the dose of compound 1 is gradually increased to 8.0 mg, the mean fasting C-peptide level only slightly increases to 541.7 pmol / L from baseline (about 2%). As the dose of compound 1 is gradually increased to 10.0 mg, the mean fasting C-peptide level decreases to 511.1 pmol / L on day 106 and to 435.4 pmol / L on day 108, resulting in an approximate decrease of fasting C-peptide level of 18% from baseline. This data indicates that at doses of compound 1 above 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 of pancreatic beta cells.

[0289] Fasting glucagon Patients in cohort 1 have a mean fasting baseline plasma glucagon level of 14.79 pmol / L. As the dose of compound 1 is gradually increased to 4.5 mg, the mean fasting glucagon level decreases to 6.65 pmol / L on day 78 and to 8.19 pmol / L on day 80, resulting in an approximate decrease of 45 - 55% from baseline.

[0290] Patients in Cohort 2 have an average fasting baseline glucagon level of 9.83 pmol / L. As the dose of Compound 1 is gradually increased to 6.0 mg, the average fasting glucagon level decreases to 3.65 pmol / L, resulting in an approximate decrease of 63% from the baseline. When the dose of Compound 1 is gradually increased to 8.0 mg, the average fasting glucagon level decreases to 2 pmol / L from the baseline on day 80. When the dose of Compound 1 is gradually increased to 10.0 mg, the average fasting glucagon level decreases to 1.98 pmol / L from the baseline on day 106 and to 1.93 pmol / L from the baseline on day 108. This data indicates that at doses of Compound 1 above 6.0 mg, fasting plasma glucagon can be reduced by approximately 80%.

[0291] Fasting total cholesterol Patients in Cohort 1 have an average fasting total cholesterol level of 5.065 mmol / L. As the dose of Compound 1 is gradually increased to 4.5 mg, the average fasting total cholesterol level decreases to 4.275 mmol / L on day 78 and to 4.461 mmol / L on day 80, resulting in an approximate decrease of 12 - 16% from the baseline.

[0292] Patients in Cohort 2 have an average fasting baseline total cholesterol level of 4.971 mmol / L. As the dose of Compound 1 is gradually increased to 6.0 mg, the average fasting total cholesterol level decreases to 3.673 mmol / L on day 64, resulting in an approximate decrease of 26% from the baseline. When the dose of Compound 1 is gradually increased to 8.0 mg, the average fasting total cholesterol level decreases to 3.614 mmol / L (approximately 27%) from the baseline on day 85. When the dose of Compound 1 is gradually increased to 10.0 mg, the average total cholesterol level decreases to 3.454 mmol / L on day 106 and to 3.441 mmol / L on day 108, resulting in an approximate decrease of 31% in the fasting total cholesterol level from the baseline. This data indicates that at doses of Compound 1 above 8.0 mg, the fasting total cholesterol level can be reduced by 30%.

[0293] Fasting LDL cholesterol Patients in cohort 1 have a mean fasting LDL cholesterol level of 2.852 mmol / L. As the dose of compound 1 is gradually increased to 4.5 mg, the mean fasting LDL cholesterol level decreases to 2.56 mmol / L on day 78 and on day 80, resulting in an approximate decrease from the 10% baseline.

[0294] Patients in cohort 2 have a mean fasting baseline LDL cholesterol level of 2.796 mmol / L. As the dose of compound 1 is gradually increased to 6.0 mg, the mean fasting LDL cholesterol level decreases to 1.997 mmol / L on day 64, resulting in an approximate decrease of 29% from the baseline. As the dose of compound 1 is gradually increased to 8.0 mg, the mean fasting LDL cholesterol level decreases to 1.954 mmol / L (approx. 30%) from the baseline on day 85. As the dose of compound 1 is gradually increased to 10.0 mg, the mean fasting LDL cholesterol level decreases to 1.859 mmol / L on day 106 and to 1.849 mmol / L on day 108, resulting in an approximate decrease in fasting LDL cholesterol level of 33 - 34% from the baseline. This data indicates that at a dose of compound 1 of 8.0 mg or more, the fasting LDL cholesterol level can be reduced by 30% or more.

