Use of GLP-1 / GIP peptide or pharmaceutical composition containing same

Abstract

Provided is a method for treating type 2 diabetes (T2D) using a new dosing regimen of a GLP-1 / GIP peptide, the peptide being a GLP-1 / GIP co-agonist, and provided is a method for inducing T2D remission using a new dosing regimen of a GLP-1 / GIP peptide. Also provided is a method for treating obesity using a new dosing regimen of a GLP-1 / GIP peptide. Further provided is a method for treating overweight with hypertension / obesity with hypertension using a GLP-1 / GIP peptide, the method for treating hypertension comprising a step of administering to a subject in need thereof a therapeutically effective amount of the GLP-1 / GIP peptide or a pharmaceutical composition containing same.

Description

Use of GLP-1 / GIP peptides or pharmaceutical compositions containing them

[0001] Cross-reference declaration

[0002] This disclosure claims priority to Chinese Patent Application No. 202411177780.7, filed on August 26, 2024, entitled "Method for treating type 2 diabetes or obesity in patients in need". The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference.

[0003] This disclosure claims priority to Chinese Patent Application No. 2025101210490, filed on January 24, 2025, entitled "Use of GLP-1 / GIP peptide or pharmaceutical composition containing the same". The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0004] This disclosure pertains to the field of pharmaceutical technology, specifically relating to the use of a GLP-1 / GIP peptide or a pharmaceutical composition containing the same. Background Technology

[0005] Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic β-cells and protecting pancreatic β-cells in the presence of glucose. Glucagon-like peptide-1 (GLP-1) is a 37-amino acid peptide that stimulates insulin secretion, protects pancreatic β-cells, and inhibits glucagon secretion, gastric emptying, and food intake, leading to weight loss. GIP and GLP-1 are secreted by K cells and L cells of the small intestinal endothelium, respectively, and are collectively known as incretins. Incretin receptor signaling plays a crucial physiological role in glucose homeostasis.

[0006] Both GIP and GLP-1 exert their physiological effects by binding to their specific receptors, namely the GIP (GIPR) receptor and the GLP-1 receptor (GLP-1R). Studies have shown that co-activation of GLP-1R / GIPR can exert a synergistic hypoglycemic effect, and dual receptor agonists of GIP and GLP-1 may produce even better hypoglycemic effects and insulin secretion stimulation. Therefore, the development of GLP-1 and GIP dual receptor agonists and their drug combinations with good efficacy has been one of the research hotspots in the treatment of metabolic diseases such as diabetes and obesity.

[0007] Obesity combined with hypertension is a common and serious combination of chronic diseases, posing a significant burden on individual health and socioeconomic status. According to a 2022 study published in *The Lancet*, the number of obese individuals worldwide more than doubled between 1990 and 2022, reaching 2.5 billion overweight adults globally in 2022, representing 43% of the adult population, of whom 890 million were obese. The World Health Organization (WHO) has defined obesity as a serious chronic disease requiring focused management. Studies show that up to 80% of primary hypertension cases are closely related to overweight or obesity, with 78% of hypertension cases in men and 65% in women attributable to obesity. Obesity is not only a major risk factor for hypertension, but hypertension is also a common complication of obesity.

[0008] The pathogenesis of obesity-related hypertension has become a research hotspot and has attracted widespread attention from scholars. Insulin resistance is one of the important pathogenic factors. First, insulin resistance leads to increased sodium reabsorption in the renal tubules and high salt sensitivity, thereby promoting sodium retention. Second, insulin resistance accompanied by hyperinsulinemia enhances sympathetic nerve activity through the central nervous system, thereby promoting increased heart rate and vasoconstriction, leading to increased peripheral vascular resistance and promoting the activation of the RAAS (renin-angiotensin-aldosterone system), exacerbating hypertension. Third, insulin resistance weakens the effect of insulin in stimulating nitric oxide (NO) synthesis, resulting in decreased vasodilatory capacity. Endothelial cells secrete more endothelin, exacerbating vasoconstriction and inducing oxidative stress and inflammatory responses. These mechanisms further damage vascular endothelial function, leading to arterial stiffness and elevated blood pressure. Fourth, insulin resistance is associated with an imbalance in the secretion of obesity-related adipokines (such as leptin and adiponectin), and this imbalance further affects blood pressure regulation. In summary, addressing insulin resistance may be an effective approach to treating obesity-related hypertension.

[0009] Previous studies have shown that GLP-1 receptor agonists can significantly reduce the homeostasis model index of insulin resistance (HOMA-IR) and improve insulin sensitivity in patients with type 2 diabetes. Simultaneously, in non-diabetic obese patients, GLP-1 receptor agonists are believed to significantly reduce insulin resistance through weight loss and metabolic improvements, suggesting that GLP-1 receptor agonists may be effective drugs for treating obesity-related hypertension. However, the antihypertensive effect of GLP-1 receptor agonists in obese patients is limited. Clinical trials of Tirzepatide have also published some data on blood pressure changes in obese patients; however, Tirzepatide has a slow onset of action in obese patients with hypertension, and a certain antihypertensive effect is only observed over very long treatment periods, with poor efficacy in patients with blood pressure ≥140 / 90 mmHg. Summary of the Invention

[0010] The prior patent applications WO2022199629A1 and WO2024061310A1, as the applicant's prior art, are cited as part of this disclosure.

[0011] The purpose of this disclosure is to provide the use of a GLP-1 / GIP peptide or a pharmaceutical composition containing the same.

[0012] Another object of this disclosure is to provide a method for preventing and / or treating diabetes.

[0013] Another object of this disclosure is to provide a method for preventing and / or treating obesity.

[0014] Another object of this disclosure is to provide a method for preventing and / or treating overweight with hypertension and / or obesity with hypertension.

[0015] One aspect of this disclosure provides a method for treating type 2 diabetes or obesity in patients in need, comprising:

[0016] The minimum titration dose of GLP-1 / GIP peptide administered to the patient was approximately two weeks; and subsequently...

[0017] The patient was given a maintenance dose of this GLP-1 / GIP peptide; wherein the titration dose was approximately 50% of the maintenance dose.

[0018] In some embodiments, a method for treating type 2 diabetes or obesity in patients in need is provided, comprising:

[0019] The first titration dose of GLP-1 / GIP peptide was administered to the patient within approximately two weeks; and subsequently...

[0020] The second titration dose of this GLP-1 / GIP peptide was administered to the patient at least two weeks later; and subsequently...

[0021] The patient was given a maintenance dose of this GLP-1 / GIP peptide; wherein the first titration dose was approximately 25% of the maintenance dose and the second titration dose was approximately 50% of the maintenance dose.

[0022] In some embodiments, a method for treating type 2 diabetes or obesity in patients in need is provided, comprising:

[0023] The first titration dose of GLP-1 / GIP peptide was administered to the patient within approximately two weeks; and subsequently...

[0024] The second titration dose of this GLP-1 / GIP peptide was administered to the patient at least two weeks later; and subsequently...

[0025] The third titration dose of this GLP-1 / GIP peptide was administered to the patient at least two weeks later; and subsequently...

[0026] The patient was given a maintenance dose of the GLP-1 / GIP peptide; wherein the first titer was approximately 16.67% of the maintenance dose, the second titer was approximately 33.33% of the maintenance dose, and the third titer was approximately 66.67% of the maintenance dose.

[0027] In some embodiments, a method for treating type 2 diabetes or obesity in patients in need is provided, comprising:

[0028] The patients were given titrated doses of GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0029] The patient was given a maintenance dose of this GLP-1 / GIP peptide; wherein the titration dose was approximately 50% of the maintenance dose.

[0030] In some embodiments, a method for treating type 2 diabetes or obesity in patients in need is provided, comprising:

[0031] The patient was given the first titration dose of GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0032] The patient was given a second titration dose of this GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0033] The patient was given a maintenance dose of this GLP-1 / GIP peptide; wherein the first titration dose was approximately 25% of the maintenance dose and the second titration dose was approximately 50% of the maintenance dose.

[0034] In some embodiments, a method for treating type 2 diabetes or obesity in patients in need is provided, comprising:

[0035] The patient was given the first titration dose of GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0036] The patient was given a second titration dose of this GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0037] The patients were given the third titration dose of this GLP-1 / GIP peptide for 2–6 weeks; and subsequently

[0038] The patient was given a maintenance dose of the GLP-1 / GIP peptide; wherein the first titer was approximately 16.67% of the maintenance dose, the second titer was approximately 33.33% of the maintenance dose, and the third titer was approximately 66.67% of the maintenance dose.

[0039] In some implementations, methods for treating type 2 diabetes or obesity in patients in need are provided, including:

[0040] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0041] The patient was given a maintenance dose of 5 mg of this GLP-1 / GIP peptide.

[0042] In some implementations, methods for treating type 2 diabetes or obesity in patients in need are provided, including:

[0043] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0044] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0045] The patient was given a maintenance dose of 10 mg of this GLP-1 / GIP peptide.

[0046] In some implementations, methods for treating type 2 diabetes or obesity in patients in need are provided, including:

[0047] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0048] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0049] The patient was given a third titration dose of 10 mg / week for four weeks; and subsequently...

[0050] The patient was given a maintenance dose of 15 mg of this GLP-1 / GIP peptide per week.

[0051] In some implementations, a treatment method is provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, including:

[0052] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0053] The patient was given a maintenance dose of 5 mg of this GLP-1 / GIP peptide.

[0054] In some implementations, a treatment method is provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, including:

[0055] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0056] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0057] The patient was given a maintenance dose of 10 mg of this GLP-1 / GIP peptide.

[0058] In some implementations, a treatment method is provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, including:

[0059] The patient was given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0060] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0061] The patient was given a third titration dose of 10 mg / week for four weeks; and subsequently...

[0062] The patient was given a maintenance dose of 15 mg of this GLP-1 / GIP peptide per week.

[0063] In some embodiments, a treatment method is also provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, wherein the method, after administration of a background drug, such as metformin or sulfonylureas, is followed by administration of a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0064] The patient was given a maintenance dose of 5 mg of this GLP-1 / GIP peptide.

[0065] In some embodiments, a treatment method is also provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, wherein, after administration of a background drug, such as metformin or sulfonylureas, the patient is given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0066] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0067] The patient was given a maintenance dose of 10 mg of this GLP-1 / GIP peptide.

