Composition for preventing or treating metabolic disease comprising glp-1r agonist

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating a metabolic disease, comprising a therapeutically effective amount of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. The composition provides an appropriate dosage regimen and dose for exhibiting optimal preventive or therapeutic effects in a subject having a metabolic disease, preferably diabetes mellitus (especially type 2 diabetes mellitus), obesity or overweightness, and weight-related comorbidities.

Description

Composition for the prevention or treatment of metabolic diseases containing a GLP-1R agonist

[0001] The present invention relates to an appropriate dosage and administration of a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a GLP-1R agonist, specifically to a pharmaceutical composition for the prevention or treatment of diabetes (particularly type 2 diabetes), obesity or overweight and weight-related comorbidities, and an appropriate dosage and administration thereof.

[0002] Type 2 diabetes is a chronic metabolic disease characterized by insulin resistance, in which cells fail to respond effectively to insulin, leading to abnormally elevated blood sugar levels. If blood sugar is not properly controlled and insulin resistance continues to worsen, the body requires increasingly more insulin, resulting in the progression of pancreatic beta-cell dysfunction over the long term. These pathological changes can cause various complications, including damage to the nervous and vascular systems.

[0003] According to recent reports, as of 2017, approximately 462 million people, or about 6.28% of the global population, were diagnosed with Type 2 diabetes, with a prevalence rate of 6,059 cases per 100,000 people. Additionally, more than one million people die annually from diabetes-related complications, ranking among the leading causes of death worldwide. The prevalence of Type 2 diabetes is on a continuous upward trend globally and is projected to reach approximately 7,079 cases per 100,000 people by 2030.

[0004] Although various pharmaceutical treatment options for diabetes are currently being developed, there are limitations in that a significant number of patients fail to reach target glycated hemoglobin (HbA1c) levels. Consequently, there is a continuous demand for more effective and sustainable treatment alternatives.

[0005] Meanwhile, GLP-1 (Glucagon-Like Peptide-1) is a neuroendocrine hormone secreted primarily in the small intestine after food intake. It exerts effects such as promoting insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying through the activation of GLP-1 receptors. Based on this mechanism, GLP-1 receptor agonists (GLP-1 RAs) have been approved and are clinically utilized as treatments for type 2 diabetes, and recently, their scope of application has expanded to include weight management treatment for obese and overweight patients.

[0006] However, most currently commercialized GLP-1 RAs are provided in the form of injections, and side effects such as nausea and gastrointestinal adverse reactions are frequently reported. In addition, the injection method of administration acts as a factor that can reduce medication adherence in patients with chronic or metabolic diseases requiring long-term treatment.

[0007] Accordingly, there is a growing need for the development of oral formulations of therapeutic agents that are effective in preventing or treating metabolic diseases such as type 2 diabetes, obesity, and overweight, while also offering improved convenience of administration.

[0008] The present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0009] The present invention provides an appropriate method and dosage of a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0010] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and provides an appropriate method and dosage of use of said composition.

[0011]

[0012] By using the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof in the dosage and method provided by the present invention, there is an advantage of obtaining optimal preventive or therapeutic effects for metabolic diseases, preferably diabetes (particularly type 2 diabetes), obesity or overweight, and weight-related comorbidities. In addition, sufficient safety is provided, as the increase in the safety profile, including gastrointestinal adverse events, is lower than that of improved weight loss or improved blood glucose reduction.

[0013] In one aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0014] In one aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, administered at a total daily dose of 25 mg to 400 mg based on a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0015] [Chemical Formula 1]

[0016] .

[0017] In the present invention, the compound represented by Chemical Formula 1 is (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid. The compound is a GLP-1R agonist with excellent effects in increasing the activity of GLP-1 receptors.

[0018] In the present invention, the composition may be administered once or twice a day, preferably once a day.

[0019] In one aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered once or twice daily in a total amount of 25 mg to 400 mg.

[0020] In the present invention, the dosage of the composition may be based on the free base of the compound represented by Formula 1, that is, the compound represented by Formula 1. For example, a total of 25 mg to 400 mg per day means a total of 25 mg to 400 mg of the compound represented by Formula 1.

[0021] The compound represented by the above chemical formula 1 or its pharmaceutically acceptable salt exhibits excellent therapeutic efficacy based on novel methods and dosages for metabolic diseases, preferably diabetes mellitus (particularly type 2 diabetes mellitus), obesity or overweight and weight-related comorbidities, etc.

[0022] In the present invention, the compound represented by Formula 1 may exist in the form of a "pharmaceutically acceptable salt." As used herein, "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt that has a relatively non-toxic and harmless active effect on the patient, and whose side effects resulting from the salt do not impair the beneficial efficacy of the compound of Formula 1.

[0023] In addition, the "pharmaceuticalally acceptable salt" above refers to a salt commonly used in the pharmaceutical industry and may be, for example, an inorganic ion salt prepared with calcium, sodium, etc.; an inorganic salt prepared with phosphoric acid, bromic acid, iodic acid, sulfuric acid, etc.; an organic salt prepared with hydrochloric acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, carboxylic acid, vanillic acid, etc.; a sulfonate prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; an amino acid salt prepared with glycine, arginine, etc.; and an amine salt prepared with tris (or tromethamine), trimethylamine, triethylamine, etc.

[0024] Preferably, the pharmaceutically acceptable salt may be any one salt selected from the group consisting of hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, tris, and methanesulfonic acid.

[0025] More preferably, the pharmaceutically acceptable salt may be a Tris (or tromethamine) salt.

[0026] In the present invention, a pharmaceutically acceptable salt of a compound represented by Formula 1 of the present invention may have the structure of Formula 2 below.

[0027] [Chemical Formula 2]

[0028] .

[0029] The compound of Chemical Formula 2 above is the Tris salt of the compound of Chemical Formula 1 above.

[0030] The pharmaceutical composition of the present invention can be formulated into various formulations according to conventional methods, and specifically, can be manufactured as an oral formulation.

[0031] The oral administration preparation may be an oral administration solid formulation, specifically a tablet, pill, powder, granule, or capsule, and more specifically a tablet or capsule. In one embodiment, the preparation may be a capsule.

[0032] These oral solid formulations may include at least one pharmaceutically acceptable carrier in the composition. The pharmaceutically acceptable carrier may include, but is not limited to, one or more selected from the group consisting of those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, pregelatinized starch, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium starch glycolate, polyvinylpyrrolidone, water, talc, colloidal silicon dioxide, and magnesium stearate. In addition, the pharmaceutical composition of the present invention may include, but is not limited to, fillers, extenders, binders, wetting agents, disintegrants, diluents or excipients such as surfactants, lubricants such as sodium stearyl fumarate, coating agents, and other pharmaceutically acceptable additives.

[0033] In the present invention, based on an average adult weighing about 60 kg, a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof may be orally administered in a total daily dose of 25 mg to 400 mg based on the compound of Formula 1, preferably in a total daily dose of 25 mg to 400 mg based on the compound of Formula 1.

[0034] In one embodiment, the composition according to the present invention may be administered in a total of 25 mg to 400 mg per day, preferably in a total of 25 to 250 mg per day, more preferably in a total of 25 to 200 mg per day, even more preferably in a total of 50 to 200 mg per day, even more preferably in a total of 50 to 100 mg per day, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day, and most preferably in a total of 50 mg, 75 mg, or 100 mg per day.

[0035] The above administration may be administered once or twice a day. Preferably, it may be administered once a day.

[0036] In one embodiment, the composition according to the present invention may be administered once or twice daily in a total of 25 mg to 400 mg, preferably in a total of 25 to 250 mg once or twice daily, more preferably in a total of 25 to 200 mg once or twice daily, even more preferably in a total of 50 to 200 mg once or twice daily, even more preferably in a total of 50 to 100 mg once or twice daily, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg once or twice daily, and most preferably in a total of 50 mg, 75 mg, or 100 mg once or twice daily.

[0037] In one embodiment, the composition according to the present invention may be administered once a day in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and preferably, may be administered once a day in a total of 50 mg, 75 mg, or 100 mg.

[0038] In one embodiment, the composition according to the present invention may be administered before or after a meal. Specifically, the composition of the present invention [is administered before or after a meal] with a systemic exposure (AUC last Since the degree is similar, it may be administered once or twice a day at any time regardless of whether a meal is taken or the time of the meal, and preferably, it may be administered once a day. The composition according to the present invention can exhibit excellent therapeutic efficacy even when administered or taken once a day.

[0039] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 32 weeks. More specifically, it may be administered once daily for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. Any period between 1 week and 32 weeks is included within the administration range of the present invention.

[0040] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 16 weeks. More specifically, it may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. Any period between 1 and 16 weeks is included within the administration range of the present invention.

[0041] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0042] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0043] In one embodiment, the composition according to the present invention may be administered once a day for a total of 50 mg, 75 mg, or 100 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0044] In one embodiment, the composition according to the present invention may be administered once a day for a total of 50 mg, 75 mg, or 100 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0045] By using the pharmaceutical composition according to the present invention in the aforementioned dosage and method, an optimal preventive or therapeutic effect for metabolic diseases can be obtained in patients with metabolic diseases.

[0046] Preferably, by using the pharmaceutical composition according to the present invention in the aforementioned dosage and method, an optimal preventive or therapeutic effect for diabetes (especially type 2 diabetes) can be obtained in a patient with diabetes (especially type 2 diabetes).

[0047] Preferably, by using the pharmaceutical composition according to the present invention in the aforementioned dosage and method, an optimal effect of preventing or treating obesity or overweight and weight-related comorbidities can be obtained in patients with obesity or overweight and weight-related comorbidities.

[0048] In the present invention, the metabolic disease is diabetes mellitus, idiopathic type 1 diabetes mellitus, latent autoimmune diabetes mellitus in adults (LADA), early-onset type 2 diabetes mellitus (EOD), atypical diabetes mellitus in minors (YOAD), adult-onset diabetes mellitus in minors (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, visceral fat accumulation, obstructive sleep apnea, obesity, childhood obesity / overweight, overweight and weight-related comorbidities, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), metabolic disorder-related steatohepatitis, atherosclerosis, hypertension, cardiovascular disease, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, metabolic acidosis, ketosis, arthritis, It may be a disease including osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, vision loss, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, restenosis, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyper-apo-B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

[0049] In one embodiment, the pharmaceutical composition of the present invention may be used for the medical prevention or treatment of the following:

[0050] (i) Prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (adult-onset diabetes mellitus in minors), gestational diabetes, and / or reduced HbA1c;

[0051] (ii) delay or prevention of the progression of diabetic disease, such as the progression of type 2 diabetes, delay of the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay of the progression of non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes;

[0052] (iii) prevention and / or treatment of eating disorders (e.g., obesity) by, for example, reducing food intake, weight loss, suppressing appetite, or inducing satiety; treatment or prevention of binge eating disorder, bulimia nervosa and / or obesity induced by the administration of psychotropic drugs or steroids; reduction of gastric motility; and / or delay of gastric fasting.

[0053] Preferably, the pharmaceutical composition of the present invention can be used for the prevention or treatment of diabetes, obesity or overweight and weight-related comorbidities.