[0295] Fasting triglyceride Patients in cohort 1 have a mean fasting triglyceride level of 2.938 mmol / L. As the dose of compound 1 is gradually increased to 4.5 mg, the mean fasting triglyceride level decreases to 1.456 mmol / L on day 78 and to 2.084 mmol / L on day 80, resulting in an approximate decrease of 29 - 50% from the baseline.

[0296] Patients in cohort 2 have an average fasting baseline triglyceride level of 1.867 mmol / L. As the dose of compound 1 is gradually increased to 6.0 mg, the average fasting triglyceride level decreases to 1.055 mmol / L on day 64, resulting in an approximate decrease from the baseline of 43%. As the dose of compound 1 is gradually increased to 8.0 mg, the average fasting triglyceride level decreases from the baseline to 0.855 mmol / L on day 85 (approximately 54%). As the dose of compound 1 is gradually increased to 10.0 mg, the average fasting triglyceride level decreases to 0.86 mmol / L on day 106 and to 0.985 mmol / L on day 108, resulting in an approximate decrease in fasting triglyceride levels from the baseline of 47 - 54%. This data indicates that at doses of compound 1 above 6.0 mg, fasting triglyceride levels can be reduced by more than 50%.

[0297] Body weight Patients in cohort 1 have an average baseline weight of 97.19 kg. The dose of LY was gradually increased to 4.5 mg, and the average weight decreased to 94.0 kg on day 78 with an average percent change from the baseline of -3.03%.

[0298] Patients in cohort 2 have an average baseline weight of 94.9 kg. As the dose of compound 1 is gradually increased to 4.0 mg, the average weight decreases to 90.38 kg on day 43 with an average percent change from the baseline of -4.04%. As the dose of compound 1 is gradually increased to 6.0 mg, the average weight decreases to 87.69 kg on day 64 with an average percent change from the baseline of -7.07%. As the dose of compound 1 is gradually increased to 8.0 mg, the average weight decreases to 85.88 kg on day 85 with an average percent change from the baseline of -9.05%. As the dose of compound 1 is gradually increased to 10 mg, the average weight decreases to 82.55 kg on day 109 with an average percent change from the baseline of -12.71%.

[0299] Body weight remained decreased from baseline after 16 weeks of compound 1 dosing and at the end of dosing. On day 134, the mean body weight of the compound 1 group in cohort 2 was 84.05 kg with a mean percent change from baseline of -11.14%. On day 162, the mean body weight of the compound 1 group in the second cohort was 88.96 kg with a mean percent change from baseline of -6.56%. These results indicate that a dose of compound 1 above 6 mg can result in a body weight reduction of more than 9%. Furthermore, a dose of compound 1 of 10 mg or more can reduce body weight by up to 12%.

[0300] Waist circumference Patients in cohort 1 had a mean baseline waist circumference of 108.66 cm. As the dose of LY increased gradually to 4.5 mg, the mean waist circumference decreased to 105.66 cm on day 78, an approximate 3% reduction from baseline.

[0301] Patients in cohort 2 had a mean baseline waist circumference of 106.93 cm. As the dose of compound 1 increased gradually to 4.0 mg, the mean waist circumference decreased to 103.38 cm on day 43, an approximate 3% reduction from baseline. As the dose of compound 1 increased gradually to 6.0 mg, the mean waist circumference decreased to 101.31 cm on day 64, an approximate 5% reduction from baseline. As the dose of compound 1 increased gradually to 8.0 mg, the mean waist circumference decreased to 98.58 cm on day 85, an approximate 8% reduction from baseline. As the dose of compound 1 increased gradually to 10 mg, the mean waist circumference decreased to 96.56 cm on day 109, an approximate 10% reduction from baseline.

[0302] The abdominal circumference remained decreased from the baseline after 16 weeks of LY dosage and the end of administration. On the 134th day, the average abdominal circumference of the compound 1 group in the second cohort was 97.59 cm, which was approximately a 9% reduction from the baseline. On the 162nd day, the average abdominal circumference of the compound 1 group in the second cohort was 102.79 cm, which was approximately a 4% reduction from the baseline. This data indicates that a compound 1 dosage greater than 6.0 mg can bring about an improvement in body composition with a reduction in abdominal circumference greater than 5%.