[0068] In some embodiments, a treatment method is also provided for patients with poorly controlled type 2 diabetes who receive GLP-1 / GIP peptide in combination with metformin monotherapy or metformin and sulfonylureas, wherein, after administration of a background drug, such as metformin or sulfonylureas, the patient is given a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week for four weeks; and subsequently...

[0069] The patient was given a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0070] The patient was given a third titration dose of 10 mg / week for four weeks; and subsequently...

[0071] The patient was given a maintenance dose of 15 mg of this GLP-1 / GIP peptide per week.

[0072] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0073] a) Administer titrated doses of GLP-1 / GIP peptide to the patients for 2–6 weeks; and subsequently

[0074] b) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0075] The titration dose is approximately 50% of the maintenance dose.

[0076] In one embodiment, a method for treating type 2 diabetes with a combination of sulfonylureas is provided, comprising:

[0077] a) Administer titrated doses of GLP-1 / GIP peptide to the patients for 2–6 weeks; and subsequently

[0078] b) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0079] The titration dose is approximately 50% of the maintenance dose.

[0080] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0081] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0082] b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0083] c) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0084] The first titration dose is approximately 25% of the maintenance dose, and the second titration dose is approximately 50% of the maintenance dose.

[0085] In one embodiment, a method for treating type 2 diabetes with a combination of sulfonylureas is provided, comprising:

[0086] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0087] b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0088] c) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0089] The first titration dose is approximately 25% of the maintenance dose, and the second titration dose is approximately 50% of the maintenance dose.

[0090] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0091] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0092] b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0093] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0094] d) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0095] The first titration dose was approximately 16.67% of the maintenance dose, the second titration dose was approximately 33.33% of the maintenance dose, and the third titration dose was approximately 66.67% of the maintenance dose.

[0096] In one embodiment, a method for treating type 2 diabetes with a combination of sulfonylureas is provided, comprising:

[0097] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0098] b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0099] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently

[0100] d) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient;

[0101] The first titration dose was approximately 16.67% of the maintenance dose, the second titration dose was approximately 33.33% of the maintenance dose, and the third titration dose was approximately 66.67% of the maintenance dose.

[0102] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0103] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently...

[0104] b) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0105] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0106] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently...

[0107] b) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently

[0108] c) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient;

[0109] In one embodiment, a method is provided for administering GLP-1 / GIP peptides in combination with sulfonylureas to treat type 2 diabetes in patients of need, comprising:

[0110] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently...

[0111] b) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently

[0112] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0113] d) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0114] Sulfonylureas include, but are not limited to, chlorpropamide, tolbutamide, glimepiride, gliclazide, glipizide, and glimepiride.

[0115] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0116] a) administering metformin or metformin combined with sulfonylureas to the patient; and subsequently

[0117] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0118] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0119] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0120] a) administering metformin or metformin combined with sulfonylureas to the patient; and subsequently

[0121] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0122] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0123] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient;

[0124] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0125] a) administering metformin or metformin combined with sulfonylureas to the patient; and subsequently

[0126] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0127] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0128] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0129] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0130] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0131] a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently

[0132] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0133] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0134] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0135] a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently

[0136] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0137] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0138] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient.

[0139] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0140] a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently

[0141] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0142] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0143] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0144] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0145] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0146] a) Administer metformin to the patient at a dose of not less than 1500 mg / day for not less than 8 weeks; and subsequently

[0147] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0148] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0149] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0150] a) Administer metformin to the patient at a dose of not less than 1500 mg / day for not less than 8 weeks; and subsequently

[0151] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0152] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0153] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient;

[0154] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0155] a) Administer metformin to the patient at a dose of not less than 1500 mg / day for not less than 8 weeks; and subsequently

[0156] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0157] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0158] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0159] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0160] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0161] a) Administer metformin to the patient at the maximum tolerated dose of metformin (which can be determined by referring to the drug's package insert or by titration, e.g., <1500 mg / day but ≥1000 mg / day), for at least 8 weeks; and subsequently

[0162] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0163] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0164] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0165] a) Administer metformin to the patient at the maximum tolerated dose of metformin (which can be determined by referring to the drug's package insert or by titration, e.g., <1500 mg / day but ≥1000 mg / day), for at least 8 weeks; and subsequently

[0166] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0167] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0168] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient;

[0169] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0170] a) Administer metformin to the patient at the maximum tolerated dose of metformin (which can be determined by referring to the drug's package insert or by titration, e.g., <1500 mg / day but ≥1000 mg / day), for at least 8 weeks; and subsequently

[0171] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0172] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0173] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0174] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0175] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0176] a) Administer metformin and sulfonylureas to the patient in combination, with the metformin dose not less than 1500 mg / day and the sulfonylurea dose not less than its minimum therapeutic dose (which can be determined with reference to the drug instructions), for a period of not less than 8 weeks; and subsequently;

[0177] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0178] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0179] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0180] a) Administer metformin and sulfonylureas to the patient in combination, with the metformin dose not less than 1500 mg / day and the sulfonylurea dose not less than its minimum therapeutic dose (which can be determined with reference to the drug instructions), for a period of not less than 8 weeks; and subsequently;

[0181] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0182] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0183] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient;

[0184] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0185] a) Administer metformin and sulfonylureas to the patient in combination, with the metformin dose not less than 1500 mg / day and the sulfonylurea dose not less than its minimum therapeutic dose (which can be determined with reference to the drug instructions), for a period of not less than 8 weeks; and subsequently;

[0186] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0187] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0188] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0189] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0190] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0191] a) Administer metformin and sulfonylureas to the patient in combination, wherein the maximum tolerated dose of metformin (which can be determined with reference to the drug's package insert, for example, <1500 mg / day but ≥1000 mg / day) and the daily dose of sulfonylureas is not less than the minimum therapeutic dose (which can be determined with reference to the drug's package insert), and the administration is continued for at least 8 weeks; and subsequently;

[0192] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0193] c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

[0194] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0195] a) Administer metformin and sulfonylureas to the patient in combination, wherein the maximum tolerated dose of metformin (which can be determined with reference to the drug's package insert, for example, <1500 mg / day but ≥1000 mg / day) and the daily dose of sulfonylureas is not less than the minimum therapeutic dose (which can be determined with reference to the drug's package insert), and the administration is continued for at least 8 weeks; and subsequently;

[0196] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0197] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0198] d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient.

[0199] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0200] a) Administer metformin and sulfonylureas to the patient at the maximum tolerated dose of metformin (which can be determined with reference to the drug's package insert, for example, <1500 mg / day but ≥1000 mg / day), and at a daily dose of sulfonylureas not less than their minimum therapeutic dose (which can be determined with reference to the drug's package insert), for at least 8 weeks; and subsequently;

[0201] b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently

[0202] c) Administer to the patient a second titration dose of this GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0203] d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0204] e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

[0205] The sulfonylurea drugs mentioned above include, but are not limited to, chlorpropamide, tolbutamide, glimepiride, gliclazide, glipizide, and glimepiride.

[0206] In one embodiment, a method for treating type 2 diabetes is provided, comprising:

[0207] a) Administer metformin to the patient by titration until the dose reaches 1500 mg / day or the patient’s maximum tolerated dose (e.g., <1500 mg / day but ≥1000 mg / day), then continue metformin administration at 1500 mg / day or the patient’s maximum tolerated dose for at least 8 weeks; and subsequently;

[0208] b) Administer GLP-1 / GIP peptide to the patient.

[0209] If a patient is receiving metformin at a daily dose ≥1500 mg or at the maximum tolerated dose (<1500 mg / day, but ≥1000 mg / day) for ≥8 weeks at screening time, they can directly enter a 4-week placebo induction period. Then they will enter the treatment period (including the dose titration period).

[0210] If a patient's daily metformin dose is <1500 mg and has not yet reached the maximum tolerated dose at screening, they will first enter a 0–4 week metformin dose titration period (the investigator will provide an individualized titration rate within 4 weeks based on the patient's condition and clinical treatment routine). After the metformin dose titration period (V1a, up to 4 weeks) to titrate the patient's daily metformin dose to 1500 mg or the maximum tolerated dose (<1500 mg / day but ≥1000 mg / day), the patient will enter a metformin dose stabilization period (V1b, 8 weeks) at this dose. During this period, the participant's metformin dosage should remain unchanged. Patients who complete the 8-week metformin dose stabilization period and have good adherence to metformin and sulfonylureas (if applicable) (80%–120%) will enter a 4-week placebo acclimation period.

[0211] If a patient was screened using sulfonylureas, regardless of which of the above procedures they go through to enter the placebo transition period, they must simultaneously meet the requirement that they have been receiving stable treatment with sulfonylureas for at least 8 weeks (with a fixed daily dose of at least the minimum therapeutic dose specified in the drug's instructions) before entering the placebo transition period.

[0212] In some embodiments, a method for treating obesity is provided, comprising the steps of:

[0213] a) Administer an initial titration dose of 2.5 mg / week to patients in need for 2–6 weeks; and subsequently...

[0214] b) Administer the second titration dose of GLP-1 / GIP peptide, 5 mg / week, to the patient for 2–6 weeks; and subsequently

[0215] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for 2–6 weeks; and subsequently

[0216] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient, 15 mg / week, for a total of 2–6 weeks; and subsequently

[0217] e) Administer a maintenance dose of 20 mg / week of this GLP-1 / GIP peptide to the patient.

[0218] In some embodiments, a method for treating obesity is provided, comprising the steps of:

[0219] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to patients in need for two weeks; and subsequently...

[0220] b) Administer the patient with a second titration dose of GLP-1 / GIP peptide, 5 mg / week, for two weeks; and subsequently...

[0221] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for two weeks; and subsequently

[0222] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient for four weeks at a dose of 15 mg / week; and subsequently

[0223] e) Administer a maintenance dose of 20 mg / week of this GLP-1 / GIP peptide to the patient.

[0224] In some embodiments, a method for treating obesity is provided, comprising the steps of:

[0225] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently...

[0226] b) Administer the patient with a second titration dose of GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0227] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0228] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient for four weeks at a dose of 15 mg / week; and subsequently

[0229] e) Administer a maintenance dose of 20 mg / week of this GLP-1 / GIP peptide to the patient.