[0054] In one embodiment, the “subject” receiving the pharmaceutical composition of the present invention may be a subject having a metabolic disease, specifically a subject having diabetes, obesity, or overweight and weight-related comorbidities. Additionally, the subject may be a subject requiring weight control.

[0055] In one embodiment, the pharmaceutical composition of the present invention may be used for the treatment of a subject suffering from diabetes. Preferably, the subject suffering from diabetes may be a subject suffering from any form of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (adult-onset diabetes mellitus in minors), gestational diabetes, and / or reduced HbA1c.

[0056] In one embodiment, the pharmaceutical composition of the present invention may be used in a method for treating or preventing obesity. All subjects suffering from obesity are considered to also suffer from overweight, and obesity may include overweight and weight-related comorbidities.

[0057] In one embodiment, the pharmaceutical composition of the present invention may be used for weight loss or weight control of a subject suffering from obesity or overweight and weight-related comorbidities. Additionally, it may be used for weight control of a subject requiring weight control.

[0058] In one embodiment, weight control may be chronic weight control, and said weight control may be selected from the group consisting of weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight, and prevention of weight gain.

[0059] In one embodiment, the subject suffering from obesity is a human being, such as an adult human or a pediatric human (including infants, children, and adolescents). Body Mass Index (BMI) is a measure of body fat based on height and weight. The calculation formula is BMI = Weight (kg) / Height (m). 2 is. Specifically, human subjects suffering from obesity have a weight of 30 kg / m² 2 They may have a BMI above this level; such subjects may also be referred to as obese.

[0060] In one embodiment, the pharmaceutical composition of the present invention may be used in a method for treating or preventing overweight, optionally in the presence of at least one weight-related comorbidity. In one embodiment, the subject suffering from overweight is a human being, such as an adult human or a pediatric human (including infants, children, and adolescents). In one embodiment, the human subject suffering from overweight has a weight of 25 kg / m² 2 A BMI of the above, for example, 27 kg / m² 2 A person may have a BMI greater than or equal to 25 kg / m². In one embodiment, a human subject suffering from overweight has a BMI of 25 kg / m² 2 100 kg / m² or more to 30 kg / m² 2 A range of less than or 27 kg / m² 2 100 kg / m² or more to 30 kg / m² 2Having a BMI in the range of less than. In one embodiment, weight-related comorbidities are selected from the group consisting of hypertension, diabetes (such as type 2 diabetes), dyslipidemia, hypercholesterolemia, and obstructive sleep apnea.

[0061] In one embodiment, preferably, the patient subject to weight loss according to the present invention (subject suffering from obesity or overweight) has a body mass index (BMI) of 30 kg / m² 2 or greater than, or 27 kg / m² 2 30 kg / m² or more 2 They may have at least one weight-related comorbidity (currently being treated or untreated) while being under 100%.

[0062] Specifically, weight-related comorbidities are as follows:

[0063] - Hypertension: Taking antihypertensive drugs or having a systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg at the time of screening.

[0064] - Dyslipidemia: Taking lipid-lowering agents, or having low-density lipoprotein (LDL) ≥160 mg / dL (4.1 mmol / L) or triglycerides ≥150 mg / dL (1.7 mmol / L), or high-density lipoprotein (HDL) <40 mg / dL (1.0 mmol / L), or in the case of women, HDL <50 mg / dL (1.3 mmol / L).

[0065] - Cardiovascular disease: e.g., ischemic cardiovascular disease, New York Heart Association [NYHA] Functional Classification Grade I-III heart failure.

[0066] - Obstructive sleep apnea.

[0067] As used in the present invention, the term "prevention or treatment" refers to any act of suppressing or delaying the onset of the metabolic disease by using the pharmaceutical composition according to the present invention, and in particular, "treatment" refers to any act of improving or beneficially altering the metabolic disease by using the composition.

[0068] The term “safety profile” as used herein refers to a concept including adverse events and adverse drug reactions observed during a clinical trial in relation to an administered drug or other substance, and refers to an indicator for evaluating the tolerability of the clinical trial subjects.

[0069] In one embodiment, the safety profile includes Treatment Emergent Adverse Events (TEAEs) that occurred after administration of the investigational drug, and said adverse events may be evaluated by standardizing according to the MedDRA classification system (version 26.1) based on systemic organ classification and preferred terminology.

[0070] In one embodiment, the term “increase in safety profile” as used herein refers to a pattern in which the frequency or severity of adverse events increases with increasing dose or changes in administration conditions, and includes, for example, cases in which blood bilirubin levels increase or the frequency of gastrointestinal adverse events increases relatively in a specific dose group.

[0071] In one embodiment, “gastrointestinal adverse event” refers to a symptom corresponding to a gastrointestinal disorder as defined by MedDRA, and in some embodiments includes one or more symptoms selected from the group consisting of nausea, vomiting, diarrhea, epigastric discomfort, and abdominal tenderness.

[0072] In one embodiment, when the pharmaceutical composition (test drug) of the present invention was administered orally once or repeatedly to healthy adults, most observed adverse events and adverse drug reactions were evaluated as mild or moderate (Grade 2 or lower) and showed a pattern of spontaneous recovery without separate pharmacological treatment. The Grade 3 increase in blood bilirubin reported in some embodiments also occurred transiently and recovered to a normal or clinically insignificant abnormal range without additional treatment.

[0073] In one embodiment, the pharmaceutical composition of the present invention provides a clinically acceptable safety profile and acceptable tolerability without serious adverse events, death, or adverse events resulting in discontinuation of the clinical trial within a therapeutic dose range where systemic exposure is ensured. These results suggest that the compound represented by Formula 1 of the present invention and its pharmaceutically acceptable salt act within a predictable safety range compared to approved drugs of the same class.

[0074] In one embodiment, the pharmaceutical composition of the present invention has characteristics suitable for long-term administration, such as maintaining an effective blood concentration for about 18 hours or more after a single or repeated oral administration, and exhibiting a pharmacokinetic profile in which no accumulation in the body is observed following repeated administration.

[0075] In one embodiment, the pharmaceutical composition of the present invention can be administered orally and can be administered without a stepwise dose titration process prior to administration, thereby improving medication convenience. This is an advantage compared to existing GLP-class drugs that require dose titration due to concerns about gastrointestinal adverse reactions.

[0076] Furthermore, in terms of safety, the pharmaceutical composition of the present invention provides sufficiently acceptable tolerability without dose titration, as no gastrointestinal adverse reactions are observed without dose titration, or if they occur, they are mild and resolve naturally.

[0077] Furthermore, in clinical trials involving single or repeated oral administration of the pharmaceutical composition of the present invention, liver enzyme levels (AST and ALT) remained within the normal range across all dose groups, and no significant increase in liver enzyme levels was observed with repeated administration. In other words, this suggests that the pharmaceutical composition of the present invention can be administered for a long period without concerns regarding liver toxicity. The pharmaceutical composition of the present invention possesses superior safety compared to existing drugs, as no serious adverse reactions related to gastrointestinal disorders or liver toxicity, which are reported as major side effects of existing GLP-class drugs, were observed.

[0078] In one embodiment, it was confirmed that the pharmaceutical composition of the present invention exhibits a sufficient therapeutic effect even at a dose of 50 mg. Based on this, it provides the possibility of setting a dose of approximately 25 mg as an effective dose for the treatment of obesity and diabetes. The pharmaceutical composition of the present invention has a wide therapeutic dose range, allowing for flexible dose setting according to the patient's condition.

[0079] Accordingly, the pharmaceutical composition of the present invention can provide a composition for the prevention or treatment of metabolic diseases, preferably diabetes (particularly type 2 diabetes), obesity or overweight and weight-related comorbidities, which has clinical utility and commercial competitiveness by simultaneously satisfying excellent convenience of administration and cost-effectiveness with high therapeutic effect while having a low risk of side effects.

[0080]

[0081] In another aspect of the present invention, a method for preventing or treating a metabolic disease is provided, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject requiring prevention or treatment of a metabolic disease in a total daily dose of 25 mg to 400 mg.

[0082] In another aspect of the present invention, a method for preventing or treating a metabolic disease is provided, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject requiring prevention or treatment of a metabolic disease in an amount of 25 mg to 400 mg once or twice daily.

[0083] The description of the “compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof” above is as previously described.

[0084] In one embodiment, the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered in a total of 25 mg to 400 mg per day, preferably 25 to 250 mg per day, more preferably 25 to 200 mg per day, more preferably 50 to 200 mg per day, even more preferably 50 to 100 mg per day, even more preferably 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day, and most preferably 50 mg, 75 mg, or 100 mg per day.

[0085] In one embodiment, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered once or twice daily in a total of 25 to 400 mg, preferably in a total of 25 to 250 mg once or twice daily, more preferably in a total of 25 to 200 mg once or twice daily, even more preferably in a total of 50 to 200 mg once or twice daily, even more preferably in a total of 50 to 100 mg once or twice daily, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg once or twice daily, and most preferably in a total of 50 mg, 75 mg, or 100 mg once or twice daily.

[0086] In one embodiment, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered once daily in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and preferably in a total of 50 mg, 75 mg, or 100 mg once daily.

[0087] In the method for preventing or treating metabolic diseases according to the present invention, the dosage may be based on the free base of the compound represented by Chemical Formula 1, that is, the compound represented by Chemical Formula 1.

[0088] In one embodiment, the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered before or after a meal. Specifically, the systemic exposure (AUC) when the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is administered before or after a meal lastSince the degree is similar, it may be administered once or twice a day at any time regardless of whether a meal is taken or the time of the meal, and preferably once a day. The compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may exhibit excellent therapeutic efficacy even when taken once a day.

[0089] In one embodiment, once-daily administration of the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered for 1 to 32 weeks. More specifically, it may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 weeks. Any period between 1 and 32 weeks is included within the scope of administration of the present invention.

[0090] In one embodiment, once-daily administration of the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered for 1 to 16 weeks. More specifically, it may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. Any period between 1 and 16 weeks is included within the scope of administration of the present invention.

[0091] In one embodiment, the compound represented by Formula 1 according to the present invention or the pharmaceutically acceptable salt thereof may be administered once daily in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0092] In one embodiment, the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered once daily in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0093] In one embodiment, the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered once daily in a total of 50 mg, 75 mg, or 100 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0094] In one embodiment, the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered once daily in a total of 50 mg, 75 mg, or 100 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0095] By using a compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof in the aforementioned dosage and method, an optimal preventive or therapeutic effect against metabolic disease can be obtained in patients with metabolic disease.

[0096] Preferably, by using a compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof in the aforementioned dosage and method, an optimal preventive or therapeutic effect for diabetes (especially type 2 diabetes) can be obtained in a patient with diabetes (especially type 2 diabetes).

[0097] Preferably, by using a compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof in the aforementioned dosage and method, an optimal preventive or therapeutic effect against obesity or overweight and weight-related comorbidities can be obtained in patients with obesity or overweight and weight-related comorbidities.

[0098] The descriptions of the above “metabolic disease,” “diabetes,” “obesity,” or “overweight and weight-related comorbidities,” and “subjects with metabolic disease,” “subjects with diabetes,” “obesity,” or “subjects with overweight and weight-related comorbidities,” are as previously stated.