[0303] Fasting insulin resistance Patients in cohort 1 had an average fasting insulin resistance HOMA-IR index of 4.704. As the dosage of compound 1 gradually increased to 4.5 mg, the average HOMA-IR index decreased to 4.289 on the 78th day and to 4.271 on the 80th day, resulting in an approximate reduction of 9% from the baseline.

[0304] Patients in cohort 2 had an average fasting insulin resistance HOMA-IR index of 2.7. As the dosage of compound 1 gradually increased to 6.0 mg, the average HOMA-IR index decreased to 2.158 on the 64th day, resulting in an approximate reduction of 20% from the baseline. As the dosage of compound 1 gradually increased to 8.0 mg, the average HOMA-IR index decreased to 1.976 on the 85th day from the baseline (approximately 27%). As the dosage of compound 1 gradually increased to 10.0 mg, the average HOMA-IR index decreased to 1.325 on the 108th day, resulting in an approximate reduction of 51% in HOMA-IR from the baseline. This data indicates that with a dosage of compound 1 exceeding 6.0 mg, fasting insulin resistance can be reduced by more than 25%. With a dosage of compound 1 of 10 mg or more, the fasting insulin resistance index can be reduced by 50%.

[0305] Fasting pancreatic beta cells Patients in Cohort 1 have an average fasting pancreatic beta cell HOMA-B index of insulin secretion of 15.791. As the dose of Compound 1 was gradually increased to 4.5 mg, the average HOMA-B index increased to 38.762 on day 80, resulting in an approximate increase of 145% from the baseline.

[0306] Patients in Cohort 2 have an average fasting pancreatic beta cell HOMA-B index of insulin secretion of 9.108. As the dose of Compound 1 was gradually increased to 6.0 mg, the average HOMA-B index increased to 16.072 on day 64 from the baseline, resulting in an approximate increase of 76%. As the dose of Compound 1 was gradually increased to 8.0 mg, the average HOMA-B index increased to 16.689 on day 85 from the baseline (approx. 83%). As the dose of Compound 1 was gradually increased to 10.0 mg, the average HOMA-B index increased to 12.077 on day 108 from the baseline, resulting in an approximate increase of 33% in HOMA-B from the baseline. This data is consistent with the attenuation of the increase in fasting HOMA-B index of insulin secretion at doses of Compound 1 exceeding 8.0 mg and the reduced requirement for insulin secretion in the context of improved fasting insulin sensitivity and reduced fasting glucose levels.

[0307] MMTT - Glucose Level Patients in Cohort 1 had a baseline mean area under the curve from 0 to 3 hours for glucose levels during the mixed meal tolerance test, which was 43.06 h * mmol / L. As the dose of Compound 1 was gradually increased to mg, the mean area under the curve from 0 to 3 hours for glucose levels decreased to 25.76 h * mmol / L on day 80, resulting in an approximate decrease of 40% from the baseline.

[0308] Patients in Cohort 2 had a baseline mean area under the curve from 0 to 3 hours for glucose levels during the mixed meal tolerance test of 38.27 h * mmol / L. As the dose of Compound 1 was gradually increased to 10.0 mg, the area under the curve from 0 to 3 hours for glucose levels was 25.76 h on day 108* It decreased to mmol / L, resulting in an approximate decrease in the food-stimulated glucose level of 38% from the baseline.

[0309] MMTT-insulin level Patients in cohort 1 had a baseline mean area under the curve for insulin levels from 0 to 3 hours during the mixed meal tolerance test, which was 125.233 h * at mIU / L. As the dose of compound 1 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 * at mIU / L, resulting in an approximate increase of 51% from the baseline.

[0310] Patients in cohort 2 had a baseline mean area under the curve for insulin levels from 0 to 3 hours during the mixed meal tolerance test of 77.692 h * at mIU / L. As the dose of compound 1 gradually increased to 10.0 mg, the area under the curve for insulin levels from 0 to 3 hours was 69.847 h on day 108 * at mIU / L, resulting in an approximate decrease in the food-stimulated insulin level of 10% from the baseline. This data indicates that the dose of compound 1 up to 4.5 mg stimulates insulin secretion from the baseline in response to a mixed meal. Doses of compound 1 greater than 4.5 mg and up to 10 mg do not stimulate insulin secretion from the baseline in response to a mixed meal and are consistent with reducing the pancreatic beta cell workload while also decreasing 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 meal tolerance test, which was 4391.4 h * at pmol / L. As the dose of compound 1 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 * at pmol / L, resulting in an approximate increase of 33% from the baseline.