[0230] In some implementations, a method for treating obesity includes the steps of:

[0231] a) Administer a first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for 2–6 weeks; and subsequently

[0232] b) Administer the second titration dose of GLP-1 / GIP peptide, 5 mg / week, to the patient for 2–6 weeks; and subsequently

[0233] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for 2–6 weeks; and subsequently

[0234] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient, 15 mg / week, for a total of 2–6 weeks; and subsequently

[0235] e) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient at 20 mg / week for a total of 2–6 weeks; and subsequently

[0236] f) Administer a maintenance dose of 25 mg / week of this GLP-1 / GIP peptide to the patient.

[0237] In some implementations, a method for treating obesity includes the steps of:

[0238] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for two weeks; and subsequently...

[0239] b) Administer the patient with a second titration dose of GLP-1 / GIP peptide, 5 mg / week, for two weeks; and subsequently...

[0240] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for two weeks; and subsequently

[0241] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient for four weeks at a dose of 15 mg / week; and subsequently

[0242] e) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient, 20 mg / week, for a total of four weeks; and subsequently

[0243] f) Administer a maintenance dose of 25 mg / week of this GLP-1 / GIP peptide to the patient.

[0244] In some implementations, a method for treating obesity includes the steps of:

[0245] a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently...

[0246] b) Administer the patient with a second titration dose of GLP-1 / GIP peptide, 5 mg / week, for four weeks; and subsequently...

[0247] c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently

[0248] d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient for four weeks at a dose of 15 mg / week; and subsequently

[0249] e) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient, 20 mg / week, for a total of four weeks; and subsequently

[0250] f) Administer a maintenance dose of 25 mg / week of this GLP-1 / GIP peptide to the patient.

[0251] In some embodiments, in the method of treating obesity, the patient's BMI is >35.0 kg / m². 2The patient in question is not diabetic.

[0252] In the method for treating type 2 diabetes or obesity disclosed herein, the GLP-1 / GIP peptide is preferably BGM0504, whose structure is as follows:

[0253] The method for treating type 2 diabetes or obesity described in this disclosure, wherein the GLP-1 / GIP peptide is used in a pharmaceutical composition comprising the GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

[0254] The method for treating type 2 diabetes or obesity disclosed herein, wherein the stabilizer is selected from propylene glycol, mannitol, or glycerol; and the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate.

[0255] The method for treating type 2 diabetes or obesity according to this disclosure includes a pharmaceutical composition comprising a GLP-1 / GIP peptide, a stabilizer, and a buffer salt, wherein the stabilizer is propylene glycol, the buffer salt is disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4; and wherein, in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5–30 mg / mL, the concentration of the propylene glycol is 10–20 mg / mL, and the concentration of the disodium hydrogen phosphate dodecahydrate is 7–23 mg / mL.

[0256] The method for treating type 2 diabetes or obesity described in this disclosure involves subcutaneous injection once a week.

[0257] This disclosure provides a method for curing diabetes or obesity in patients in need, the method comprising: administering two titration doses (about 25% and about 50% of the maintenance dose), starting with a 25% dose and wherein each titration dose is administered for about 4 weeks, after which the next higher dose is administered until the therapeutic dose is reached. Another embodiment of this disclosure is the method described above, wherein three titration doses (about 16.67%, about 33.66%, and about 66.67% of the maintenance dose) are administered, starting with a 16.67% dose and wherein each titration dose is administered for about 4 weeks, after which the next higher dose is administered until the maintenance dose is reached.

[0258] The diabetic patients described in this disclosure include type 2 diabetic patients whose glycemic control is poor with metformin monotherapy or metformin in combination with sulfonylureas.

[0259] The concentration of the GLP-1 / GIP peptide agent described in this disclosure is 2 to 36 mg / mL; for example, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, etc.; preferably 5 to 30 mg / mL. In this disclosure, a stabilizer refers to a substance used to stabilize the structure and biological activity of polypeptides in solution.

[0260] In some specific embodiments, the stabilizer described in this disclosure is propylene glycol, mannitol, or glycerol. Based on the results of formulation screening tests and stability tests, this disclosure preferentially selects propylene glycol as a stabilizer, which can effectively maintain the structure and biological activity of the active pharmaceutical ingredient, while also stabilizing the pH value of the pharmaceutical composition during storage.

[0261] In some embodiments, the concentration of the stabilizer described in this disclosure is 10–20 mg / mL; for example, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, etc.; preferably 14 mg / mL. It is worth mentioning that in polypeptide formulations, sodium chloride is considered to maintain electrolyte balance and stabilize polypeptide structures, and it exists as a stabilizer in many existing polypeptide formulations. However, when the inventors of this disclosure use sodium chloride to replace propylene glycol (for example, 2 mL of a pharmaceutical composition contains 40.0 mg BGM0504, 3.58 mg disodium hydrogen phosphate dodecahydrate, and 16.4 mg sodium chloride; the pH is adjusted to 7 using a pH adjuster, and the remaining amount is made up with water for injection), the solubility of BGM0504 is only 0.15 mg / mL, which is far from meeting the requirements. When propylene glycol is used as a stabilizer (e.g., 1 mL of the pharmaceutical composition contains 20.0 mg BGM0504, 3.58 mg disodium hydrogen phosphate dodecahydrate, and 14 mg propylene glycol, with the pH adjusted to 7 using a pH adjuster and the remainder made up with water for injection), the solubility of BGM0504 can reach over 30 mg / mL, meeting the solubility requirements of the active pharmaceutical ingredient. Therefore, in some preferred embodiments of this disclosure, the pharmaceutical composition does not contain sodium chloride. In some embodiments, the pH value of the pharmaceutical composition of this disclosure is 6.5–8.5; for example, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, etc.; preferably 7.0–8.4; more preferably 7.2–8.2; and even more preferably 7.2–7.6. In some specific embodiments, the pH adjuster described in this disclosure is hydrochloric acid and / or sodium hydroxide. This disclosure preferably uses a 0.1M hydrochloric acid and / or 0.1M sodium hydroxide solution.

[0262] This disclosure does not specifically limit the type of buffer salt, which can be determined by those skilled in the art according to actual needs. In some embodiments, the buffer salt described in this disclosure is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate. In some specific embodiments, the buffer salt described in this disclosure is disodium hydrogen phosphate dodecahydrate or sodium citrate dihydrate. In some preferred embodiments, the buffer salt described in this disclosure is disodium hydrogen phosphate dodecahydrate. In some embodiments, the concentration of the buffer salt described in this disclosure is 7–23 mM; for example, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, etc.; preferably 7–20 mM; more preferably 7–15 mM. Based on the results of formulation screening tests and considering the risk level of the drug composition in clinical applications such as injectable formulations, this disclosure prioritizes low-concentration buffer salts, such as 10 mM. The GLP-1 / GIP peptide described in this disclosure is a linear peptide containing 40 amino acids, and the initial pH value of the formulation is set between 7.2 and 8.2. It is highly susceptible to microbial degradation, and generally, the addition of antimicrobial agents (such as phenol) to the formulation is considered to improve product stability.

[0263] This disclosure also provides a method for preparing the pharmaceutical composition, comprising the following steps: preparing a solution of a stabilizer, a buffer salt, and a GLP-1 / GIP peptide, and adjusting the pH of the solution to a target value. In some specific embodiments, the method for preparing the pharmaceutical composition comprises the following steps: dissolving the stabilizer and the buffer salt in a solvent, adding the GLP-1 / GIP peptide, adding a pH adjuster to completely dissolve the GLP-1 / GIP peptide, and then adjusting the pH of the solution to a target value using the pH adjuster.

[0264] In some more specific embodiments, the preparation method of the pharmaceutical composition includes the following steps: dissolving a prescribed amount of disodium hydrogen phosphate dodecahydrate and propylene glycol in purified water or water for injection, adding a prescribed amount of GLP-1 / GIP peptide, and adding sodium hydroxide to completely dissolve the GLP-1 / GIP peptide, then adjusting the pH of the solution to 6.5-8.5 using hydrochloric acid and / or sodium hydroxide, and finally making up the volume with purified water or water for injection to obtain the final product.

[0265] The inventors made a surprising discovery: the treatment regimen disclosed herein can overcome the shortcomings of existing GLP-1 / GIP peptide drug treatments, significantly reduce the number of titrations required for existing GLP-1 / GIP peptide drugs, rapidly achieve an effective therapeutic dose, and enable patients to quickly obtain significant therapeutic effects, achieving unexpected technical results.

[0266] In some embodiments, the method of this disclosure reduces gastrointestinal adverse events in the subjects. In some embodiments, the method of this disclosure reduces gastrointestinal adverse events of the form of nausea in the subjects. In some embodiments, the term "reduced gastrointestinal adverse events" as used herein refers to the occurrence of fewer gastrointestinal adverse events, for example, a lower incidence of gastrointestinal adverse events compared to other GLP-1 / GIP peptide drugs. The disclosed injection, administered once weekly for 14–18 weeks, demonstrated good overall safety and tolerability. Most adverse events occurring during the study were similar to and related to those of drugs with the same target of action, and the vast majority were mild and transient gastrointestinal adverse events. No hypoglycemic events or treatment-related serious adverse events occurred in any dose group of BGM0504 injection, and no subjects discontinued treatment due to treatment-related serious adverse events.

[0267] On the other hand, there is the use of a GLP-1 / GIP peptide or a pharmaceutical composition containing thereto for:

[0268] (i) Prevention and / or treatment of hypertension; and

[0269] (ii) Prepare drugs for the prevention and / or treatment of hypertension.

[0270] In one embodiment, the hypertension is hypertension in the context of being overweight and / or obese.

[0271] In one embodiment, the patient with hypertension has a sitSBP of not less than 140 mmHg.

[0272] In one embodiment, the patient with hypertension has a sitSBP of 140–179 mmHg.

[0273] In one embodiment, the patient with hypertension has a sitSBP of 140–159 mmHg.

[0274] In one embodiment, the patient with hypertension has a sitSBP of not less than 160 mmHg.

[0275] In one embodiment, the patient with hypertension has a sitSBP of 160–179 mmHg.

[0276] In one embodiment, the patient with hypertension has a sitSBP of not less than 180 mmHg.

[0277] In one embodiment, the hypertensive patient's sitDBP is not lower than 90 mmHg.

[0278] In one embodiment, the patient with hypertension has a sitDBP of 90–109 mmHg.

[0279] In one embodiment, the patient with hypertension has a sitDBP of 90–100 mmHg.

[0280] In one embodiment, the patient with hypertension has a sitDBP of 90–99 mmHg.