[0099]

[0100] In another aspect of the present invention, the present invention relates to a composition for use in the prevention or treatment of metabolic diseases by administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a total amount of 25 mg to 400 mg per day.

[0101] In another aspect of the present invention, the present invention relates to a composition for use in the prevention or treatment of metabolic diseases by administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in an amount of 25 mg to 400 mg once or twice daily.

[0102] The description of the “compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof” above is as previously described.

[0103] In one embodiment, the composition according to the present invention may be administered in a total of 25 mg to 400 mg per day, preferably in a total of 25 to 250 mg per day, more preferably in a total of 25 to 200 mg per day, even more preferably in a total of 50 to 200 mg per day, even more preferably in a total of 50 to 100 mg per day, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day, and most preferably in a total of 50 mg, 75 mg, or 100 mg per day.

[0104] In one embodiment, the composition according to the present invention may be administered once or twice daily in a total of 25 mg to 400 mg, preferably in a total of 25 to 250 mg once or twice daily, more preferably in a total of 25 to 200 mg once or twice daily, even more preferably in a total of 50 to 200 mg once or twice daily, even more preferably in a total of 50 to 100 mg once or twice daily, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg once or twice daily, and most preferably in a total of 50 mg, 75 mg, or 100 mg once or twice daily.

[0105] In one embodiment, the composition according to the present invention may be administered once a day in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and preferably, may be administered once a day in a total of 50 mg, 75 mg, or 100 mg.

[0106] In the present invention, the dosage of the composition may be based on the free base of the compound represented by Chemical Formula 1, that is, the compound represented by Chemical Formula 1.

[0107] In one embodiment, the composition according to the present invention may be administered before or after a meal. Specifically, the composition of the present invention [is administered before or after a meal] with a systemic exposure (AUC last Since the degree is similar, it may be administered once or twice a day at any time regardless of whether a meal is taken or the time of the meal, and preferably, it may be administered once a day. The composition according to the present invention can exhibit excellent therapeutic efficacy even with once-daily administration.

[0108] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 32 weeks. More specifically, it may be administered once daily for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. Any period between 1 week and 32 weeks is included within the administration range of the present invention.

[0109] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 16 weeks. More specifically, it may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. Any period between 1 and 16 weeks is included within the administration range of the present invention.

[0110] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0111] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0112] In one embodiment, the composition according to the present invention may be administered once a day in a total of 50 mg, 75 mg, or 100 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0113] In one embodiment, the composition according to the present invention may be administered once a day in a total of 50 mg, 75 mg, or 100 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0114] By using the composition according to the present invention in the aforementioned usage and dosage, an optimal preventive or therapeutic effect for metabolic diseases can be obtained in patients with metabolic diseases.

[0115] Preferably, by using the composition according to the present invention in the aforementioned usage and dosage, an optimal preventive or therapeutic effect for diabetes (especially type 2 diabetes) can be obtained in a patient with diabetes (especially type 2 diabetes).

[0116] Preferably, by using the composition according to the present invention in the aforementioned dosage and method, an optimal preventive or therapeutic effect against obesity or overweight and weight-related comorbidities can be obtained in patients with obesity or overweight and weight-related comorbidities.

[0117] The descriptions of the above “metabolic disease,” “diabetes,” “obesity,” or “overweight and weight-related comorbidities,” and “subjects with metabolic disease,” “subjects with diabetes,” “obesity,” or “subjects with overweight and weight-related comorbidities,” are as previously stated.

[0118]

[0119] In another aspect of the present invention, the present invention relates to the use of a composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for producing a medicine for the prevention or treatment of metabolic diseases by administering a total of 25 mg to 400 mg per day.

[0120] In another aspect of the present invention, the present invention relates to the use of a composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for producing a medicine for the prevention or treatment of metabolic diseases by administering a total of 25 mg to 400 mg once or twice a day.

[0121] The description of the “compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof” above is as previously described.

[0122] In one embodiment, the composition according to the present invention may be administered in a total of 25 mg to 400 mg per day, preferably in a total of 25 to 250 mg per day, more preferably in a total of 25 to 200 mg per day, even more preferably in a total of 50 to 200 mg per day, even more preferably in a total of 50 to 100 mg per day, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day, and most preferably in a total of 50 mg, 75 mg, or 100 mg per day.

[0123] In one embodiment, the composition according to the present invention may be administered once or twice daily in a total of 25 mg to 400 mg, preferably in a total of 25 to 250 mg once or twice daily, more preferably in a total of 25 to 200 mg once or twice daily, even more preferably in a total of 50 to 200 mg once or twice daily, even more preferably in a total of 50 to 100 mg once or twice daily, even more preferably in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg once or twice daily, and most preferably in a total of 50 mg, 75 mg, or 100 mg once or twice daily.

[0124] In one embodiment, the composition according to the present invention may be administered once a day in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and preferably, may be administered once a day in a total of 50 mg, 75 mg, or 100 mg.

[0125] In the present invention, the dosage of the composition may be based on the free base of the compound represented by Chemical Formula 1, that is, the compound represented by Chemical Formula 1.

[0126] In one embodiment, the composition according to the present invention may be administered before or after a meal. Specifically, the composition of the present invention [is administered before or after a meal] with a systemic exposure (AUC last Since the degree is similar, it may be administered once or twice a day at any time regardless of whether a meal is taken or the time of the meal, and preferably, it may be administered once a day. The composition according to the present invention can exhibit excellent therapeutic efficacy even with once-daily administration.

[0127] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 32 weeks. More specifically, it may be administered once daily for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks. Any period between 1 week and 32 weeks is included within the administration range of the present invention.

[0128] In one embodiment, once-daily administration of the composition according to the present invention may be administered for 1 to 16 weeks. More specifically, it may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. Any period between 1 and 16 weeks is included within the administration range of the present invention.

[0129] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0130] In one embodiment, the composition according to the present invention may be administered once a day for a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0131] In one embodiment, the composition according to the present invention may be administered once a day in a total of 50 mg, 75 mg, or 100 mg for 1 to 32 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, or 32 weeks.

[0132] In one embodiment, the composition according to the present invention may be administered once a day in a total of 50 mg, 75 mg, or 100 mg for 1 to 16 weeks. Specifically, it may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

[0133] By using the composition according to the present invention in the aforementioned usage and dosage, an optimal preventive or therapeutic effect for metabolic diseases can be obtained in patients with metabolic diseases.

[0134] Preferably, by using the composition according to the present invention in the aforementioned usage and dosage, an optimal preventive or therapeutic effect for diabetes (especially type 2 diabetes) can be obtained in a patient with diabetes (especially type 2 diabetes).

[0135] Preferably, by using the composition according to the present invention in the aforementioned dosage and method, an optimal preventive or therapeutic effect against obesity or overweight and weight-related comorbidities can be obtained in patients with obesity or overweight and weight-related comorbidities.

[0136] The descriptions of the above “metabolic disease,” “diabetes,” “obesity,” or “overweight and weight-related comorbidities,” and “subjects with metabolic disease,” “subjects with diabetes,” “obesity,” or “subjects with overweight and weight-related comorbidities,” are as previously stated.

[0137] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, wherein optimal preventive or therapeutic effects can be obtained for metabolic diseases (particularly diabetes), obesity or overweight and weight-related comorbidities by using the composition in an appropriate manner and dosage.

[0138] Figure 1 shows a schematic diagram of the single-dose administration test (SAD) of Example 1.

[0139] Figure 2 shows a schematic diagram of the formula effect evaluation test (FE) of Example 1.

[0140] Figure 3 shows the pharmacokinetic analysis results of the single-dose test (SAD) of Example 1 (C max and AUC last It represents ).

[0141] Figure 4 shows the average plasma concentration-time profile of the test drug after a single oral administration in the single-dose administration test (SAD) of Example 1.

[0142] Figure 5 shows the blood concentration of the test drug according to fasting and high-fat diet in the dietary effect evaluation test (FE) of Example 1.

[0143] Figure 6 shows the change in body weight (kg) of each test group in the repeated administration test (MAD) of Example 2.

[0144] Figure 7 shows the percentage change in body weight of each test group in the repeated administration test (MAD) of Example 2.

[0145] Figure 8 shows the weight loss rate of each test group of 5% or more in the repeated administration test (MAD) of Example 2.

[0146] Figure 9 shows the change in waist circumference of each test group in the repeated administration test (MAD) of Example 2.

[0147] Figure 10 shows the change in body fat mass of each test group in the repeated administration test (MAD) of Example 2.

[0148] Figure 11 shows the change in serum glucose concentration over 4 hours after taking the glucose solution in the oral glucose tolerance test (OGTT) according to the repeated administration test (MAD) of Example 2, compared before administration (Baseline, Day -2) and after administration (Day 12).

[0149] Figure 12 shows the OGTT blood glucose AUC measured on Day 12 in the repeated administration study (MAD) of Example 2. 0-4h This represents the change amount relative to the baseline.

[0150] Figure 13 shows the results of continuous blood glucose monitoring in the placebo group and each test group during a repeated administration period of 4 weeks.

[0151] Hereinafter, preferred embodiments are presented to aid in understanding the present invention; however, the following embodiments are merely illustrative of the invention and the scope of the invention is not limited to the following embodiments.

[0152]

[0153] Example 1. Analysis of safety, tolerability, and pharmacokinetic characteristics according to single-dose administration study (SAD) and dietary effect assessment study (FE) (Phase 1 clinical trial)

[0154] A dose-group, randomized, double-blind, placebo-controlled, stepwise dose-escalation, Phase 1 clinical trial was conducted to evaluate the safety, tolerability, and pharmacokinetic characteristics of a single oral administration of the salt of the compound of Formula 1 of the present invention to healthy adults.

[0155] 1. Test Design

[0156] The study was composed of a total of four cohorts based on the dose group and whether dietary effects were evaluated. For the dose escalation cohorts (1–3), eight subjects per cohort were randomized to either the test group or the placebo group in a 3:1 ratio. The dose escalation between each dose group was determined after confirming the safety and tolerability indicators identified in the previous dose group.

[0157] - Single-dose administration (SAD) study: 8 subjects per cohort (6 in the test group, 2 in the placebo group) were recruited, and the study was conducted with 3 dose groups (Cohorts 1 / 2 / 3: 100 / 200 / 400 mg; 100 mg, 200 mg, and 400 mg are based on the compound of Formula 1).

[0158] Subjects deemed suitable for this clinical trial were given a single oral dose of the investigational drug (i.e., a salt of the compound of Formula 1 of the present invention or the test drug) with 150 mL of water according to a planned schedule on the morning of the day of administration of the investigational drug (1d) after fasting for at least 10 hours (Fig. 1).

[0159] - Dietary Effect Assessment (FE): A separate cohort 4 for the dietary effect assessment was recruited, with 6 participants per sequence group, for a total of 12 participants, and the study was conducted with a single dose of 100 mg after fasting and a high-fat diet.

[0160] Cohort 4 was admitted in two phases with an interval of at least 7 days from the date of administration to evaluate the effect of diet. On the morning of the 1st day of each phase, a single oral dose of the investigational drug was administered with 150 mL of water, depending on the assigned treatment group, either on an empty stomach or after a standard high-fat diet (900 kcal or more, fat content 35% or more) (Fig. 2).