[0312] Patients in cohort 2 had a baseline mean area under the curve from 0 to 3 hours for C-peptide levels during a mixed meal tolerance test of 3604.1 h * pmol / L. As the dose of compound 1 was increased incrementally to 10.0 mg, the area under the curve from 0 to 3 hours for C-peptide levels decreased to 3147.4 h * pmol / L on day 108, resulting in an approximate decrease in food-stimulated C-peptide levels from baseline of 13%. This data indicates that doses of compound 1 up to 4.5 mg stimulate insulin secretion in proinsulin processing from baseline in response to a mixed meal. Doses of compound 1 greater than 4.5 mg and up to 10 mg do not stimulate insulin secretion in proinsulin in response to a mixed meal and are consistent with reducing pancreatic beta cell workload while also decreasing glucose levels.

[0313] MMTT-glucagon Patients in cohort 1 had a baseline mean area under the curve from 0 to 3 hours for glucagon levels during a mixed meal tolerance test of 64.98 h * pmol / L. As the dose of compound 1 was increased incrementally to 4.5 mg, the mean area under the curve from 0 to 3 hours for glucagon levels decreased to 27.93 h * pmol / L on day 80, resulting in an approximate decrease from baseline of 57%.

[0314] Patients in cohort 2 had a baseline mean area under the curve from 0 to 3 hours for glucagon levels during a mixed meal tolerance test of 39.89 h * pmol / L. As the dose of compound 1 was increased incrementally to 10.0 mg, the area under the curve from 0 to 3 hours for glucagon levels decreased to 7.61 h *It decreased to pmol / L, resulting in an approximate reduction of food-stimulated glucagon levels from 81% of the baseline. This data indicates that doses of Compound 1 up to 4.5 mg reduce glucagon secretion by more than 50% from the baseline in response to a mixed diet. Doses of Compound 1 up to 10 mg reduce glucagon secretion by more than 80% from the baseline in response to a mixed diet.

[0315] MMTT-Matsuda Insulin Sensitivity Index (ISI-M) Patients in Cohort 1 had a baseline Matsuda Insulin Sensitivity Index (ISI-M) calculated from mixed meal tolerance test parameters of 3.568. As the dose of Compound 1 was incrementally increased to 4.5 mg, the mean Matsuda index was 3.567 on day 80, indicating no change from the baseline.

[0316] Patients in Cohort 2 had a baseline Matsuda Insulin Sensitivity Index (ISI-M) calculated from mixed meal tolerance test parameters of 4.616. As the dose of Compound 1 was incrementally increased to 10.0 mg, the Matsuda index increased to 10.7 on day 108, and an increase of approximately 132% from the baseline indicated increased insulin sensitivity. This data indicates that doses of Compound 1 up to 4.5 mg do not improve insulin sensitivity in response to a mixed diet. Doses of Compound 1 up to 10 mg significantly increase insulin sensitivity from the baseline in response to a mixed diet.

[0317] Adverse events No deaths occurred during this trial. Throughout the trial, as summarized in Table 9, a total of 17 patients (94.4%) who received Compound 1 reported TEAE, and 6 patients (100%) who received placebo reported TEAE. Most of the TEAEs reported during the trial were mild in severity (88.5%). Overall, the TEAE most frequently reported by participants who received LY3305677 was gastrointestinal disorders. · Nausea 7 (38.9%), · Vomiting 5 (27.8%), · Flatulence 4 (22.2%), · Diarrhea 4 (22.2%), · Abdominal pain 1 (5.6%), and · Constipation 2 (11.1%).

[0318]

Table 10

[0319] During this trial, as shown in Table 10, one SAE was reported in one patient treated with the test intervention.

[0320]

Table 11

[0321] Example 2: Clinical Trial Overview This trial is designed to evaluate the safety, tolerability, PD, and PK of higher doses of Compound 1 in individuals with obesity. The Multiple Ascending Dose (MAD) trial is a randomized, physician- and participant-blinded, placebo-controlled, multiple ascending dose, single- or multi-site trial conducted in individuals with obesity (i.e., women or men aged 18 - 70 years, BMI in the range of 27 kg / m 2 ~ 50 kg / m 2 . Participants should have a stable body weight for at least 3 months prior to the start of the trial.