[0281] In one embodiment, the patient with hypertension has a sitDBP of not less than 100 mmHg.

[0282] In one embodiment, the patient with hypertension has a sitDBP of 100–109 mmHg.

[0283] In one embodiment, the patient with hypertension has a sitDBP of not less than 110 mmHg.

[0284] In one implementation, the patient with hypertension meets any of the following conditions:

[0285] 1) Sit SBP: 140–179 mmHg or sit SBP not less than 180 mmHg; and / or sit DBP: 90–109 mmHg or sit DBP not less than 110 mmHg; or

[0286] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0287] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg; or

[0288] 4) SitSBP: 140–159 mmHg and SitDBP < 90 mmHg; or

[0289] 5) SitSBP: 160–179 mmHg and SitDBP < 90 mmHg; or

[0290] 6) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP ≤ 99 mmHg; or

[0291] 7) sitSBP < 140 mmHg and 100 mmHg ≤ sitDBP ≤ 109 mmHg; or

[0292] 8) sitSBP ≥ 180 mmHg and sitDBP < 90 mmHg; or

[0293] 9) sitSBP < 140 mmHg and sitDBP ≥ 110 mmHg.

[0294] In one implementation, the hypertensive patient meets any of the following conditions:

[0295] 1) sitSBP: 140–179 mmHg; and / or sitDBP: 90–109 mmHg; or

[0296] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0297] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

[0298] In one embodiment, the overweight patient with hypertension and / or the obese patient with hypertension has a BMI ≥ 24.0 kg / m². 2 .

[0299] In one embodiment, the overweight patient with hypertension and / or the obese patient with hypertension has a BMI ≥ 26.0 kg / m². 2 .

[0300] In one implementation, the overweight patient with hypertension and / or the obese patient with hypertension exhibits any of the following symptoms:

[0301] (a) BMI ≥ 30.0 kg / m 2 ;

[0302] (b) BMI ≥ 26.0 kg / m 2 And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

[0303] In one embodiment, the patient with hypertension is not a patient with refractory hypertension, hypertensive emergency, hypertensive subacute, and / or secondary hypertension.

[0304] In one implementation, the overweight patients with hypertension and / or obese patients with hypertension are not patients with type 1 or type 2 diabetes.

[0305] In one embodiment, the overweight patients with hypertension and / or obese patients with hypertension are not obese due to secondary diseases or medications.

[0306] In one embodiment, the overweight patients with hypertension and / or obese patients with hypertension are not obese due to secondary diseases or medications, including: obesity caused by elevated cortisol hormones (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, and obesity caused by reduction / discontinuation of weight-loss drugs.

[0307] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered via parenteral administration.

[0308] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered by injection.

[0309] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered once a week.

[0310] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5-15 mg per dose.

[0311] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is slowly increased.

[0312] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg / time, 5 mg / time, 10 mg / time, 12.5 mg / time, or 15 mg / time.

[0313] In one embodiment, the GLP-1 / GIP peptide structure is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof.

[0314] In one embodiment, the pharmaceutical composition is a liquid formulation.

[0315] In one embodiment, the pharmaceutical composition is an injection.

[0316] In one embodiment, the stabilizer in the pharmaceutical composition is a polyol; preferably, the stabilizer is selected from at least one of propylene glycol, mannitol, and glycerol; more preferably, the stabilizer is propylene glycol, mannitol, or glycerol; more preferably, the stabilizer is propylene glycol.

[0317] In one embodiment, the concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL.

[0318] In one embodiment, in the pharmaceutical composition, the buffer salt is selected from at least one of hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate or sodium citrate hydrate; more preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate.

[0319] In one embodiment, the concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

[0320] In one embodiment, the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; more preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; and more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.

[0321] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; the pH adjuster is hydrochloric acid and / or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster; the water is preferably purified water and / or water for injection.

[0322] In one embodiment, the pharmaceutical composition does not contain an antibacterial agent.

[0323] In one embodiment, the pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4.

[0324] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10 to 20 mM.

[0325] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5 to 25 mg / ml, the concentration of the propylene glycol is 14 mg / ml, and the concentration of the disodium hydrogen phosphate dodecahydrate is 10 mM.

[0326] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide; preferably, the water is purified water and / or water for injection.

[0327] In one embodiment, the pharmaceutical composition comprises 5–25 mg / mL GLP-1 / GIP peptide, 14 mg / mL propylene glycol, and 10 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.2–7.6.

[0328] On the other hand, this disclosure provides a method for preventing and / or treating hypertension, comprising the steps of administering a therapeutically effective amount of GLP-1 / GIP peptide or a pharmaceutical composition containing thereto to a subject in need.

[0329] In one implementation, the desired subjects are overweight subjects with hypertension and / or obese subjects with hypertension.

[0330] In one implementation, the desired subjects are overweight and / or obese subjects with hypertension who have not achieved satisfactory weight loss results by diet and / or exercise alone.

[0331] In one implementation, the subject in need has previously undergone at least 12 weeks of diet control and / or exercise alone, with a weight change of <5.0%.

[0332] In one implementation, the desired object is selected from any of the following:

[0333] (a) BMI ≥ 30.0 kg / m 2 ;

[0334] (b) BMI ≥ 26.0 kg / m 2 And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

[0335] In one implementation, the desired subject is a subject with essential hypertension.

[0336] In one implementation, the desired recipient is a patient with stage I, II, or III hypertension.

[0337] In one implementation, the desired recipient is a patient with grade II or III hypertension.

[0338] In one implementation, the desired recipient is a patient with grade II hypertension.

[0339] In one implementation, the desired individuals are overweight patients with grade I, II, or III hypertension, or obese patients with grade I, II, or III hypertension.

[0340] In one implementation, the desired individuals are overweight patients with grade II or III hypertension or obese patients with grade II or III hypertension.

[0341] In one implementation, the desired individuals are overweight patients with grade II hypertension or obese patients with grade II hypertension.

[0342] In one embodiment, the patient with hypertension has a sitSBP of not less than 140 mmHg.

[0343] In one embodiment, the patient with hypertension has a sitSBP of 140–179 mmHg.

[0344] In one embodiment, the patient with hypertension has a sitSBP of 140–159 mmHg.

[0345] In one embodiment, the patient with hypertension has a sitSBP of not less than 160 mmHg.

[0346] In one embodiment, the patient with hypertension has a sitSBP of 160–179 mmHg.

[0347] In one embodiment, the patient with hypertension has a sitSBP of not less than 180 mmHg.

[0348] In one embodiment, the hypertensive patient's sitDBP is not lower than 90 mmHg.

[0349] In one embodiment, the patient with hypertension has a sitDBP of 90–109 mmHg.

[0350] In one embodiment, the patient with hypertension has a sitDBP of 90–100 mmHg.

[0351] In one embodiment, the patient with hypertension has a sitDBP of 90–99 mmHg.

[0352] In one embodiment, the patient with hypertension has a sitDBP of not less than 100 mmHg.

[0353] In one embodiment, the patient with hypertension has a sitDBP of 100–109 mmHg.

[0354] In one embodiment, the patient with hypertension has a sitDBP of not less than 110 mmHg.

[0355] In one implementation, the patient with hypertension meets any of the following conditions:

[0356] 1) Sit SBP: 140–179 mmHg or sit SBP not less than 180 mmHg; and / or sit DBP: 90–109 mmHg or sit DBP not less than 110 mmHg; or

[0357] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0358] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg; or

[0359] 4) SitSBP: 140–159 mmHg and SitDBP < 90 mmHg; or

[0360] 5) SitSBP: 160–179 mmHg and SitDBP < 90 mmHg; or

[0361] 6) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP ≤ 99 mmHg; or

[0362] 7) sitSBP < 140 mmHg and 100 mmHg ≤ sitDBP ≤ 109 mmHg; or

[0363] 8) sitSBP ≥ 180 mmHg and sitDBP < 90 mmHg; or

[0364] 9) sitSBP < 140 mmHg and sitDBP ≥ 110 mmHg.

[0365] In one implementation, the object in need must satisfy any of the following conditions:

[0366] 1) sitSBP: 140–179 mmHg and / or sitDBP: 90–109 mmHg; or

[0367] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0368] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

[0369] In one implementation, the required object has a BMI ≥ 24.0 kg / m². 2 .

[0370] In one implementation, the required object has a BMI ≥ 26.0 kg / m². 2 .

[0371] In one embodiment, the desired patient is not a patient with refractory hypertension, hypertensive emergency, hypertensive urgency, and / or secondary hypertension. Preferably, the patient with secondary hypertension is selected from at least one of renal parenchymal hypertension, Cushing's syndrome, primary aldosteronism, pheochromocytoma, and drug-induced hypertension.

[0372] In one implementation, the desired subject is not a patient whose obesity is caused by a secondary disease or medication, including obesity caused by elevated cortisol levels (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, and obesity caused by dose reduction / discontinuation of weight-loss drugs.

[0373] In one implementation, the person in need is not a patient with type 1 or type 2 diabetes.

[0374] In one embodiment, the administration method is non-enteric administration.

[0375] In one embodiment, the administration method is injection.

[0376] In one embodiment, the administration method is subcutaneous injection, intramuscular injection, intravenous injection, intradermal injection, or intraperitoneal injection.

[0377] In one embodiment, the administration method is subcutaneous injection, and the subcutaneous injection site is selected from one or more of the following: abdomen, front of the thigh, outer side of the upper arm, lower edge of the deltoid muscle of the upper arm, outer thigh, and back.

[0378] In one embodiment, the administration method is subcutaneous injection into the abdomen.

[0379] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is avoided from being injected consecutively at the same site.

[0380] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered 1-3 times per week, for example, once or twice.

[0381] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered once a week.

[0382] In one embodiment, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5-15 mg.

[0383] In one embodiment, the single-dose dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, or 15 mg.

[0384] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg / time, 5 mg / time, 10 mg / time, 12.5 mg / time, or 15 mg / time.

[0385] In one embodiment, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5-15 mg.

[0386] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is slowly increased.

[0387] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 6 weeks, not less than 7 weeks, not less than 10 weeks, not less than 11 weeks, not less than 12 weeks, not less than 14 weeks, and not less than 20 weeks; for example, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, and 40 weeks.

[0388] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 56 weeks.

[0389] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 40 weeks.

[0390] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 30 weeks.

[0391] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 28 weeks.

[0392] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 26 weeks.