[0161] The specific test method is as follows.

[0162] (1) Test group design

[0163] - Number of subjects: 36 in total

[0164] Single-dose study (SAD), 3 cohorts: Total 24 participants (18 in the study group, 6 in the placebo group)

[0165] Dietary Effects Assessment (FE), 1 cohort: Total 12 participants (12 participants in the test group)

[0166] - Single-dose study (SAD) Total number of subjects: 24

[0167] Cohort Dose Group Number of Subjects (persons) Investigational Medicinal Drug (Test Drug) 1100 mg Salt of Compound 6 of Formula 1 Capsule 100 mg 1 Capsule 2 Capsules Placebo 1 2200 mg Salt of Compound 6 of Formula 1 Capsule 100 mg 2 Capsules 2 Capsules Placebo 2 3400 mg Salt of Compound 6 of Formula 1 Capsule 100 mg 4 Capsules 2 Capsules Placebo 4

[0168] Unit: (persons) Cohort 1 Salt of compound of Formula 1 100 mg Cohort 2 Salt of compound of Formula 1 200 mg Cohort 3 Salt of compound of Formula 1 400 mg Pooled Placebo Total Randomization 666624 Safety Analysis Set 666624 PK Analysis Set 666NA18

[0169] - Total number of subjects in the Dietary Effects (FE) study: 12

[0170] Cohort Dose Group Number of Subjects Investigational Medicinal Product (Test Drug) 4 * 100 mg 12 Salts of Compound of Chemical Formula 1 1 Capsule 100 mg

[0171] *Cohort 4 subjects were divided into two sequential groups of six to evaluate the effects of diet.

[0172] Cohort 4 units: (persons) Sequence 1 Test drug 100 mg (Fasted → Fed) Sequence 2 Test drug 100 mg (Fed → Fasted) Total Randomization 6612 Safety Analysis Set 6612 PK Analysis Set 6612

[0173] (2) Selection of test subjects

[0174] - Subjects for this test were selected from those who satisfied the following subject selection criteria:

[0175] 1) Healthy adult volunteers aged 19 to 50 at the time of screening

[0176] 2) Weight is between 40.0 kg and 90.0 kg, and Body Mass Index (BMI) is 18.5 kg / m² 2 Above 29.9 kg / m² 2 Persons below

[0177] Body Mass Index (BMI, kg / m²) 2 ) = Weight (kg) / {Height (m)} 2

[0178] 3) For female volunteers, those who are not pregnant or breastfeeding, or who are in natural menopause (natural amenorrhea for at least 12 months) or surgically infertile (bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, etc.)

[0179] 4) Persons who, after receiving a sufficient explanation and understanding of this clinical trial, voluntarily decide to participate and consent in writing to comply with the precautions.

[0180] 5) Persons deemed suitable as subjects for this study by the Principal Investigator (or study manager) based on physical examination, clinical laboratory tests, medical history, etc.

[0181]

[0182] - For this test, individuals who met any of the following exclusion criteria were excluded from the test subjects:

[0183] 1) Persons with a history of or currently active clinically significant diseases corresponding to the hepatobiliary system (severe liver impairment, viral hepatitis, etc.), kidney (severe renal impairment, etc.), nervous system, immune system, respiratory system, digestive system, endocrine system, hematology / oncology, cardiovascular system (heart failure, Torsades de pointes, etc.), urinary system, psychiatric system (mood disorders, obsessive-compulsive disorder, etc.), sexual dysfunction, pancreatitis, and medullary thyroid cancer, etc. (provided that registration is possible if a history of complete recovery does not affect the current health status).

[0184] 2) Persons with a history of gastrointestinal diseases (Crohn's disease, ulcer, gastritis, gastric cramps, gastroesophageal reflux disease, etc.) or surgery (excluding simple appendectomy or hernia surgery) that may affect the evaluation of the safety and pharmacokinetics of the investigational medicinal product.

[0185] 3) Persons who have a hypersensitivity reaction to the components of the investigational medicinal product or drugs of the same class, or other drugs (aspirin, antibiotics, etc.), or who have a history of clinically significant hypersensitivity reactions.

[0186] 4) Those who showed one or more of the following results in clinical laboratory tests during the screening process

[0187] · Blood AST or ALT > 1.5 times the upper limit of normal

[0188] · Blood Total bilirubin > 1.5 times the upper limit of normal

[0189] · Glomerular filtration rate (eGFR, CKD-EPI) < 60 mL / min / 1.73m 2

[0190] 5) Those who test positive in serum tests (Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV), Syphilis).

[0191] 6) Persons with a history of alcohol or drug abuse, or who have tested positive for abused drugs in alcohol breath tests or urine drug screening tests.

[0192] 7) Those who show any of the following values ​​in vital signs measured in a seated position after resting for at least 5 minutes during the screening test.

[0193] · Systolic blood pressure < 90 mmHg or > 150 mmHg

[0194] · Diastolic blood pressure < 60 mmHg or > 100 mmHg

[0195] 8) Those who showed QT / QTc > 450 msec (male), QT / QTc > 470 msec (female), or clinically significant abnormalities in the 12-lead electrocardiogram results during the screening test.

[0196] 9) Persons who have taken any prescription drugs or herbal medicines within 2 weeks prior to the scheduled date of administration of the investigational drug, or who have taken any over-the-counter (OTC) drugs, health functional foods including liver function supplements, or vitamin preparations within 1 week, or who are expected to take such drugs (provided that they may participate in the clinical trial if it is determined by the Principal Investigator (or investigator) that there will be no effect on the clinical trial results).

[0197] 10) Persons who have taken drug-metabolizing enzyme-inducing drugs such as barbiturates or drug-metabolizing enzyme-inhibiting drugs such as clarithromycin within 30 days prior to the scheduled date of administration of the investigational drug.

[0198] 11) Persons who received the investigational drug by participating in another clinical trial (including bioequivalence studies) within 180 days prior to the scheduled date of administration of the investigational drug.

[0199] 12) Persons who have donated whole blood within 60 days or apheresis within 30 days prior to the scheduled date of administration of the investigational drug, or who have received a blood transfusion.

[0200] 13) Smokers (provided that subjects who have quit smoking 90 days prior to the scheduled date of administration of the investigational drug may be selected as subjects)

[0201] 14) Persons who continuously consume alcohol (exceeding 21 units / week, 1 unit = 10 g of pure alcohol) or who are unable to abstain from alcohol during the period from 3 days prior to the scheduled date of administration of the investigational drug until the end of the clinical trial.

[0202] 15) Persons who have continuously consumed excessive caffeine (exceeding 5 units / day, 1 unit = 80 mg of caffeine) or who cannot refrain from consuming caffeine-containing foods (coffee, tea (black tea, green tea, etc.), carbonated beverages, coffee milk, energy drinks, sports drinks, etc.) during the period from 3 days before the scheduled date of administration of the investigational drug until the end of the clinical trial.

[0203] 16) Those with unusual dietary habits (e.g., consuming more than 1 liter of grapefruit juice per day) or those unable to consume the standardized diet provided by the clinical trial center during hospitalization

[0204] 17) For women of childbearing age*, those who tested positive for pregnancy (Urine hCG) prior to the start of administration of the investigational drug

[0205] *Fertile period: When one year has not passed since menopause, or when surgical sterilization (hysterectomy, bilateral salpingectomy, etc.) has not been performed

[0206] 18) Persons who, from the time of written consent until at least 90 days after administration of the investigational drug, are unable or unwilling to use medically acceptable contraception, and persons who do not consent not to donate sperm for at least 90 days or eggs for at least 4 weeks.

[0207] ※ Medically accepted contraception

[0208] · Use of an intrauterine device with a proven pregnancy failure rate for oneself or one's spouse (or partner)

[0209] · Physical barriers used in combination with chemical barriers (spermicides) (diaphragms, uterine caps, condoms, etc.)

[0210] · Surgery on yourself or your spouse (or partner) (vasectomy, salpingectomy / ligation, hysterectomy)

[0211] 19) Persons whom the Principal Investigator (or investigator) has determined to be unsuitable for participation in the clinical trial for reasons other than those listed above.

[0212] (3) Procedure for administering investigational drugs

[0213] On the day of administration of the investigational drug (1d), at around 9:00 AM, the subject was given a single oral dose of the assigned investigational drug or placebo while on an empty stomach after fasting for at least 10 hours.

[0214] Subjects of the dietary effect assessment cohort were administered the investigational drug on an empty stomach or on a standard high-fat diet (900 kcal or more, fat content 35% or more) according to the treatment group assigned on the morning of each administration day (1d). For post-meal administration, the high-fat diet was started 30 minutes before the administration of the investigational drug, the meal was completed within 20 minutes, and the administration of the investigational drug was carried out. All subjects were instructed to swallow the investigational drug whole with 150 mL of water and not to chew or crush the drug before swallowing.

[0215] (4) Investigational drug

[0216] - Test drug: Salt capsule of compound of Chemical Formula 1, 100 mg (hard capsule with white upper and lower parts, filled with white to off-white powder)

[0217] - Placebo: Placebo capsule for the salt of the compound of Formula 1 (capsule of the test drug component excluding the salt of the compound of Formula 1)

[0218] 2. Analysis Method

[0219] 2-1. Safety Analysis

[0220] All safety analyses were summarized by treatment group for the Safety Analysis Set.

[0221] 1) Adverse Events

[0222] All adverse events (AEs) were standardized according to the Medical Dictionary for Regulatory Activities (MedDRA) version 26.1, and the principal investigator and authorized investigators evaluated the severity of adverse events based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Treatment Emergent Adverse Events (TEAEs) were defined as adverse events that occurred after administration of the investigational medicinal product or adverse events whose severity worsened after administration of the investigational medicinal product.

[0223] Adverse events were listed for each subject, along with information on symptoms and signs, start time, end time, course, outcome, severity, causal relationship with the investigational medicinal product, measures taken in relation thereto, and whether it was a serious adverse event. Serious adverse events (SAEs), death / life-threatening adverse events (TEAEs Resulting in Death / Life-Threatening), and adverse events leading to discontinuation of the clinical trial (TEAEs Leading to Discontinuation) were listed separately.

[0224] The number and proportion of subjects who experienced one or more adverse events, and the incidence rate were summarized by treatment group based on System Organ Class (SOC), Preferred Term (PT), causal relationship with the investigational drug, and severity.

[0225] 2) Clinical laboratory test

[0226] In the clinical laboratory tests, descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum) for each treatment group and each visit of the single-dose study (SAD) group regarding the values ​​of continuous variables and the change from baseline were presented. For the dietary effect assessment (FE) group, descriptive statistics for each order group and each visit were presented.

[0227] For categorical variables, the number and percentage of subjects for each treatment group and each visit in the single-dose study (SAD) group were presented, and the number and percentage of subjects for each order group and each visit in the dietary effect assessment (FE) group were presented.

[0228] All clinical laboratory test results were classified as Normal, Clinically Insignificant Abnormal (NCS), or Clinically Significant Abnormal (CS), and the number and percentage of subjects for each treatment group and each visit were presented.