[0322] Treatment The doses of Compound 1 are evaluated in two cohorts over 20 weeks with once-weekly dosing. Each cohort includes 12 patients, 9 patients are administered Compound 1, and 3 patients are administered placebo.

[0323] The dosages for Cohort 1 are 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 dosages for Cohort 2 are 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 are collected periodically from Day 1 to Day 138 to determine plasma concentrations of Compound 1 over increasing dosages in individuals with obesity.

[0326] HbA1c, C-peptide, glucagon, serum glucose, and insulin are measured at multiple time points fasting over the dosages from Day 1 to Day 138, for the mixed meal tolerance test (MMTT) at baseline before the first dose and at Week 20, for each of the analytes using methods known in the art. Mean absolute and percent change in fasting glucose, insulin, C-peptide, and glucagon 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.

[0327] Parameters obtained from fasting samples and MMTT to evaluate insulin resistance and pancreatic β-cell function include the following. - Homeostatic Model Assessment (HOMA)-B, - HOMA-IR, and - insulin sensitivity (Matsuda index).

[0328] Insulin sensitivity (Matsuda index) is calculated according to the following formula.

[0329]

Equation

[0330] The mean parameters for a plurality of indices related to blood glucose control, pancreatic beta cell function, and insulin sensitivity on day 138 are derived from fasting and MMTT measurements for compound 1 and placebo groups within each cohort and will be compared to the baseline.

[0331] The Satisfaction VAS is measured fasting at multiple time points over the dose from day 1 to day 138. The appetite sensation is evaluated using the VAS for parameters of hunger, fullness, satisfaction, and expected food intake, and a composite appetite score is calculated.

[0332] Measure body weight and waist circumference at frequent intervals over the dosing period from Day 1 to Day 138 and during the long-term follow-up period after dosing ends. Calculate the mean absolute and percent change in body weight for Compound 1 and placebo groups within each cohort and compare to baseline at multiple time points from Day 1 to Day 138 and throughout the long-term follow-up period after dosing ends. Calculate the mean absolute and percent change in waist circumference for Compound 1 and placebo groups within each cohort and compare to baseline at multiple time points from Day 1 to Day 138 and throughout the long-term follow-up period after dosing ends. The weight loss described in Example 1 is in the T2D patient population, although greater weight loss is typical in the obese patient population. A multiplier of 1.6 - 1.8 may be applied to the percent weight loss moving from the T2D population to the obese population.

[0333] Measure the lipid profile, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, fasting at multiple time points over the dosing period from Day 1 to Day 138. Calculate the mean absolute and percent change in the fasting lipid profile, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, for Compound 1 and placebo groups within each cohort and compare to baseline at multiple time points from Day 1 to Day 138.

[0334] Monitor vital signs, including heart rate, pulse rate, systolic blood pressure, and diastolic blood pressure, at frequent intervals over the dosing period from Day 1 to Day 138.

[0335] Safety parameters evaluated during the study include AE (of particular interest are GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examinations / medical evaluations, vital signs and ECG, BW, injection site reactions, hypersensitivity reactions, and glucose monitoring (with particular attention to hypoglycemia).

[0336] Body weight During the dosing period of multiple doses of Compound 1, a decrease in mean body weight was observed in all treatment groups at each time point evaluated. The trend of body weight loss was dose-dependent, and the mean percent change from the baseline body weight 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 body weight loss data at various time points in the two cohorts are as follows. Day 85 / Week 12 (4 weeks after 8 mg): Placebo +0.2%, Cohort 1 -10.7%, Cohort 2 -11.7% Day 99 / Week 14 (2 weeks after 10 mg in Cohort 2): Placebo +0.07%, Cohort 2 -13.4% Day 113 / Week 16 (4 weeks after 12 mg in Cohort 1, 2 weeks after 13 mg in Cohort 2): Placebo +0.7%, Cohort 1 -15.4%, Cohort 2 -16.2% Day 138 / Week 20 (4 weeks after 16 mg): Placebo +0.5%, Cohort 1 -19.4%, Cohort 2 -20.6%.