[0393] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 24 weeks.

[0394] In one embodiment, the method includes the steps of administering a GLP-1 / GIP peptide or a pharmaceutical composition containing the same to a subject in need at a dose of 5 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks, or 24 weeks.

[0395] In one embodiment, the method includes the step of administering a GLP-1 / GIP peptide or a pharmaceutical composition containing the same to a subject in need at a dose of 10 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks.

[0396] In one embodiment, the method includes the steps of administering GLP-1 / GIP peptide or a pharmaceutical composition containing it to a subject in need at a dose of 15 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks, or 24 weeks.

[0397] In one implementation, the method includes the steps of:

[0398] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0399] b) Administer a maintenance dose of 5 mg of GLP-1 / GIP peptide to the subjects in need.

[0400] In one implementation, the method includes the steps of:

[0401] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0402] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0403] c) Administer a maintenance dose of 10 mg of GLP-1 / GIP peptide to the subject in need.

[0404] In one implementation, the method includes the steps of:

[0405] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0406] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0407] c) Administer the third titration dose of GLP-1 / GIP peptide, 10 mg / week, to the subjects in need for four weeks; and subsequently...

[0408] d) Administer a maintenance dose of 15 mg / week of GLP-1 / GIP peptide to the subjects in need.

[0409] In one implementation, the method includes the steps of:

[0410] During the first two weeks, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0411] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0412] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0413] In week 11 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0414] In one implementation, the method includes the steps of:

[0415] During weeks 1 to 4, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0416] During weeks 5 to 8, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0417] During weeks 9–12, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0418] In week 13 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0419] In one implementation, the method includes the steps of:

[0420] During the first two weeks, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0421] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0422] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0423] During weeks 11 to 52, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0424] In one embodiment, the GLP-1 / GIP peptide structure is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof.

[0425] In one embodiment, the pharmaceutical composition contains a GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

[0426] In one embodiment, the pharmaceutical composition is a liquid formulation.

[0427] In one embodiment, the pharmaceutical composition is an injection.

[0428] In one embodiment, the stabilizer in the pharmaceutical composition is a polyol; preferably, the stabilizer is propylene glycol, mannitol, or glycerol; more preferably, the stabilizer is propylene glycol.

[0429] In one embodiment, the concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL.

[0430] In one embodiment, in the pharmaceutical composition, the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate or sodium citrate hydrate; more preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate.

[0431] In one embodiment, the concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

[0432] Further, the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; more preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.

[0433] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; the pH adjuster is hydrochloric acid and / or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster; the water is preferably purified water and / or water for injection.

[0434] In one embodiment, the pharmaceutical composition does not contain an antibacterial agent.

[0435] In one embodiment, the pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4.

[0436] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10 to 20 mM.

[0437] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5 to 25 mg / ml, the concentration of the propylene glycol is 14 mg / ml, and the concentration of the disodium hydrogen phosphate dodecahydrate is 10 mM.

[0438] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide; preferably, the water is purified water and / or water for injection.

[0439] In one embodiment, the pharmaceutical composition comprises 5–25 mg / mL GLP-1 / GIP peptide, 14 mg / mL propylene glycol, and 10 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.2–7.6.

[0440] On the other hand, this disclosure provides a method for preventing and / or treating overweight with hypertension and / or obesity with hypertension, comprising the steps of: administering a therapeutically effective amount of GLP-1 / GIP peptide or a pharmaceutical composition containing thereto to a subject in need.

[0441] In one implementation, the desired subjects are overweight and / or obese subjects with hypertension who have not achieved satisfactory weight loss results by diet and / or exercise alone.

[0442] In one implementation, the subject in need has previously undergone at least 12 weeks of diet control and / or exercise alone, with a weight change of <5.0%.

[0443] In one implementation, the desired object is selected from any of the following:

[0444] (a) BMI ≥ 30.0 kg / m 2 ;and

[0445] (b) BMI ≥ 26.0 kg / m 2And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

[0446] In one implementation, the desired subject is a subject with essential hypertension.

[0447] In one implementation, the desired individuals are overweight patients with grade I, II, or III hypertension, or obese patients with grade I, II, or III hypertension.

[0448] In one implementation, the desired individuals are overweight patients with grade II or III hypertension or obese patients with grade II or III hypertension.

[0449] In one implementation, the desired individuals are overweight patients with grade II hypertension or obese patients with grade II hypertension.

[0450] In one implementation, the required object sitSBP is not less than 140 mmHg.

[0451] In one implementation, the required object sitSBP is not less than 160 mmHg.

[0452] In one embodiment, the required object sitSBP is 140–179 mmHg.

[0453] In one implementation, the required object sitSBP is 140–159 mmHg.

[0454] In one implementation, the required object sitSBP is 160–179 mmHg.

[0455] In one implementation, the required object sitSBP is not less than 180 mmHg.

[0456] In one implementation, the required object sitDBP is not less than 90 mmHg.

[0457] In one embodiment, the patient with hypertension has a sitDBP of not less than 100 mmHg.

[0458] In one implementation, the required object sitDBP is 90–109 mmHg.

[0459] In one implementation, the required object sitDBP is 90–99 mmHg.

[0460] In one implementation, the required object sitDBP is not less than 110 mmHg.

[0461] In one implementation, the object in need satisfies any of the following conditions:

[0462] 1) Sit SBP: 140–179 mmHg or sit SBP not less than 180 mmHg; and / or sit DBP: 90–109 mmHg or sit DBP not less than 110 mmHg; or

[0463] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0464] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg; or

[0465] 4) SitSBP: 140–159 mmHg and SitDBP < 90 mmHg; or

[0466] 5) SitSBP: 160–179 mmHg and SitDBP < 90 mmHg; or

[0467] 6) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP ≤ 99 mmHg; or

[0468] 7) sitSBP < 140 mmHg and 100 mmHg ≤ sitDBP ≤ 109 mmHg; or

[0469] 8) sitSBP ≥ 180 mmHg and sitDBP < 90 mmHg; or

[0470] 9) sitSBP < 140 mmHg and sitDBP ≥ 110 mmHg.

[0471] In one implementation, the object in need must satisfy any of the following conditions:

[0472] 1) sitSBP: 140–179 mmHg and / or sitDBP: 90–109 mmHg; or

[0473] 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or

[0474] 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

[0475] In one implementation, the required object has a BMI ≥ 24.0 kg / m².2 .

[0476] In one implementation, the required object has a BMI ≥ 26.0 kg / m². 2 .

[0477] In one embodiment, the desired patient is not a patient with refractory hypertension, hypertensive emergency, hypertensive urgency, and / or secondary hypertension. Preferably, the patient with secondary hypertension is selected from at least one of renal parenchymal hypertension, Cushing's syndrome, primary aldosteronism, pheochromocytoma, and drug-induced hypertension.

[0478] In one implementation, the desired subject is not a patient whose obesity is caused by a secondary disease or medication, including obesity caused by elevated cortisol levels (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, and obesity caused by dose reduction / discontinuation of weight-loss drugs.

[0479] In one implementation, the person in need is not a patient with type 1 or type 2 diabetes.

[0480] In one embodiment, the administration method is non-enteric administration.

[0481] In one embodiment, the administration method is injection.

[0482] In one embodiment, the administration method is subcutaneous injection, intramuscular injection, intravenous injection, intradermal injection, or intraperitoneal injection.

[0483] In one embodiment, the administration method is subcutaneous injection, and the subcutaneous injection site is selected from one or more of the following: abdomen, front of the thigh, outer side of the upper arm, lower edge of the deltoid muscle of the upper arm, outer thigh, and back.

[0484] In one embodiment, the administration method is subcutaneous injection into the abdomen.

[0485] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is avoided from being injected consecutively at the same site.

[0486] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered 1-3 times per week, for example, once or twice.

[0487] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered once a week.

[0488] In one embodiment, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5-15 mg.

[0489] In one embodiment, the single-dose dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, or 15 mg.

[0490] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg / time, 5 mg / time, 10 mg / time, 12.5 mg / time, or 15 mg / time.

[0491] In one embodiment, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5-15 mg.

[0492] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is slowly increased.

[0493] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 6 weeks, not less than 7 weeks, not less than 10 weeks, not less than 11 weeks, not less than 12 weeks, not less than 14 weeks, and not less than 20 weeks; for example, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, and 40 weeks.

[0494] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 56 weeks.

[0495] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 40 weeks.

[0496] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 30 weeks.

[0497] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 28 weeks.

[0498] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 26 weeks.

[0499] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 24 weeks.

[0500] In one embodiment, the method includes the steps of administering a GLP-1 / GIP peptide or a pharmaceutical composition containing the same to a subject in need at a dose of 5 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks, or 24 weeks.

[0501] In one embodiment, the method includes the step of administering a GLP-1 / GIP peptide or a pharmaceutical composition containing the same to a subject in need at a dose of 10 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks.

[0502] In one embodiment, the method includes the steps of administering GLP-1 / GIP peptide or a pharmaceutical composition containing it to a subject in need at a dose of 15 mg / week for a period of 40 weeks, or 36 weeks, or 32 weeks, or 30 weeks, or 28 weeks, or 26 weeks, or 24 weeks.

[0503] In one implementation, the method includes the steps of:

[0504] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0505] b) Administer a maintenance dose of 5 mg of GLP-1 / GIP peptide to the subjects in need.

[0506] In one implementation, the method includes the steps of:

[0507] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0508] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0509] c) Administer a maintenance dose of 10 mg of GLP-1 / GIP peptide to the subject in need.

[0510] In one implementation, the method includes the steps of:

[0511] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0512] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0513] c) Administer the third titration dose of GLP-1 / GIP peptide, 10 mg / week, to the subjects in need for four weeks; and subsequently...

[0514] d) Administer a maintenance dose of 15 mg / week of GLP-1 / GIP peptide to the subjects in need.

[0515] In one implementation, the method includes the steps of:

[0516] During the first two weeks, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0517] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0518] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0519] In week 11 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0520] In one implementation, the method includes the steps of:

[0521] During weeks 1 to 4, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0522] During weeks 5 to 8, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0523] During weeks 9–12, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0524] In week 13 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0525] In one implementation, the method includes the steps of:

[0526] During the first two weeks, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0527] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0528] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0529] During weeks 11 to 52, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0530] In one embodiment, the GLP-1 / GIP peptide structure is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof.