[0229] For all clinical laboratory test items, the number and percentage of subjects who changed from normal or clinically insignificant abnormality (NCS) to clinically significant abnormality (CS) before administration of the investigational drug were presented. A shift table was presented for test items that changed to clinically significant abnormality (CS) after administration of the investigational drug.

[0230] For subjects who showed clinically significant abnormalities (CS) after administration of the investigational drug, a list of laboratory test results for the relevant test items was presented.

[0231] 3) Vital signs

[0232] Descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum) for vital signs regarding the change from baseline were presented for each treatment group and each visit.

[0233] A list of vital signs was presented for subjects who experienced one or more clinically significant abnormalities (CS) after administration of the investigational drug.

[0234] 4) 12-Lead ECG

[0235] For the 12-lead electrocardiogram, descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum) regarding the change from baseline were presented for each treatment group and each visit. The number and percentage of subjects who changed from normal or clinically insignificant abnormality (NCS) to clinically significant abnormality (CS) prior to administration of the investigational drug were presented, and the corresponding test results were to be presented as a list.

[0236] 2-2. Pharmacokinetic Analysis

[0237] Pharmacokinetics Software Phoenix WinNonlin ® (Version 8.3.3, Certara, NJ, USA) was used, and pharmacokinetic parameters were calculated using a non-compartmental analysis method. The results of the pharmacokinetic evaluation were presented as descriptive statistics according to the dose group or treatment group. To evaluate the dose-proportionality of the investigational drug, C according to dose max and AUC last Regression analysis was performed on each parameter, and after dose-normalized, the differences between dose groups were compared through parametric and non-parametric statistical tests.

[0238] For Cohort 4, C to evaluate dietary effects max and AUC last The geometric mean ratio and 90% confidence interval of the high-fat diet state compared to the fasting state were calculated by log-transforming it.

[0239] 3. Analysis Results

[0240] 3-1. Safety Analysis Results

[0241] In both the single-dose study (SAD) and the dietary effect assessment study (FE), no serious adverse events or gastrointestinal adverse reactions such as diarrhea, abdominal pain, or upper abdominal discomfort were observed. It was confirmed that all adverse events that occurred after administration resolved without drug treatment.

[0242] Accordingly, it was confirmed that the salt of the compound of Formula 1 of the present invention has fewer side effects compared to other drugs in a similar dosage range.

[0243] 3-2. Results of Pharmacokinetic Analysis

[0244] (1) Single-dose test (SAD)

[0245] The results of the single-dose administration (SAD) pharmacokinetic analysis are as shown in Table 5, Figure 3, and Figure 4 below.

[0246] Parameter mean Cohort 1 Test drug 100 mg (N=6) Cohort 2 Test drug 200 mg (N=6) Cohort 3 Test drug 400 mg (N=6) T max (h)4.005.465.42C max (μg / L)1215.171955.832606.50AUC last (μg·h / L)7544.5610780.2416172.25AUC inf (μg·h / L)7592.7410796.8416187.37t 1 / 2 (h)2.903.654.41CL / F (L / h)16.1926.6830.11V d / F (L)66.24127.58192.93A e (mg)0.030.030.07f e (%)0.030.020.02CL R (L / h)0.00400.00290.0036

[0247] (* CL / F: Apparent Clearance, V d / F: Volume of Distribution, A e : Amount excreted in urine)

[0248] Referring to Table 5 and Figure 3, C after a single administration of the test drug (SAD) max It occurred at a median of 3.50 to 6.00 hours after administration in all treatment groups, and the mean terminal elimination half-life (t 1 / 2 ) was calculated to be 2.90 to 4.41 hours. Whole-body exposure (C max , AUC last ) showed an increasing trend as the single dose was stepwise increased to 100, 200, and 400 mg. Mean f e (Fractional Excretion) ranged from 0.02 to 0.03%, and CL R Renal Clearance ranged from 0.0029 to 0.0040 L / h. Whole-body exposure (AUC last ) increased dose-proportionally in the dose range of 100 to 400 mg.

[0249] In addition, the SAD clinical trial confirmed that once-daily oral administration of the investigational drug is feasible. In all test groups, blood free drug levels remained at the effective concentration (EC10 measured in the in vitro cAMP test) for more than 18 hours. 90 It exceeded the standard and confirmed that the drug maintained an effective concentration in the blood for more than 18 hours (Fig. 4).

[0250] (2) Food Effect (FE) Test

[0251] The results of the pharmacokinetic analysis of the dietary effect assessment (FE) test are as shown in Table 6 and Figure 5 below.

[0252] Parameter mean Cohort 4 Test drug 100 mg (Fasted) (N=12) Cohort 4 Test drug 100 mg (Fed) (N=12) T max (h)4.736.50C max (μg / L)1170.67740.08AUC last (μg·h / L)8378.338660.89AUC inf (μg·h / L)8405.418693.18t 1 / 2(h)3.714.45CL / F (L / h)12.4813.02V d / F (L)64.7278.85A e (mg)0.020.01fe (%)0.020.01CL R (L / h)0.00210.0016

[0253] (* CL / F: Apparent Clearance, V d / F: Volume of Distribution, A e : Amount excreted in urine)

[0254] Referring to Table 6 and Figure 5, in the dietary effect assessment (FE) study, the time taken to reach maximum blood concentration was similar when a single dose of 100 mg of the test drug was administered on an empty stomach and after a high-fat meal, with a median of 6.00 hours, and compared to administration on an empty stomach, C when administered after a high-fat meal max It decreased by approximately 34%. However, systemic exposure (AUC) of the test drug upon fasting and post-meal administration last The degree was similar.

[0255]

[0256] In conclusion, systemic exposure to the test drug increased dose-proportionally in the dose range of 100 to 400 mg upon single administration, and it was confirmed that the presence or absence of food did not affect this.

[0257]

[0258] Example 2. Analysis of safety, tolerability, and pharmacokinetic characteristics according to repeated administration study (MAD) (Phase 1 clinical trial)

[0259] A randomized, double-blind, placebo-controlled, repeated-dose, stepwise dose-escalation Phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic characteristics of the test drug after oral administration to healthy adults.

[0260] 1. Test Design

[0261] The repeated administration (MAD) clinical trial recruited 12 participants per cohort (10 in the treatment group and 2 in the placebo group) and was conducted with three dose groups (Cohorts 1 / 2 / 3: 50 / 100 / 200 mg), administered orally for 4 weeks without dose titration. A total of 36 participants were randomized, and 31 completed the study.

[0262] The test subjects were selected based on the same criteria as in Example 1.

[0263] 2. Analysis Method

[0264] 2-1. Safety Analysis

[0265] The safety analysis was conducted on the safety analysis set, which consisted of all subjects who received the investigational medicinal product at least once. Subjects were analyzed based on the drug administered, rather than the drug to which they were randomly assigned. Adverse events were analyzed by treatment group based on evaluation criteria such as severity, seriousness, causality, measures taken, outcomes, and treatments. Descriptive statistics for laboratory tests, vital signs, and 12-lead ECG results at each time point were summarized by treatment group. Physical examinations were comprehensively reviewed, and summaries were presented where clinical significance was found. Results from the Gastrointestinal Symptom Scale were summarized by treatment group based on the total scores according to five major symptom categories.

[0266] 1) Adverse Events

[0267] Adverse events were coded using MedDRA (version 27.1). Summary tables of adverse events (TEAEs) (or adverse drug reactions (ADRs)) occurring after treatment were presented for all subjects in the safety analysis set and for each treatment group. These included the number of subjects who experienced serious adverse events (SAEs) and serious adverse drug reactions (SADRs), TEAEs / ADRs leading to discontinuation of drug administration, and TEAEs / ADRs leading to death, along with the incidence rate (%), number of occurrences, and two-sided 95% exact confidence intervals. The number of subjects in the safety analysis set was used as the denominator when calculating the incidence rate.

[0268] All TEAEs and ADRs that occurred during the clinical trial were summarized by class of administration (SOC) and preferred term (PT), and the total number of subjects, incidence rate (%), and number of cases by administration group were presented. In addition, the number of subjects, incidence rate (%), and number of cases by SOC and PT were presented according to severity and causality with the investigational drug.

[0269] When calculating the number of subjects with adverse events, if a subject experienced the same TEAE multiple times under the same SOC and PT, the number of subjects was counted as one. However, each individual TEAE was included in the count of occurrences. The types of TEAEs (based on SOC and PT criteria) were also presented by severity, classified based on the highest grade (maximum severity) among the TEAEs.

[0270] 2) Clinical laboratory test

[0271] Clinical test results, including hematology, clinical chemistry, urinalysis, and coagulation tests, were summarized by treatment group and time of visit. For continuous variables, descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and maximum) were presented for each measurement and the change from baseline. Categorical variables were summarized by treatment group and time of visit using the number of subjects (N) and percentages (%).

[0272] All clinical test items were classified into Normal, Abnormal NCS, or Abnormal CS based on the normal range. The number of subjects (N) and percentage (%) according to the administration group were summarized for each visit, and the denominator for calculating the percentage was based on the number of subjects for whom results were available at that visit.

[0273] All clinical test results were presented as a list, and a separate list was provided for subjects and items that were normal or clinically insignificant abnormal (Abnormal NCS) at baseline but shifted to clinically significant abnormal (Abnormal CS) at least once after administration of the investigational drug (IP).

[0274] 3) Vital signs

[0275] Vital signs (blood pressure, heart rate, and body temperature) were summarized by treatment group and time of visit using descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and maximum) for each measurement and the change from baseline.

[0276] Vital signs were classified as Normal, Abnormal NCS, or Abnormal CS. The number of subjects (N) and percentage (%) according to the treatment group were summarized for each visit.

[0277] A list was compiled of subjects and items that were normal or clinically insignificant abnormal (Abnormal NCS) at baseline but shifted to clinically significant abnormal (Abnormal CS) at least once after administration of the investigational drug (IP).

[0278] 4) 12-lead electrocardiogram

[0279] 12-lead electrocardiogram results were summarized by treatment group and time of visit using descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and maximum) for each measurement and the change from baseline.

[0280] The 12-lead electrocardiogram comprehensive readings were classified as normal, clinically insignificant abnormal (Abnormal NCS), or clinically significant abnormal (Abnormal CS), and the number of subjects (N) and percentage (%) by treatment group were summarized at each visit.

[0281] A list of individual subjects including information on the administration group was created.

[0282] 5) Physical examination

[0283] For the physical examination, a list of subjects showing abnormal findings, including baseline results, was compiled. The list included information on the treatment group.

[0284] 6) Gastrointestinal Symptom Rating Scale (GSRS)

[0285] For GSRS, the results and changes from baseline for the top symptom categories (abdominal pain, reflux, indigestion, diarrhea, constipation) were presented in a list.

[0286] 2-2. Pharmacokinetic Analysis

[0287] Pharmacokinetic analysis was performed on a pharmacokinetic analysis set that had completed the clinical trial, had no significant protocol violations that could affect the analysis, and had evaluable pharmacokinetic results. Appropriate and validated pharmacokinetic software Phoenix WinNonlin was used. ® After obtaining subject-specific pharmacokinetic parameters using the non-compartmental analysis method (Version 8.3.3, Certara, NJ, USA), descriptive statistics of the evaluation variables were presented according to the administered dose.