[0338] Waist circumference During the dosing period of multiple doses of Compound 1, a decrease in mean waist circumference was observed in Cohort 1 and Cohort 2. Day 85 / Week 12 (4 weeks after 8 mg): Placebo +0.04%, Cohort 1 -5.2%, Cohort 2 -7.6% Day 99 / Week 14 (2 weeks after 10 mg in Cohort 2): Placebo +1.0%, Cohort 2 -6.8% Day 113 / Week 16 (4 weeks after 12 mg in Cohort 1, 2 weeks after 13 mg in Cohort 2): Placebo +1.3%, Cohort 1 -6.3%, Cohort 2 -12.6% Day 138 / Week 20 (4 weeks after 16 mg): Placebo +0.4%, Cohort 1 -11.5%, Cohort 2 -16.6% Adverse events No deaths occurred during this trial. No serious adverse events were observed. The most common adverse events occurring under treatment with mazdutide were gastrointestinal in nature (nausea, vomiting, diarrhea), consistent with GLP-1 receptor agonists. The incidence of nausea, vomiting, and diarrhea was similar across the high doses of 10 - 16 mg and was mild or moderate in severity.

[0339] Example 3: Clinical Trial Overview This trial was designed to further evaluate the efficacy and safety of Compound 1 in a population of obese or overweight individuals. The trial is a randomized, physician- and participant-blinded, placebo-controlled trial conducted in women or men aged 18 - 75 years who are obese or overweight without diabetes (i.e., obese prior to randomization and having a BMI of 30 kg / m or more at screening, or overweight prior to randomization and having a BMI of 27 kg / m 2 or more or less than 30 kg / m 2 at screening), and having one or more weight-related comorbidities such as hypertension, dyslipidemia, cardiovascular disease, osteoarthritis, or obstructive sleep apnea, but not having T2DM. Participants should have had a stable weight for at least 3 months prior to the start of the trial. 2

[0340] Treatment Multiple doses of Compound 1 are evaluated over 48 weeks in cohorts administered Compound 1 or placebo. Approximately 60 individuals are included in each cohort.

[0341] Compound 1 is administered to multiple cohorts from week 1 to week 20 or week 32 to achieve different maintenance or maximum doses that are administered from week 21 or week 32 (or the earliest week at which the dose is first achieved) to week 48. The starting dose of the dosing regimen can vary by cohort, for example, starting doses of 1.5 mg, 2.0 mg, or 3.0 mg. The time intervals between dosing steps can vary within and across cohorts and include dose increases after 2-week, 3-week, or 4-week intervals. The magnitude of the dose increases can vary within and across cohorts, and dose increases of 1.5 mg, 2.0 mg, 3.0 mg, 4.0 mg, or 5.0 mg occur over the dosing steps to achieve the specified doses.

[0342] In this study, the first dosing regimen (cohort 1) is as follows. - 1.5 mg QW of compound 1 for 4 weeks, - 3.0 mg QW of compound 1 for 28 weeks, and - 6 mg QW of compound 1 for 16 weeks.

[0343] The second dosing 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, - 8 mg QW of compound 1 for 4 weeks, and - 10 mg QW of compound 1 for 32 weeks.

[0344] The third dosing 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, - 9 mg QW of compound 1 for 4 weeks, - 12 mg QW of compound 1 for 4 weeks, and - 16 mg QW of compound 1 for 28 weeks

[0345] Three cohorts were administered compound 1, with one cohort being administered 1.5 mg from weeks 1 to 4, 3.0 mg from weeks 5 to 32, and 6.0 mg from weeks 33 to 48, the second cohort being administered 1.5 mg from weeks 1 to 4, 3.0 mg from weeks 5 to 8, 6.0 mg from weeks 9 to 12, 8.0 mg from weeks 13 to 16, and 10.0 mg from weeks 17 to 48, and the third cohort being administered 1.5 mg from weeks 1 to 4, 3.0 mg from weeks 5 to 8, 6.0 mg from weeks 9 to 12, 9.0 mg from weeks 13 to 16, 12.0 mg from weeks 17 to 20, and 16.0 mg from weeks 21 to 48.