[0531] In one embodiment, the pharmaceutical composition contains a GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

[0532] In one embodiment, the pharmaceutical composition is a liquid formulation.

[0533] In one embodiment, the pharmaceutical composition is an injection.

[0534] In one embodiment, the stabilizer in the pharmaceutical composition is a polyol; preferably, the stabilizer is propylene glycol, mannitol, or glycerol; more preferably, the stabilizer is propylene glycol.

[0535] In one embodiment, the concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL.

[0536] In one embodiment, in the pharmaceutical composition, the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate or sodium citrate hydrate; more preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate.

[0537] In one embodiment, the concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

[0538] Further, the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; more preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.

[0539] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; the pH adjuster is hydrochloric acid and / or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster; the water is preferably purified water and / or water for injection.

[0540] In one embodiment, the pharmaceutical composition does not contain an antibacterial agent.

[0541] In one embodiment, the pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4.

[0542] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10 to 20 mM.

[0543] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5 to 25 mg / ml, the concentration of the propylene glycol is 14 mg / ml, and the concentration of the disodium hydrogen phosphate dodecahydrate is 10 mM.

[0544] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide; preferably, the water is purified water and / or water for injection.

[0545] In one embodiment, the pharmaceutical composition comprises 5–25 mg / mL GLP-1 / GIP peptide, 14 mg / mL propylene glycol, and 10 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.2–7.6.

[0546] This disclosure provides the use of a GLP-1 / GIP peptide or a pharmaceutical composition containing the same for:

[0547] (i) Prevention and / or treatment of overweight with hypertension and / or obesity with hypertension; and / or

[0548] (ii) To prepare drugs for the prevention and / or treatment of overweight with hypertension and / or obesity with hypertension;

[0549] The GLP-1 / GIP peptide structure is as follows:

[0550] In one implementation, the overweight or obese patient with hypertension exhibits any of the following symptoms:

[0551] (a) BMI ≥ 30.0 kg / m 2 ;

[0552] (b) BMI ≥ 26.0 kg / m 2And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

[0553] In one implementation, the screening period / baseline sitSBP of the overweight with hypertension and / or obese with hypertension patients is not less than 140 mmHg.

[0554] In one embodiment, the baseline sitSBP of the overweight and / or obese patients with hypertension during the screening period is 140–179 mmHg.

[0555] In one implementation, the screening period / baseline sitDBP of the overweight with hypertension and / or obese with hypertension patients is not less than 90 mmHg.

[0556] In one implementation, the baseline sitDBP for overweight patients with hypertension and / or obese patients with hypertension during the screening period is 90–109 mmHg.

[0557] In one implementation, the overweight patient with hypertension and / or the obese patient with hypertension meets any of the following criteria:

[0558] 1) Grade 1 or 2 hypertension: i.e., screening / baseline sitting systolic blood pressure (sitSBP) and sitting diastolic blood pressure (sitDBP): sitSBP: 140–179 mmHg and / or sitDBP: 90–109 mmHg; or

[0559] 2) Isolated systolic hypertension: i.e., screening / baseline sitSBP: 140–179 mmHg and sitDBP < 90 mmHg; or

[0560] 3) Isolated diastolic hypertension: i.e., screening period / baseline sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

[0561] In one embodiment, the overweight and / or obese patients with hypertension are not patients with refractory hypertension, hypertensive urgency, hypertensive subacuteness, and / or secondary hypertension. Preferably, the secondary hypertension is selected from at least one of renal parenchymal hypertension, Cushing's syndrome, primary aldosteronism, pheochromocytoma, and drug-induced hypertension.

[0562] In one embodiment, the overweight patients with hypertension and / or obese patients with hypertension are not obese due to secondary diseases or medications, including: obesity caused by elevated cortisol hormones (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, and obesity caused by reduction / discontinuation of weight-loss drugs.

[0563] In one implementation, the overweight patients with hypertension and / or obese patients with hypertension are not patients with type 1 or type 2 diabetes.

[0564] In one embodiment, the pharmaceutical composition contains a GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

[0565] In one embodiment, the pharmaceutical composition is a liquid formulation.

[0566] In one embodiment, the pharmaceutical composition is an injection.

[0567] In one embodiment, the stabilizer in the pharmaceutical composition is a polyol; preferably, the stabilizer is selected from at least one of propylene glycol, mannitol, and glycerol; more preferably, the stabilizer is propylene glycol, mannitol, or glycerol; more preferably, the stabilizer is propylene glycol.

[0568] In one embodiment, the concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL.

[0569] In one embodiment, in the pharmaceutical composition, the buffer salt is selected from at least one of hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate or sodium citrate hydrate; more preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate.

[0570] In one embodiment, the concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

[0571] In one embodiment, the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; more preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; and more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.

[0572] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; the pH adjuster is hydrochloric acid and / or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster; the water is preferably purified water and / or water for injection.

[0573] In one embodiment, the pharmaceutical composition does not contain an antibacterial agent.

[0574] In one embodiment, the pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4.

[0575] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10 to 20 mM.

[0576] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5 to 25 mg / ml, the concentration of the propylene glycol is 14 mg / ml, and the concentration of the disodium hydrogen phosphate dodecahydrate is 10 mM.

[0577] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide; preferably, the water is purified water and / or water for injection.

[0578] In one embodiment, the pharmaceutical composition comprises 5–25 mg / mL GLP-1 / GIP peptide, 14 mg / mL propylene glycol, and 10 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.2–7.6.

[0579] On the other hand, this disclosure provides a method for preventing and / or treating overweight with hypertension and / or obesity with hypertension, comprising the steps of: administering a therapeutically effective amount of GLP-1 / GIP peptide or a pharmaceutical composition containing thereto to a subject in need;

[0580] The GLP-1 / GIP peptide structure is as follows:

[0581] In one embodiment, the pharmaceutical composition contains a GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

[0582] In one embodiment, the pharmaceutical composition is a liquid formulation.

[0583] In one embodiment, the pharmaceutical composition is an injection.

[0584] In one embodiment, the stabilizer in the pharmaceutical composition is a polyol; preferably, the stabilizer is propylene glycol, mannitol, or glycerol; more preferably, the stabilizer is propylene glycol.

[0585] In one embodiment, the concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL.

[0586] In one embodiment, in the pharmaceutical composition, the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate; preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate or sodium citrate hydrate; more preferably, the buffer salt is disodium hydrogen phosphate dodecahydrate.

[0587] In one embodiment, the concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

[0588] Further, the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; more preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.

[0589] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; the pH adjuster is hydrochloric acid and / or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster; the water is preferably purified water and / or water for injection.

[0590] In one embodiment, the pharmaceutical composition does not contain an antibacterial agent.

[0591] In one embodiment, the pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4.

[0592] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10 to 20 mM.

[0593] In one embodiment, the pH of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5 to 25 mg / ml, the concentration of the propylene glycol is 14 mg / ml, and the concentration of the disodium hydrogen phosphate dodecahydrate is 10 mM.

[0594] In one embodiment, the pharmaceutical composition further comprises a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide; preferably, the water is purified water and / or water for injection.

[0595] In one embodiment, the pharmaceutical composition comprises 5–25 mg / mL LGLP-1 / GIP peptide, 14 mg / mL propylene glycol, and 10 mM disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.2–7.6.

[0596] In one implementation, the desired subjects are overweight subjects with hypertension and / or obese subjects with hypertension.

[0597] In one implementation, the desired subjects are overweight and / or obese subjects with hypertension who have not achieved satisfactory weight loss results by diet and / or exercise alone.

[0598] In one implementation, the subject in need has previously undergone at least 12 weeks of diet control and / or exercise alone, with a weight change of <5.0%.

[0599] In one implementation, the desired object is selected from any of the following:

[0600] (a) BMI ≥ 30.0 kg / m 2 ;and

[0601] (b) BMI ≥ 26.0 kg / m 2 And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

[0602] In one implementation, the desired subject is a subject with essential hypertension.

[0603] In one implementation, the required object screening period / baseline sitSBP is not less than 140 mmHg.

[0604] In one implementation, the required object screening period / baseline sitSBP is 140–179 mmHg.

[0605] In one implementation, the required object screening period / baseline sitDBP is not less than 90 mmHg.

[0606] In one implementation, the required object screening period / baseline sitDBP is 90–109 mmHg.

[0607] In one implementation, the object in need must satisfy any of the following conditions:

[0608] 1) Grade 1 or 2 hypertension: i.e., screening / baseline sitting systolic blood pressure (sitSBP) and sitting diastolic blood pressure (sitDBP): sitSBP: 140–179 mmHg and / or sitDBP: 90–109 mmHg; or

[0609] 2) Isolated systolic hypertension: i.e., screening / baseline sitSBP: 140–179 mmHg and sitDBP < 90 mmHg; or

[0610] 3) Isolated diastolic hypertension: i.e., screening period / baseline sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

[0611] In one embodiment, the desired patient is not a patient with refractory hypertension, hypertensive emergency, hypertensive urgency, and / or secondary hypertension. Preferably, the patient with secondary hypertension is selected from at least one of renal parenchymal hypertension, Cushing's syndrome, primary aldosteronism, pheochromocytoma, and drug-induced hypertension.

[0612] In one implementation, the desired subject is not a patient whose obesity is caused by a secondary disease or medication, including obesity caused by elevated cortisol levels (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, and obesity caused by dose reduction / discontinuation of weight-loss drugs.

[0613] In one implementation, the person in need is not a patient with type 1 or type 2 diabetes.

[0614] In one embodiment, the administration method is non-enteric administration.

[0615] In one embodiment, the administration method is injection.

[0616] In one embodiment, the administration method is subcutaneous injection, intramuscular injection, intravenous injection, intradermal injection, or intraperitoneal injection.

[0617] In one embodiment, the administration method is subcutaneous injection, and the subcutaneous injection site is selected from one or more of the following: abdomen, front of the thigh, outer side of the upper arm, lower edge of the deltoid muscle of the upper arm, outer thigh, and back.

[0618] In one embodiment, the administration method is subcutaneous injection into the abdomen.

[0619] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is avoided from being injected consecutively at the same site.

[0620] In one embodiment, the GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered once a week.

[0621] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5-15 mg / kg.

[0622] In one embodiment, the dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is slowly increased.