[0288] The dose proportionality (C_max,ss and AUCtau,ss) of the investigational medicinal product in the steady state was evaluated using dose-normalized comparisons and a log-log power model.

[0289] 2-3. Pharmacodynamic Analysis

[0290] Pharmacodynamic (PD) analysis was performed on a pharmacodynamic analysis set that had completed clinical trials, had no significant protocol violations that could affect the pharmacodynamic analysis, and had evaluable pharmacodynamic results.

[0291] For the pharmacodynamic evaluation, after calculating the values ​​of evaluation variables for each subject, descriptive statistics were presented for the measured values ​​and evaluation variables of the pharmacodynamic evaluation items by dose group and measurement time period.

[0292] For specific evaluation indicators, including serum glucose / insulin and continuous glucose monitoring (CGM) derived measurements, differences between groups were evaluated using parametric or non-parametric statistical tests depending on whether the distribution was normal.

[0293] 3. Analysis Results

[0294] 3-1. Results of Pharmacodynamic Analysis

[0295] (1) Change in weight

[0296] The results of the analysis of weight changes are as shown in Table 7 and Figures 6 to 8 below.

[0297] Body weight (kg) Cohort 1: Test drug 50 mg (N=9) Cohort 2: Test drug 100 mg (N=9) Cohort 3: Test drug 200 mg (N=8) Pooled Placebo (N=5) Total (N=31) Baseline: Day 1 (0h): Mean (SD) 86.33 (5.44) 83.07 (8.30) 88.99 (10.13) 87.66 (13.40) 86.28 (8.92) Day 15 (0h): Mean (SD) 83.51 (5.56) 80.16 (8.76) 84.88 (9.83) 86.00 (13.10) 83.29 (8.89) Change from baseline at Day 15 (0h): Mean (SD) -2.82 (1.42)-2.91(1.02)-4.11(1.45)-1.66(0.80)-2.99(1.43) Percentage of change from initial value at Day 15 (0h) (%) Mean (SD)-3.28 (1.62)-3.58 (1.39)-4.63(1.47)-1.89(0.89)-3.49(1.61) Day 29 (0h) Mean (SD)81.59 (5.94)77.46 (9.25)80.18 (9.33)84.94 (12.74)80.56 (8.98) Change from initial value at Day 29 (0h) Mean (SD)-4.74(2.87)-5.61 (2.11)-8.81 (3.22)-2.72 (1.78)-5.72 (3.25) Percentage of change from initial value at Day 29 (0h) (%) Mean (SD)-5.50 (3.27)-6.89 (2.82)-9.88 (3.02)-3.07 (1.96)-6.64 (3.60)

[0298] As a result of the analysis, dose-dependent weight loss was observed after 28 days of administration, and in particular, statistically significant weight loss was observed in the 100 / 200 mg dose groups compared to placebo (Fig. 6). In addition, the highest dose group (200 mg) showed an excellent average weight loss rate of 9.9% (maximum 13.8%), while the 50 mg and 100 mg test groups showed average weight loss of 5.5% and 6.9%, respectively, and the 200 mg test group showed an average reduction of 9.9% and a maximum reduction of 13.8%, confirming dose-dependent efficacy (Fig. 7). The proportion of subjects who experienced a weight loss of 5% or more was 66.7% in the 100 mg test group and 87.5% in the 200 mg test group, compared to 0% in the placebo group (Fig. 8).

[0299] In other words, it was confirmed that the test drug can show a weight loss of 5.5% to 13.8% over 4 weeks when administered at a daily dose of 50 mg to 200 mg.

[0300] (2) Change in waist circumference

[0301] The results of the waist circumference analysis are as shown in Table 8 and Figure 9 below.

[0302] Waist Circumference (cm) Cohort 1: Test drug 50 mg (N=9) Cohort 2: Test drug 100 mg (N=9) Cohort 3: Test drug 200 mg (N=8) Pooled Placebo (N=5) Total (N=31) Baseline: Day 1 (0h) Mean (SD) 95.82 (5.16) 99.49 (3.34) 101.00 (6.57) 97.94 (3.28) 98.56 (5.08) Day 15 (0h) Mean (SD) 94.53 (5.65) 96.89 (3.29) 98.94 (6.89) 96.80 (4.28) 96.72 (5.26) Change from baseline at Day 15 (0h) Mean (SD) -1.29 (0.99)-2.60 (1.26)-2.06 (1.14)-1.14 (2.38)-1.85 (1.45) Rate of change from initial value at Day 15 (0h) (%) Mean (SD)-1.37 (1.13)-2.61 (1.27)-2.06 (1.15)-1.17 (2.40)-1.88 (1.47) Day 29 (0h) Mean (SD)93.89 (5.93)94.61 (3.73)95.30 (7.76)96.30 (4.97)94.85 (5.58) Change from initial value at Day 29 (0h) Mean (SD)-1.93 (2.14)-4.88 (2.16)-5.70 (1.45)-1.64 (2.82)-3.71 (2.67) Percentage of change from initial value at Day 29 (0h) (%) Mean (SD)-2.04 (2.24)-4.90 (2.18)-5.72 (1.65)-1.70 (2.83)-3.77 (2.71)

[0303] As a result of the analysis, on day 29 (0h), the average decrease in waist circumference from the initial value was 2.0%, 4.9%, and 5.7% in the 50mg, 100mg, and 200mg test groups, respectively, confirming dose-dependent efficacy (Table 8 and Fig. 9).

[0304] (3) Changes in body fat mass and lean body mass

[0305] The results of the body fat mass analysis are as shown in Table 9 and Figure 10 below.

[0306] Body Fat Mass (kg) Cohort 1: Test drug 50 mg (N=9) Cohort 2: Test drug 100 mg (N=9) Cohort 3: Test drug 200 mg (N=8) Pooled Placebo (N=5) Total (N=31) Baseline: Day 1 (0h) Mean (SD) 26.31 (6.09) 30.28 (3.63) 27.45 (6.10) 27.66 (5.42) 27.97 (5.34) Day 15 (0h) Mean (SD) 24.86 (6.08) 29.37 (3.87) 25.18 (6.26) 27.16 (5.57) 26.62 (5.56) Change from Baseline at Day 15 (0h) Mean (SD) -1.46 (1.48)-0.91 (0.62)-2.28 (1.16)-0.50 (0.67)-1.35 (1.21) Rate of change from initial value at Day 15 (0h) (%) Mean (SD)-5.58 (4.73)-3.11 (2.18)-8.72 (5.29)-1.96 (2.84)-5.09 (4.61) Day 29 (0h) Mean (SD)23.89 (6.63)27.83 (4.53)23.51 (6.87)26.04 (5.38)25.28 (5.96) Change from initial value at Day 29 (0h) Mean (SD)-2.42 (2.29)-2.44 (1.35)-3.94 (1.51) -1.62 (1.19) -2.69 (1.80) Percentage of change from initial value at Day 29 (0h) (%) Mean (SD) -9.64 (8.22) -8.42 (4.91) -15.35 (7.02) -5.95 (4.38) -10.17 (7.05)

[0307] As a result of the analysis, the body fat mass of the 200 mg test group decreased by an average of 15.4% (Table 9 and Figure 10).

[0308] In addition, the possibility of increasing lean body mass through the administration of the composition of the present invention was confirmed based on the analysis results of body weight and body fat mass. Accordingly, it was confirmed that the test drug has a significant effect on reducing body fat mass.

[0309] (4) Oral glucose tolerance test

[0310] Area under the blood glucose concentration-time curve (AUGC) for 4 hours after taking glucose solution 0-4h Changes in blood glucose were analyzed by calculating ). The results are shown in Figures 11 and 12.

[0311] Referring to Figures 11 and 12, it was confirmed that there was a blood glucose-lowering effect in all dose groups, and that the blood glucose-lowering effect was dose-dependent.

[0312] (5) Continuous blood glucose monitoring

[0313] Changes in blood glucose levels were monitored by administering the test drug daily for 4 weeks, and the results are shown in Figure 13. Continuous blood glucose monitoring was performed on D-7 to D+7 (14 days) and D+14 to D+28 (14 days).

[0314] Referring to Figure 13, it was confirmed that the blood glucose-lowering effect is dose-dependent and has a significantly superior blood glucose-lowering effect compared to a placebo.

[0315] 3-2. Safety Inspection Results

[0316] Safety test results showed that gastrointestinal side effects were mild even without dose titration, and liver enzyme levels remained within the normal range, raising no concerns regarding hepatotoxicity.

[0317] In addition, although total bilirubin levels increased, this was due to an increase in indirect bilirubin and did not constitute an indicator of hepatotoxicity; most subjects recovered to normal levels within 2 days after discontinuing the medication without any separate measures.

[0318] In other words, it was confirmed that the composition of the present invention is safe.

[0319]

[0320] Example 3. Evaluation of efficacy and safety in obese or overweight patients and weight-related comorbidities (Phase 2 clinical trial)

[0321] A Phase 2, randomized, double-blind, placebo-controlled, dose-range study (Phase 2 clinical trial) was conducted to evaluate the efficacy and safety of the salt of the compound of Formula 1 of the present invention in patients with obesity or overweight and weight-related comorbidities.

[0322] 1. Test Design

[0323] (1) Research period

[0324] Total study duration: 22 weeks (Screening: 4 weeks / Treatment duration: 16 weeks (Dose escalation period: 0–4 weeks) / Safety follow-up: 2 weeks)

[0325] (2) Test group

[0326] - Number of subjects:

[0327] Approximately 200 subjects are scheduled to be randomized in a 1:1:1:1 ratio to one of the three active dose groups of the investigational drug or a placebo group. To ensure a sufficient sample size for men, the enrollment cap for women is set at 70% (expected dropout rate: 25%).

[0328] - Stratification Factors:

[0329] Reference BMI: <35 kg / m² 2 (Overweight / Grade 1 Obesity) Large ≥35 kg / m² 2

[0330] Biological Sex: Male vs. Female

[0331] Random assignment ratio: 1:1:1:1

[0332] Since tolerability and efficacy may differ between men and women, randomization will be stratified according to biological sex (female vs. male). Additionally, subjects will be stratified according to BMI (<35 kg / m² vs. ≥35 kg / m² at baseline and V2 time points).

[0333] (3) Research drug

[0334] - Capacity:

[0335] · Dosage 1: Test drug capsule 50 mg

[0336] · Dosage 2: Test drug capsule 75 mg

[0337] · Dosage 3: Test drug capsule 100 mg

[0338] · Penalty

[0339] - Drug: 25 mg capsule of the test drug and a corresponding placebo

[0340] - Capacity increase plan

[0341]

[0342] (4) Selection of test subjects

[0343] Subjects for this test were selected from those who satisfied the following subject selection criteria:

[0344] 1) Male or female subjects aged 18 (or the legal age of consent in the region where the clinical trial is conducted) or older and 75 years of age or younger at the time of signing the consent form

[0345] 2) Body Mass Index (BMI) is

[0346] ≥30 kg / m 2 or

[0347] ≥27 kg / m 2 and <30 kg / m² 2 In cases where a person has at least one of the following weight-related comorbidities (currently under treatment or untreated)

[0348] Hypertension: Taking antihypertensive drugs or having a systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg at the time of screening. Subjects taking antihypertensive drugs must maintain a stable dose for at least 3 months prior to the screening test and meet the blood pressure control criteria in the clinical trial protocol.