[0346] Evaluation Approximately 40 individuals per cohort are evaluated at baseline and at week 48 for changes from baseline in multiple measurements of body composition by magnetic resonance imaging analysis, including changes in liver fat, abdominal subcutaneous adipose tissue, and visceral adipose tissue. Individuals are evaluated for changes in NAFLD characterized by 10% or more liver fat by magnetic resonance imaging.

[0347] Blood samples are collected periodically from week 1 to week 48 to determine plasma concentrations of compound 1 over increasing doses in individuals with obesity.

[0348] HbA1c, C-peptide, glucagon, serum glucose, and insulin are measured fasting at multiple time points from week 1 to week 48 over the dose range. Mean absolute and percent change in fasting glucose, insulin, C-peptide, and glucagon are calculated at weeks 32 and 48 and compared to the pre-dose week 1 baseline for each compound 1 and placebo cohort. Mean absolute and percent change in fasting glucose, insulin, C-peptide, and glucagon are calculated for each compound 1 and cohort and compared to placebo at weeks 32 and 48.

[0349] Parameters derived from fasting samples to evaluate insulin resistance and pancreatic β-cell function include homeostasis model assessment (HOMA)-B and HOMA-IR. Mean parameters of the HOMA indices related to glycemic control, pancreatic beta-cell function, and insulin sensitivity are derived from fasting measurements of each compound 1 cohort and will be compared to placebo at weeks 32 and 48.

[0350] The Satisfaction VAS is measured fasting at multiple time points from week 1 through week 48 across doses. Appetite sensations are evaluated using the VAS for parameters of hunger, fullness, satisfaction, and expected food intake, and a composite appetite score is calculated.

[0351] Body weight and waist circumference are measured at frequent intervals from week 1 through week 48 across doses and during a long-term follow-up period after dosing is completed. Mean absolute and percent change in body weight are calculated at weeks 32 and 48 and compared to the pre-dose week 1 baseline for each compound 1 and placebo cohort. Mean absolute and percent change in waist circumference are calculated at weeks 32 and 48 and compared to the pre-dose week 1 baseline for each compound 1 and placebo cohort. Mean absolute and percent change in waist circumference are calculated for each compound 1 cohort and compared to placebo at weeks 32 and 48.

[0352] Measure the lipid profile, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, fasting at multiple time points from week 1 to week 48 over the dose. Calculate the mean absolute and percent change of the fasting lipid profile, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, at week 32 and week 52 and compare to the pre-dose week 1 baseline for each compound 1 and placebo cohort. Calculate the mean absolute and percent change of the fasting lipid profile, including total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, and triglycerides, for each compound 1 cohort and compare to placebo at week 32 and week 48.

[0353] Monitor vital signs, including heart rate, pulse rate, systolic blood pressure, and diastolic blood pressure, at frequent intervals from week 1 to week 48 over the dose.

[0354] Safety parameters evaluated during the study will include AE (of particular interest for GI AEs such as nausea, vomiting, and diarrhea), laboratory parameters, physical examination / medical evaluation, vital signs and ECG, BW, injection site reactions, hypersensitivity reactions, and glucose monitoring (with particular attention to mean parameters of the HOMA index related to glycemic control, pancreatic beta cell function, and insulin sensitivity), derived from fasting measurements at week 32 and week 48 for each compound 1 and placebo cohort and compared to the pre-dose week 1 baseline.

Claims

1. A method for chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides in patients in need of chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides, comprising: the method comprising: (1) administering to the patient a once-weekly dose of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for at least about 2 weeks; and (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.

2. The method according to claim 1, wherein the increased once-weekly dose is selected from the group consisting of about 6.25 mg to about 16.0 mg, about 6.5 mg to about 16.0 mg, about 8.0 mg to about 16.0 mg, about 10 mg to about 16.0 mg, about 11.0 mg to about 16 mg, about 12.0 mg to about 16.0 mg, about 13.0 mg to about 16.0 mg, or about 14.0 mg to about 16.0 mg of the compound.

3. The method according to claim 1 or 2, wherein the increased once-weekly dose is about 6.25 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

4. The method according to claim 2, wherein the increased once-weekly dose is about 8 mg to about 16.0 mg.

5. The method according to claim 4, wherein the increased once-weekly dose is about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

6. The method according to claim 2, wherein the increased once-weekly dose is about 10 mg to about 16.0 mg.

7. The method according to claim 6, wherein the increased once-weekly dose is about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, or about 16.0 mg.