[0623] In one embodiment, during the first to second week, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0624] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0625] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0626] In week 11 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0627] In one implementation, the method includes the steps of:

[0628] During weeks 1 to 4, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0629] During weeks 5 to 8, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0630] During weeks 9–12, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0631] In week 13 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0632] In one embodiment, during the first to second week, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg.

[0633] During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg.

[0634] During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and

[0635] During weeks 11 to 52, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

[0636] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 6 weeks, not less than 7 weeks, not less than 10 weeks, not less than 11 weeks, not less than 12 weeks, not less than 14 weeks, not less than 20 weeks, not less than 30 weeks, not less than 42 weeks, and not less than 52 weeks.

[0637] In one embodiment, the administration period of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is no more than 56 weeks.

[0638] In one implementation, the method includes the steps of:

[0639] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0640] b) Administer a maintenance dose of 5 mg of GLP-1 / GIP peptide to the subjects in need.

[0641] In one implementation, the method includes the steps of:

[0642] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0643] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0644] c) Administer a maintenance dose of 10 mg of GLP-1 / GIP peptide to the subject in need.

[0645] In one implementation, the method includes the steps of:

[0646] a) Administer a first titration dose of GLP-1 / GIP peptide of 2.5 mg / week to the recipient for two weeks; and subsequently...

[0647] b) Administer a second titration dose of GLP-1 / GIP peptide of 5 mg / week to the subjects in need for four weeks; and subsequently

[0648] c) Administer the third titration dose of GLP-1 / GIP peptide, 10 mg / week, to the subjects in need for four weeks; and subsequently...

[0649] d) Administer a maintenance dose of 15 mg / week of GLP-1 / GIP peptide to the subjects in need.

[0650] The high-dose groups of BGM0504 (20mg / 25mg) disclosed herein showed efficacy in moderate to severe obesity (BMI > 35.0 kg / m²) in non-diabetic Chinese patients with moderate to severe obesity and weight control (BMI > 35.0 kg / m²) who did not respond well to diet and exercise intervention alone. 2 Adult subjects showed good weight loss results and safety, and increasing the dosage did not cause a significant increase in side effects. Attached Figure Description

[0651] Figure 1 shows a comparison of the average concentration-time curves of plasma BGM0504 after drug administration in all groups of subjects in this publicly disclosed test case - PKCS.

[0652] Figure 2 shows a comparison of the mean plasma BGM0504 concentration semi-logarithmic-time curves after drug administration in all groups of subjects in this publicly disclosed test case - PKCS.

[0653] Figure 3 shows the mean HbA1c change (%) from baseline over time in different treatment groups in this publicly disclosed test case - PDS.

[0654] Figure 4 shows the change in mean fasting blood glucose (mmol / L) from baseline over time in different treatment groups in this test case - PDS.

[0655] Figure 5 shows the mean 2-hour postprandial blood glucose change (mmol / L) over time in different treatment groups in this publicly disclosed test case - PDS.

[0656] Figure 6 shows the change in mean fasting body weight (kg) from baseline over time in different treatment groups in this publicly disclosed test case - PDS.

[0657] Figure 7 shows the percentage change in mean fasting weight from baseline over time in different treatment groups in this publicly disclosed test case - PDS.

[0658] Figure 8 shows the change in HbA1c from baseline (removing placebo effect) in this test case - BGM0504 injection 5mg-15mg dose group vs semaglutide injection 1mg group.

[0659] Figure 9 shows the change in HbA1c from baseline (removing placebo effect) in this test case - BGM0504 injection 5mg-15mg dose group vs semaglutide injection 0.5mg-1mg group.

[0660] Figure 10 shows the change in HbA1c from baseline (removing placebo effect) in this test case - BGM0504 injection 5mg-15mg dose group vs. telpolide injection 5-15mg group. Figure 11 shows the time-varying changes in systolic blood pressure (SBP) for each group in this test case.

[0661] Figure 12 shows the time-varying diastolic blood pressure (DBP) for each group.

[0662] Figure 13 shows the changes in systolic blood pressure (SBP) relative to the baseline for each group.

[0663] Figure 14 shows the changes in diastolic blood pressure (DBP) relative to baseline for each group.

[0664] Figure 15 shows the mean concentration-time curve (including standard deviation) of plasma BGM0504 in subjects after drug administration in this test case.

[0665] Figure 16 shows the mean plasma BGM0504 concentration semi-logarithmic-time curve (including standard deviation)-PKCS of subjects after drug administration in this test case.

[0666] Figure 17 shows a comparison of the changes in body weight from baseline over time in each dose group in this test case - PDS.

[0667] Figure 18 shows a comparison of waist circumference changes from baseline over time in each dose group in this test case - PDS.

[0668] Figure 19 shows the percentage change in fasting body weight from baseline (excluding placebo) in this publicly disclosed test case - BGM0504 injection 5mg-15mg dose group vs. telpolide 10mg, 15mg group.

[0669] Figure 20 shows the percentage change in fasting body weight from baseline (excluding placebo) in this publicly disclosed test case - BGM0504 injection 5mg-15mg vs telpoeptide 10mg, 15mg.

[0670] Figure 21 shows the percentage change in body weight from baseline (excluding placebo) in this publicly disclosed test case - BGM0504 injection 5mg~15mg vs smegglutide 2.4mg.

[0671] Figure 22 shows the change in waist circumference from baseline (excluding placebo) in this test case - BGM0504 injection 5mg-15mg vs telpoeptide 10mg, 15mg.

[0672] Figure 23 shows the time-varying systolic blood pressure (SBP) of each dose group in the test examples disclosed in this publication.

[0673] Figure 24 shows the time-dependent changes in diastolic blood pressure (DBP) in each dose group in this test case.

[0674] Figure 25 shows the relative baseline variation of systolic blood pressure (SBP) in each group in this test case.

[0675] Figure 26 shows the relative baseline changes in diastolic blood pressure (DBP) for each group in this test case.

[0676] Figure 27 shows the trend of blood pressure (SBP) changes in each dose group in this test case.

[0677] Figure 28 shows the trend of blood pressure (DBP) changes in each dose group in this test case.

[0678] Figure 29 shows the trend of blood pressure (SBP) relative to baseline in each dose group in this published test case (full analysis set / subgroup analysis of blood pressure stratification).

[0679] Figure 30 shows the trend of blood pressure (DBP) relative to baseline in each dose group in this published test case (full analysis set / subgroup analysis of blood pressure stratification).

[0680] Figure 31 shows the changes in systolic and diastolic blood pressure and weight in obese patients with hypertension as disclosed in this paper. Detailed Implementation

[0681] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0682] I. Definition

[0683] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0684] In this disclosure, the term “about” means that a value includes the standard deviation of the error of the apparatus or method used to determine that value.

[0685] GLP-1 / GIP peptide

[0686] In this disclosure, the term "GLP-1 / GIP peptide" refers to a peptide that simultaneously targets both GLP-1 and GIP, such as telpolide, LY3437943, SAR441255, ALT-801, HM15136, and BGM0504. In one embodiment, a "GLP-1 / GIP peptide" is represented by formula (I) below, or is a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug.

[0687] In one embodiment, the “GLP-1 / GIP peptide” is the compound shown in formula (I) (BGM0504).

[0688] In this disclosure, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of this disclosure with a relatively non-toxic acid or base. When a compound of this disclosure contains a relatively acidic functional group (e.g., a carboxyl or sulfonic acid group), a base addition salt can be obtained by contacting it with a sufficient amount of base in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When a compound of this disclosure contains a relatively basic functional group (e.g., an amino or guanidinyl group), an acid addition salt can be obtained by contacting it with a sufficient amount of acid in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate, phosphorus, bisulfate, etc.), organic acid salts (e.g., monohydrogen acetate hydrochloride, dihydrogen phosphate, phosphite, sulfate propionate, isobutyrate, malonate, succinate, octanoate, maleate, fumarate, citrate, tartrate, lactate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, glucuronic acid, etc.), and amino acid salts (e.g., arginine salts). For specific forms of pharmaceutically acceptable salts, see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66: 1-19.

[0689] In this disclosure, the term "pharmaceutically acceptable ester" refers to an ester prepared from the compounds of this disclosure and alcohols, wherein the ester is substantially non-toxic to organisms and hydrolyzes in organisms to the compounds of this invention or their salts.

[0690] Drugs or drug compositions

[0691] In this disclosure, the term "pharmaceutical composition" means comprising the active ingredient GLP-1 / GIP peptide of this disclosure, and at least one pharmaceutically acceptable excipient selected from the following, depending on the method of administration and dosage form: carrier, diluent, adjuvant, excipient, preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant, dispersant, thermosensitive material, temperature regulator, adhesive, stabilizer, suspending agent, etc.

[0692] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0693] The term "pharmaceuticalally acceptable excipients" refers to all pharmaceutical materials, other than the active pharmaceutical ingredient, added to a formulation to address the formation, efficacy, stability, and safety of the drug. In some embodiments of this disclosure, pharmaceutical excipients include stabilizers and buffer salts.

[0694] The term "active ingredient" refers to any substance or mixture of substances used in the manufacture of a pharmaceutical product that has pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, management, or prevention of a disease, or that can affect the function or structure of an organism. Active ingredients can be small molecule compounds, antibodies, vaccines, or proteins, etc. In this disclosure, an active ingredient refers to a compound of formula (I), or its pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug; preferably, it is a compound of formula (I).

[0695] In some embodiments, the pharmaceutical compositions disclosed herein include GLP-1 / GIP peptides, stabilizers, and buffer salts.

[0696] The concentration of the GLP-1 / GIP peptide described in this disclosure is 2–36 mg / mL; for example, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, etc.; preferably 5–30 mg / mL. In this disclosure, a stabilizer refers to a substance used to stabilize the structure and biological activity of polypeptides in solution.

[0697] In some specific embodiments, the stabilizer described in this disclosure is propylene glycol, mannitol, or glycerol. Based on the results of formulation screening tests and stability tests, this disclosure preferentially selects propylene glycol as a stabilizer, which can effectively maintain the structure and biological activity of the active pharmaceutical ingredient, while also stabilizing the pH value of the pharmaceutical composition during storage.