[0349] Dyslipidemia: Taking lipid-lowering agents, or having low-density lipoprotein (LDL) ≥160 mg / dL (4.1 mmol / L) or triglycerides (TG) ≥150 mg / dL (1.7 mmol / L) in a fasting state at the time of screening, or high-density lipoprotein (HDL) <40 mg / dL (1.0 mmol / L) for men and <50 mg / dL (1.3 mmol / L) for women. For subjects receiving lipid-lowering treatment, a stable dose must be maintained for 3 months prior to the screening test.

[0350] Cardiovascular disease: e.g., ischemic cardiovascular disease, New York Heart Association [NYHA] Functional Classification Grade I-III heart failure.

[0351] Obstructive sleep apnea.

[0352] 3) Weight must be stable for 3 months prior to the screening test (i.e., no increase or / or decrease of more than 5% of body weight).

[0353] 4) Participation of prediabetic subjects is permitted only if they do not meet the exclusion criteria for diabetes (i.e., HbA1c 5.7–6.4% (39–47 mmol / mol), or fasting blood glucose 100–125 mg / dL (5.6–6.9 mmol / L), or blood glucose 2 hours after the 75g oral glucose tolerance test (OGTT) 140–199 mg / dL (7.8–11.0 mmol / L)).

[0354] 5) Those who have agreed to the use of adequate contraception.

[0355]

[0356] Individuals who met any of the following exclusion criteria were excluded from the test subjects:

[0357] (Here, subjects corresponding to the above criteria regarding diabetes or blood sugar are excluded in order to more clearly confirm the clinical effects of the pharmaceutical composition of the present invention on obesity or overweight and weight-related comorbidities, and to evaluate the weight loss effect that is not affected by blood sugar control status.)

[0358] These exclusion criteria apply only to clinical evaluations regarding obesity or overweight and weight-related comorbidities, and do not imply the exclusion of these patient groups from disease treatment.

[0359] - Medical condition

[0360] - Diabetes or blood sugar related

[0361] 1. Individuals who currently suffer from or have a history of diagnosis of type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), or rare or secondary forms of diabetes. Note: Women with a history of gestational diabetes whose symptoms resolved after delivery may be selected as subjects if they meet other selection criteria.

[0362] 2. Individuals who, during the screening test, have at least one of the following central laboratory test results suggesting diabetes: Glycated hemoglobin (HbA1c) ≥6.5% (≥48 mmol / mol), fasting blood glucose (FPG) ≥126 mg / dL (≥7.0 mmol / L), or 2-hour blood glucose (2-hr PG) ≥200 mg / dL (≥11.1 mmol / L), or random blood glucose ≥200 mg / dL (≥11.1 mmol / L).

[0363] 3. History of blood glucose-lowering medication administration within 3 months prior to the screening test.

[0364] - Obesity related

[0365] 4. Those who have received drug treatment for weight management within 3 months prior to the screening test

[0366] 5. Previous or planned bariatric surgery, including vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD / DS). The following surgical treatments are excluded from the exclusion criteria: (1) liposuction and / or abdominoplasty performed at least one year prior to screening, (2) wrap banding removed at least one year prior to screening, and (3) duodenojejunal bypass sleeve removed at least one year prior to screening.

[0367] 6. If there is a plan for endoscopic and / or device-based treatment for obesity, or if the device was removed within 6 months prior to screening (this includes, but is not limited to, the following items)

[0368] · Mucosal ablation

[0369] · Gastric artery embolization

[0370] · Intragastric balloon, and

[0371] · Duodenal-jejunal endoluminal liner

[0372] 7. Individuals with obesity caused by monogenic or syndromic obesity resulting from other endocrine disorders (e.g., Cushing's syndrome, hypogonadism, growth hormone deficiency, polycystic ovary syndrome) (e.g., Melanocortin 4 Receptor deficiency or Prader-Willi Syndrome). However, well-controlled hypothyroidism is permitted.

[0373] - Cardiovascular related

[0374] 8. If there is evidence of uncontrolled hypertension (i.e., sitting mean systolic blood pressure ≥160 mmHg or sitting mean diastolic blood pressure ≥100 mmHg), renal artery stenosis, or unstable blood pressure, including symptomatic postural hypotension, at the time of screening. Blood pressure is measured three times, and the subject's eligibility is determined using the average of the three measurements. Subjects taking antihypertensive medication must maintain a stable dose for at least three months prior to screening and meet the hypertension control criteria specified in the protocol.

[0375] 9. History of myocardial infarction, unstable angina, arterial revascularization, cerebrovascular event (stroke), New York Heart Association (NYHA) functioning grade III-IV heart failure, or transient ischemic attack occurring within 6 months prior to the screening test.

[0376] 10. Individuals with a history of or ongoing frequent intermittent or chronic tachyarrhythmia syndromes (e.g., atrial fibrillation, supraventricular tachycardia, and positional orthostatic tachycardia syndrome). Note: Individuals with a history of premature atrial contractions or premature ventricular contractions may be included.

[0377] 11. Individuals exhibiting clinically significant abnormal findings on a 12-lead electrocardiogram that may affect the subject's safety or the interpretation of test results (e.g., QTcF (Fridericia) interval >450 msec, complete left bundle branch block, signs of acute or unexplained myocardial infarction, ST-T segment changes suggestive of myocardial ischemia, second-degree or third-degree atrioventricular block, or severe bradyarrhythmia or tachyarrhythmia). If the QTcF exceeds 450 msec or the QRS width exceeds 120 msec, the electrocardiogram must be repeated two more times, and the average of the three measured QTcF or QRS values ​​must be used to determine eligibility. Computer-readable electrocardiogram results must be re-read by a physician with extensive experience in reading electrocardiograms before the subject is excluded.

[0378] 12. A history of long QT syndrome in the individual or a direct family member within the first degree of kinship, a family history of sudden death before age 40 among direct family members within the first degree of kinship, or a history of syncope of unknown cause occurring within the last year.

[0379] 13. If being treated with drugs known to cause cardiac block or bradycardia, such as beta-blockers, verapamil, or diltiazem (except where such drugs are necessary for heart rate control or treatment of hypertension).

[0380] - Liver related

[0381] 14. Individuals with signs and symptoms of liver disease other than non-alcoholic fatty liver disease (NAFLD), or those meeting any of the following criteria confirmed by the central laboratory during screening (re-testing is permitted during the screening period)

[0382] · ALT or AST levels >3.0xULN

[0383] · ALP >2.0xULN

[0384] · TBL value >1.5xULN

[0385] · Current or past hepatitis B infection (defined as follows):

[0386] HBsAg positive reaction or

[0387] HBcAb positive and HBV DNA positive

[0388] · Positive for Hepatitis C antibodies and Hepatitis C virus RNA (Participants who are positive for Hepatitis C antibodies but negative for Hepatitis C virus RNA are eligible to participate)

[0389] - Endocrine related

[0390] 15. Persons who, or a direct family member within the first degree of kinship, have a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2).

[0391] 16. Those whose serum calcitonin levels meet the following criteria at screening

[0392] · eGFR calculated using the CKD-EPI formula ≥60 mL / min / 1.73m 2 In the case of, ≥20 ng / L or

[0393] · For eGFR <60 mL / min / 1.73m², ≥35 ng / L

[0394] 17. Subjects with evidence of hypothyroidism or hyperthyroidism that, in the investigator's judgment based on clinical evaluation and / or abnormal thyroid-stimulating hormone levels, may pose a risk to patient safety. Subjects who have been receiving thyroid hormone replacement therapy at a stable dose for at least 3 months, have clinically normal thyroid function, and are expected to maintain that dose throughout the study period may participate provided they meet other selection criteria.

[0395] 18. Where there is evidence of significant and uncontrolled endocrine abnormalities (e.g., thyrotoxicosis or adrenal crisis) in the researcher's judgment.

[0396] - Mental health

[0397] 19. If there is a history of active or unstable major depressive disorder or other severe mental illness (e.g., schizophrenia, bipolar disorder, or other severe mood disorder or anxiety disorder) within 2 years prior to the screening test.

[0398] 20. If the Patient Health Questionnaire-9 (PHQ-9) score is 15 or higher at the screening and baseline visit.

[0399] 21. If there has been a history of suicide attempt at least once in a lifetime, or if suicidal behavior occurred within 30 days prior to the screening test.

[0400] 22. If you answer "Yes" to question 4 or 5 in the "Suicidal Thoughts" section of the C-SSRS, and the thought occurred within 30 days prior to the screening test and baseline visit. Or if you answer "Yes" to any of the suicide-related behaviors listed in the "Suicidal Behaviors" section of the C-SSRS, and the behavior occurred within 30 days prior to the screening test and baseline visit.

[0401] - Other medical conditions

[0402] 23. Any conditions that may affect drug absorption (e.g., history of gastrectomy, history of intestinal resection, active inflammatory bowel disease, or pancreatic insufficiency).

[0403] 24. In cases of clinically significant and known gastric emptying abnormalities (e.g., severe gastroparesis or gastric outlet obstruction) or chronic use of drugs that directly affect gastrointestinal motility.

[0404] 25. Presence or history of malignant neoplasms within 5 years prior to screening (excluding basal or squamous cell skin cancer, in-situ carcinomas of the cervix, carcinoma in situ, or prostate cancer with a Gleason score of 6 or lower).

[0405] 26. The estimated glomerular filtration rate (eGFR) calculated by Chronic Kidney Disease-Epidemiology (CKD-EPI) is 45 mL / min / 1.73m 2 In cases of renal impairment below a certain level.

[0406] 27. A history of acute pancreatitis or chronic pancreatitis within 6 months prior to the screening test. If, at the time of the screening test, serum lipase levels are more than twice the upper limit of normal, serum amylase levels are more than twice the upper limit of normal, or fasting serum triglyceride levels are 500 mg / dL (or 5.65 mmol / L) or higher.

[0407] 28. Cases where there is a medical history or persistent symptoms of gallbladder disease. However, subjects who have undergone cholecystectomy, or subjects with a history of acute pancreatitis caused by gallstones who have undergone cholecystectomy to resolve the problem, may participate in the clinical trial.

[0408] 29. Where there is evidence of a severe active autoimmune disorder (e.g., lupus, Crohn's disease, ulcerative colitis, multiple sclerosis, or rheumatoid arthritis, etc.) that, in the investigator's judgment, may require concomitant systemic steroid treatment during the study period.

[0409] 30. History of human immunodeficiency virus (HIV) infection and / or confirmation of a positive HIV antibody reaction in the past or during screening tests.

[0410] 31. If 500 mL or more of blood (excluding plasma donation) was donated within 8 weeks prior to the screening test, or if there was a blood transfusion or severe bleeding within 3 months prior to the screening test.

[0411] 32. In the presence of hemoglobinopathy (e.g., hemolytic anemia, sickle cell anemia) or other diseases known to affect the measurement of glycated hemoglobin (HbA1c).