8. The method according to any one of claims 1 to 7, wherein a plurality of different once-weekly doses are administered to the patient in steps (1) and (2).

9. The method according to claim 8, wherein the first once-weekly dose is from about 1.0 mg to about 6.0 mg.

10. The method according to claim 9, wherein 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.

11. The method according to claim 10, wherein the first once-weekly dose is about 1.5 mg, about 2.0 mg, or about 3.0 mg.

12. The method according to any one of claims 9 to 11, 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 2 weeks.

13. The method 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.

14. (a) administering about 1.5 mg of the first dose of the compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks; (b) increasing the dosage to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (c) increasing the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (d) increasing the dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (e) increasing the dosage to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, the method according to any one of claims 1 to 13.

15. (a) administering about 2.0 mg of a first dosage of the compound or a pharmaceutically acceptable salt thereof once a week for at least about 2 weeks; (b) increasing the dosage to about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (c) increasing the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (d) increasing the dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (e) increasing the dosage to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks, the method according to any one of claims 1 to 13.

16. (a) administering about 1.5 mg of a first dosage of the compound or a pharmaceutically acceptable salt thereof once a week for at least about 2 weeks; (b) increasing the dosage to about 3.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about 2 weeks; (c) increasing the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (d) increasing the dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (e) increasing the dosage to about 12.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (f) increasing the dosage to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks, the method according to any one of claims 1 to 13.

17. (a) administering about 2.0 mg of a first dosage of the compound or a pharmaceutically acceptable salt thereof once a week for at least about two weeks; (b) increasing the dosage to about 4.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (c) increasing the dosage to about 6.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (d) increasing the dosage to about 8.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (e) increasing the dosage to about 10.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (f) increasing the dosage to about 13.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks; (g) increasing the dosage to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof, and administering the dosage once a week for at least about two weeks, the method according to any one of claims 1 to 13.

18. (a) administering the first dose of about 1.5 mg of said compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks; (b) increasing said dose to about 3.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (c) increasing said dose to about 6.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (d) increasing said dose to about 9.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (e) increasing said dose to about 12.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (f) increasing said dose to about 16.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks, the method according to any one of claims 1 to 13.

19. (a) administering the first dose of about 1.5 mg of said compound, or a pharmaceutically acceptable salt thereof, once a week for at least about 2 weeks; (b) increasing said dose to about 3.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (c) increasing said dose to about 6.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (d) increasing said dose to about 10.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (e) increasing said dose to about 13.0 mg of said compound, or a pharmaceutically acceptable salt thereof, and administering said dose once a week for at least about 2 weeks; (f) increasing the dosage to about 16.0 mg of the compound or a pharmaceutically acceptable salt thereof and administering the dosage once a week for at least about two weeks, the method according to any one of claims 1 to 13.

20. The method according to any one of claims 1 to 19, comprising administering the once-a-week dosage for at least about four weeks.

21. The method according to any one of claims 1 to 20, wherein the compound or a pharmaceutically acceptable salt thereof is administered subcutaneously.

22. The method according to any one of claims 1 to 21, wherein the administration of the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in the weight of the patient.

23. The method according to any one of claims 1 to 22, wherein the administration of the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in HbA1c of the patient.

24. The method according to any one of claims 1 to 23, wherein the administration of the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof results in a decrease in LDL cholesterol and / or triglyceride of the patient.

25. The method according to any one of claims 1 to 24, wherein the administration of the compound of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof does not result in unacceptable tolerance.

26. The method according to any one of claims 1 to 25, wherein the patient is overweight.

27. The method according to any one of claims 1 to 25, wherein the patient is obese.

28. The method according to any one of claims 1 to 27, wherein the patient has type 2 diabetes.

29. The compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, for use in the provision of chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides, wherein (1) the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, at a once-weekly dose 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. A compound, or a pharmaceutically acceptable salt thereof. **Claim 30** Use of the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the provision of chronic weight management, improvement of blood glucose control, and / or reduction of LDL cholesterol or triglycerides, wherein (1) the compound of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, at a once-weekly dose 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. Use.

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