[0412] 33. In the case of Gilbert syndrome or Crigler-Najjar syndrome.

[0413] - Previous / concurrent treatment or experience

[0414] 34. When receiving a potent UGT1A1 inhibitor.

[0415] 35. If you are or have received chronic systemic steroid therapy (for more than 2 weeks) within 3 months prior to the screening test.

[0416] 36. Cases where a hypoglycemic agent was used regardless of the indication for use. Examples of hypoglycemic agents are as follows, but are not limited to:

[0417] · Insulin

[0418] · Metformin

[0419] · Thiazolidinediones: Pioglitazone, Rosiglitazone

[0420] · Sulfonylurea derivatives: Acetohexamide, Chlorpropamide, Tollazamide, Tolbutamide, Glimepiride, Glipizide, Glyburide

[0421] · Meglitinide analogs: Repaglinide, Nateglinide

[0422] · DPP-4 Inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Vildagliptin, Alogliptin

[0423] · α-glucosidase inhibitors: acarbose, miglitol

[0424] · SGLT2 Inhibitors: Canagliflozin, Empagliflozin, Dapagliflozin, Ertugliflozin

[0425] · Antihyperglycemic agents: Bromocriptine, Colesevelam

[0426] · Oral GLP-1 receptor agonists: dulaglutide, liraglutide, semaglutide, exenatide, tyrzepatide

[0427] 37. If currently taking central nervous system stimulants (e.g., methylphenidate, phentermine, bupropion) (except for caffeine beverages during screening).

[0428] 38. If immunosuppressants such as cyclosporine and tacrolimus were used within 60 days prior to the screening test.

[0429] 39. At least 2 weeks prior to screening or drug half-life (t 1 / 2 When using a drug known to significantly prolong the QT or QTc interval for the longer of the five times the period.

[0430] 40. Where alcohol or recreational drug abuse is confirmed or suspected. Where average weekly alcohol intake exceeds 14 drinks per week for men and 7 drinks per week for women [1 drink = 12 oz (360 mL) of beer (5% alcohol), 5 oz (150 mL) of wine (12% alcohol), 1.5 oz (45 mL) of spirits (40% alcohol)].

[0431] 41. If there is a history of using marijuana or tetrahydrocannabinol (THC)-containing products within 3 months of the screening test, or if there is no intention to discontinue use during the test period.

[0432] 42. If the subject has used or is currently taking medications that may cause weight gain (including tricyclic antidepressants, atypical antipsychotics, mood stabilizers, etc.) within 3 months of the screening test. However, subjects who are taking such medications at a stable dose (taking them for at least 6 months and not expecting a dose change during the study period) and whose weight has remained stable over the past 6 months may be included in the clinical trial. Examples of medications that cause weight gain are as follows:

[0433] · Antidepressants: Imipramine, Amitriptyline, Mirtazapine, Paroxetine, Phenelzine

[0434] · Antipsychotic drugs: Clozapine, Olanzapine, Risperidone, Quetiapine, Chlorpromazine, Thioridazine

[0435] · Anticonvulsants: Valproic acid and its derivatives, divalproex, gabapentin

[0436] · Mood stabilizer: Lithium

[0437] However, selective serotonin reuptake inhibitors other than paroxetine are permitted.

[0438] 43. If the investigational medicinal product was administered within 30 days prior to randomization (or a period determined by regional regulations) or within 5 times the half-life of the drug, whichever is longer.

[0439] 44. If you have been exposed to a GLP-1 analog or other related compound within the past 3 months, or have a history of hypersensitivity or allergy to such drugs. If you have a known or suspected hypersensitivity reaction to investigational medicinal products, selective GLP-1 receptor agonists, GIP / GLP-1 dual receptor agonists, GLP-1 / Geg dual receptor agonists, or GIP / GLP-1 / Geg triple receptor agonists.

[0440] 45. Subjects who have previously taken GLP-1 analogs or related compounds but have discontinued the medication due to intolerance issues or lack of efficacy.

[0441] 46. ​​If medications or alternative therapies (including herbs / nutritional supplements) for weight loss were taken within 3 months of the screening test. Examples include, but are not limited to, the following:

[0442] · Saxenda ® (Liraglutide)

[0443] · Wigobi ® ( Semaglutide)

[0444] · Jebbound ® (Tyrzepatide)

[0445] · Adipex ® Or Romayara ® (Phentermine)

[0446] · Qsymia ® (Phentermine / Topiramate combination)

[0447] · Contraby ® (Naltrexone / Bupropion)

[0448] · Xenical ® / all ® (Orlystart)

[0449] · Im Si-bri ® (Cetmelanotide)

[0450] · Meridia ® (Sibutramine)

[0451] · Acutrim ® (Pyrentillpropanolamine)

[0452] · Sanorex ® (Margindol)

[0453] · Belviq ® (Locaserin)

[0454] - Other exclusions

[0455] 47. Women of childbearing age who are pregnant or breastfeeding, or who plan to become pregnant during the clinical trial.

[0456] 48. Subjects who have no intention or are unable to comply with the lifestyle considerations of the clinical trial protocol.

[0457] 49. Subjects deemed unsuitable for participation in a clinical trial based on the judgment of the investigator or sponsor.

[0458] 2. Evaluation Variables

[0459] (1) Primary efficacy evaluation variable

[0460] The primary endpoint was the percentage change in body weight from baseline at 16 weeks. A repeated measures mixed model (MMRM) was used with baseline body weight as a covariate, and the treatment group, visits, treatment-visit interaction, sex, and BMI stratification at baseline were included as fixed effects.

[0461] An atypical covariance matrix was applied to model within-subject correlations, and if the model failed to converge, Toeplitz, autoregressive, or complex symmetric structures were tested sequentially. The least squares mean, two-sided 95% confidence intervals, and nominal p-values ​​for each dose relative to placebo were presented.

[0462] In addition, an auxiliary ANCOVA using the full analysis group (FAS) was performed on the rate of change in body weight from baseline at 16 weeks, and missing data were processed using multiple supplementation based on the assumption of random omission.

[0463] (2) Secondary efficacy evaluation variable

[0464] Secondary efficacy endpoints include absolute and percentage changes in body weight, BMI, and waist circumference from baseline, the rate of achieving 5% and 10% or more of weight loss, high-sensitivity C-reactive protein, blood pressure, heart rate, blood glucose indicators (HbA1c, fasting plasma glucose, fasting plasma insulin), and lipid parameters (total cholesterol, HDL, LDL, VLDL, triglycerides).

[0465] Continuous secondary evaluation variables were analyzed using MMRM or ANCOVA with baseline values ​​as covariates, categorical secondary evaluation variables were analyzed using logistic regression or longitudinal logistic regression including repeated measures, and missing values ​​were handled using appropriate methods including multiple supplementation as otherwise specified in the statistical analysis plan.

[0466] Simulation results conducted during the development of the statistical analysis plan showed that logistic regression analysis combined with multiple imputation for missing values ​​provided smaller variance estimates than longitudinal logistic regression analysis, and accordingly, the planned analysis approach was updated.

[0467] (3) Exploratory evaluation variables

[0468] Exploratory analysis includes dose-response and exposure-response modeling for key efficacy and safety endpoints, patient-reported outcomes related to appetite and quality of life measures, and subgroup analyses based on demographics and baseline characteristics (using the appropriate method between MMRM or population PK / PD modeling).

[0469] Patient-reported outcomes (PROs) related to appetite and quality of life measurements were analyzed as exploratory endpoints. The analysis was limited to subjects with PRO assessment data at baseline and at least one PRO assessment data set since baseline. For continuous PRO endpoints (SF-36v2 and IWQOL-Lite-CT), the change from baseline was analyzed using MMRM or ANCOVA with the treatment group as a fixed effect and the baseline PRO score as a covariate. The PGI-C (Patient Gap Indicator) endpoint was descriptively summarized by treatment group and visit. When inferential analysis was performed, an appropriate ordinal model may be applied as specified in the statistical analysis protocol. Subjects were analyzed according to their randomized treatment groups.

[0470] For the normalization evaluation variable of impaired glucose tolerance (IGT) at the 16-week mark, the analysis was limited to subjects who had impaired glucose tolerance at baseline. If a 16-week classification value is missing, it is imputed using multiple imputation (MI) under the assumption of random missing values, and in the sensitivity analysis, missing values ​​may be treated as 'not normalized'.

[0471] Multiplicity adjustment was not applied to secondary or exploratory endpoints, and the results were interpreted in an exploratory manner.

[0472] 3. Results

[0473] 3-1. Efficacy Analysis

[0474] In a test group administered the compound of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof (subjects who are obese or overweight and have one or more weight-related comorbidities), the minimum dose of the once-daily test drug is expected to be superior to the placebo in terms of weight loss rate at week 16.

[0475] 3-2. Safety Analysis

[0476] Sufficient safety is expected to be observed in a test group administered the compound of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof.

Claims

1. A pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 25 mg to 400 mg: [Chemical Formula 1] .

2. A pharmaceutical composition according to claim 1, wherein the dosage of the composition is based on the free base of the compound represented by Chemical Formula 1.

3. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a Tris salt.

4. A pharmaceutical composition according to claim 1, wherein the composition is for oral administration.

5. A pharmaceutical composition according to claim 1, wherein the composition is administered once or twice a day.

6. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day.

7. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 25 to 250 mg.

8. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 25 to 200 mg.

9. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 50 to 200 mg.

10. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 50 to 100 mg.

11. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg.

12. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in a total of 50 mg, 75 mg, or 100 mg.

13. A pharmaceutical composition according to claim 1, wherein the composition is administered before a meal or after a meal.

14. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day for 1 to 32 weeks.

15. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day for 1 to 16 weeks.

16. In paragraph 1, the metabolic disease is diabetes mellitus, idiopathic type 1 diabetes mellitus, latent autoimmune diabetes mellitus in adults (LADA), early-onset type 2 diabetes mellitus (EOD), atypical diabetes mellitus in minors (YOAD), adult-onset diabetes mellitus in minors (MODY), malnutrition-associated diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, visceral fat accumulation, obstructive sleep apnea, obesity, childhood obesity / overweight, overweight and weight-related comorbidities, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), metabolic disorder-associated steatohepatitis, atherosclerosis, hypertension, cardiovascular disease, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, metabolic acidosis, A pharmaceutical composition comprising one or more selected from the group consisting of ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, vision loss, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, vascular restenosis, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyper-apo-B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

17. A pharmaceutical composition according to claim 1, wherein the metabolic disease is one or more selected from the group consisting of diabetes mellitus, idiopathic type 1 diabetes mellitus, latent autoimmune diabetes mellitus in adults (LADA), early-onset type 2 diabetes mellitus (EOD), atypical diabetes mellitus in minors (YOAD), adult-onset diabetes mellitus in minors (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, hyperglycemia, obesity, and eating disorders.

18. A pharmaceutical composition according to claim 1, wherein the metabolic disease is obesity, childhood obesity / overweight, or overweight and weight-related comorbidities.

19. A pharmaceutical composition according to claim 18, wherein the weight-related comorbidities are one or more selected from hypertension, diabetes mellitus, dyslipidemia, hypercholesterolemia, and obstructive sleep apnea.

Images