[0698] In some embodiments, the concentration of the stabilizer described in this disclosure is 10–20 mg / mL; for example, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, etc.; preferably 14 mg / mL. It is worth mentioning that in polypeptide formulations, sodium chloride is considered to maintain electrolyte balance and stabilize polypeptide structures, and it exists as a stabilizer in many existing polypeptide formulations. However, when the inventors of this disclosure use sodium chloride to replace propylene glycol (for example, 2 mL of a pharmaceutical composition contains 40.0 mg BGM0504, 3.58 mg disodium hydrogen phosphate dodecahydrate, and 16.4 mg sodium chloride; the pH is adjusted to 7 using a pH adjuster, and the remaining amount is made up with water for injection), the solubility of BGM0504 is only 0.15 mg / mL, which is far from meeting the requirements. When propylene glycol is used as a stabilizer (e.g., 1 mL of the pharmaceutical composition contains 20.0 mg BGM0504, 3.58 mg disodium hydrogen phosphate dodecahydrate, and 14 mg propylene glycol, with the pH adjusted to 7 using a pH adjuster and the remainder made up with water for injection), the solubility of BGM0504 can reach over 30 mg / mL, meeting the solubility requirements of the active pharmaceutical ingredient. Therefore, in some preferred embodiments of this disclosure, the pharmaceutical composition does not contain sodium chloride. In some embodiments, the pH value of the pharmaceutical composition of this disclosure is 6.5–8.5; for example, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, etc.; preferably 7.0–8.4; more preferably 7.2–8.2; and even more preferably 7.2–7.6. In some specific embodiments, the pH adjuster described in this disclosure is hydrochloric acid and / or sodium hydroxide. This disclosure preferably uses a 0.1M hydrochloric acid and / or 0.1M sodium hydroxide solution.

[0699] This disclosure does not specifically limit the type of buffer salt, which can be determined by those skilled in the art according to actual needs. In some embodiments, the buffer salt described in this disclosure is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate. In some specific embodiments, the buffer salt described in this disclosure is disodium hydrogen phosphate dodecahydrate or sodium citrate dihydrate. In some preferred embodiments, the buffer salt described in this disclosure is disodium hydrogen phosphate dodecahydrate. In some embodiments, the concentration of the buffer salt described in this disclosure is 7–23 mM; for example, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, etc.; preferably 7–20 mM; more preferably 7–15 mM. Based on the results of formulation screening tests and considering the risk level of the drug composition in clinical applications such as injectable formulations, this disclosure prioritizes low-concentration buffer salts, such as 10 mM. The GLP-1 / GIP peptide described in this disclosure is a linear peptide containing 40 amino acids, and the initial pH value of the formulation is set between 7.2 and 8.2. It is highly susceptible to microbial degradation, and generally, the addition of antimicrobial agents (such as phenol) to the formulation is considered to improve product stability.

[0700] This disclosure also provides a method for preparing the pharmaceutical composition, comprising the following steps: preparing a solution of a stabilizer, a buffer salt, and a GLP-1 / GIP peptide, and adjusting the pH of the solution to a target value. In some specific embodiments, the method for preparing the pharmaceutical composition comprises the following steps: dissolving the stabilizer and the buffer salt in a solvent, adding the GLP-1 / GIP peptide, adding a pH adjuster to completely dissolve the GLP-1 / GIP peptide, and then adjusting the pH of the solution to a target value using the pH adjuster.

[0701] In some more specific embodiments, the preparation method of the pharmaceutical composition includes the following steps: dissolving a prescribed amount of disodium hydrogen phosphate dodecahydrate and propylene glycol in purified water or water for injection, adding a prescribed amount of GLP-1 / GIP peptide, and adding sodium hydroxide to completely dissolve the GLP-1 / GIP peptide, then adjusting the pH of the solution to 6.5-8.5 using hydrochloric acid and / or sodium hydroxide, and finally making up the volume with purified water or water for injection to obtain the final product.

[0702] The pharmaceutical products or pharmaceutical compositions disclosed herein are delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0703] Treatment

[0704] This disclosure relates to methods for preventing and / or treating diabetes, obesity, overweight with hypertension, and / or obesity with hypertension, comprising the steps of administering a therapeutically effective amount of a GLP-1 / GIP peptide or a pharmaceutical composition containing thereto to a subject in need.

[0705] In this disclosure, the terms "overweight" or "obese" refer to excessive fat accumulation that poses a threat to health. Body shape and metabolic characteristics vary among populations in different regions of the world. Body mass index (BMI) can be used to calculate body fat, and the patient's condition is confirmed based on the different regional standards for overweight and obesity. For example, in China, overweight is defined as 24.0 ≤ BMI < 28.0, and obesity as BMI ≥ 28.0; in Japan, overweight is defined as 25.0 ≤ BMI < 30.0, and obesity as BMI ≥ 30.0; in the United States, overweight is defined as 25.0 ≤ BMI < 29.9, obesity (Grade 1) as 30.0 ≤ BMI < 34.9, obesity (Grade 2) as 35.0 ≤ BMI < 39.9, and extreme obesity (Grade 3) as BMI ≥ 40.0.

[0706] In this disclosure, the term "hypertension" refers to a chronic condition characterized by persistently elevated arterial blood pressure. Definitions of hypertension vary across countries. The United States lowered the definition of hypertension in its 2017 guidelines to systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥80 mmHg, while China and other major countries maintain the standard of systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg. The European definition is similar to China's, namely systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg.

[0707] In this disclosure, the definitions of stage I, II, and III hypertension are consistent with the hypertension classification standards in this field. The term "stage I hypertension" is defined as 140 ≤ sitSBP ≤ 159 mmHg (or 140 ≤ sitSBP < 160 mmHg), and / or 90 ≤ sitDBP ≤ 99 mmHg (or 90 ≤ sitDBP < 100 mmHg). The term "stage II hypertension" is defined as 160 ≤ sitSBP ≤ 179 mmHg (or 160 ≤ sitSBP < 180 mmHg), and / or 100 ≤ sitDBP ≤ 109 mmHg (or 100 ≤ sitDBP < 110 mmHg). The term "stage III hypertension" is defined as sitSBP ≥ 180 mmHg, and / or sitDBP ≥ 110 mmHg.

[0708] The term "sitSBP" or "sitting systolic blood pressure" refers to the blood pressure measured during the systolic phase of the heart when the patient is sitting; the term "sitDBP" or "sitting diastolic blood pressure" refers to the blood pressure measured during the diastolic phase of the heart when the patient is sitting.

[0709] In this disclosure, the term "treatment" means: after contracting a disease, exposing a subject to (e.g., administering medication) the pharmaceutical composition of this disclosure, thereby reducing the symptoms of the disease compared to when not exposed, without implying the necessity to completely suppress the symptoms of the disease. Contracting a disease means: the appearance of disease symptoms in the body.

[0710] In this disclosure, the term "prevention" means: to reduce the symptoms of a disease by exposing a subject to (e.g., administering medication) the pharmaceutical composition of this disclosure before the onset of the disease, compared to the absence of exposure, and does not imply the necessity of completely suppressing the disease.

[0711] In this disclosure, the terms “individual,” “patient,” “subject,” or “subject” include mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats), preferably humans.

[0712] In this disclosure, the term "therapeutic effective amount" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and for the required duration. The therapeutic effective amount of the compounds or pharmaceutical compositions of this disclosure can vary depending on a variety of factors such as disease state, individual age, sex, weight, and the ability of the immune adjuvant or pharmaceutical composition to elicit the desired response in an individual.

[0713] In this disclosure, the term "overweight with hypertension and / or obesity with hypertension" refers to a patient who is both overweight / obese and has hypertension. In some embodiments of this disclosure, the patient is defined as (a) BMI ≥ 30.0 kg / m². 2Or (b) BMI ≥ 26.0 kg / m 2 And accompanied by at least one of the following manifestations: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity-induced dyspnea or obstructive sleep apnea syndrome (OSAS). In a preferred embodiment, hypertension is not (1) hypertension in special populations (refractory hypertension (RH), hypertensive emergencies, hypertensive urgencies) and secondary hypertension (hypertension of renal parenchyma (RHT), Cushing syndrome-induced hypertension, primary aldosteronism (PA)-induced hypertension, pheochromocytoma (PHEO)-induced hypertension, drug-induced hypertension, etc.).

[0714] The term "secondary" refers to a condition, disease, or symptom that arises from a pre-existing cause or basis, and is not an independent primary condition. The terms "secondary disease" or "secondary illness" refer to another independent disease that develops directly or indirectly from another pre-existing disease (primary disease), with a direct causal relationship between the secondary and primary diseases. Examples include hypertension caused by renal parenchymal disease, primary aldosteronism, pheochromocytoma, Cushing's syndrome, long-term use of oral contraceptives, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), cocaine use, etc. In some embodiments of this disclosure, the overweight or obese patient with hypertension is not overweight or obese due to any secondary disease or medication.

[0715] The term "comorbidity" refers to the simultaneous or sequential presence of at least two independent diseases that are not directly causally related but may affect each other's condition or treatment. Comorbidities can coexist or occur sequentially. In the embodiments of this disclosure, the patient is overweight with hypertension or obesity with hypertension and prediabetes; overweight with hypertension or obesity with hypertension and non-alcoholic fatty liver disease; overweight with hypertension or obesity with hypertension and dyslipidemia; overweight with hypertension or obesity with hypertension and weight-bearing joint pain; overweight with hypertension or obesity with hypertension and obesity-induced dyspnea; or overweight with hypertension or obesity with hypertension and obstructive sleep apnea syndrome; or the patient is overweight with hypertension or obesity with hypertension and any one or more of the aforementioned symptoms.

[0716] In this disclosure, the GLP-1 / GIP peptide or pharmaceutical composition containing it is administered via parenteral administration, preferably by injection, such as subcutaneous injection, intramuscular injection, intravenous injection, intradermal injection, or intraperitoneal injection. In a preferred embodiment, the administration method is subcutaneous injection. In some embodiments, the subcutaneous injection site is selected from one or more of the following: abdomen, anterior thigh, lateral upper arm, lower border of the deltoid muscle of the upper arm, lateral thigh, and back. In some embodiments, continuous injection in the same area is avoided.

[0717] The term "drug administration cycle" refers to the duration of treatment or the total length of the drug treatment course. In embodiments of this disclosure, the drug administration cycle is 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, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 45 weeks, 50 weeks, 52 weeks, 54 weeks, or 56 weeks.

[0718] The term "dosage" refers to the amount of drug administered to a subject each time. In embodiments of this disclosure, the dosage is 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, etc.

[0719] The term "titration dose" refers to the dose used in a clinical trial for individualized dose adjustment. During dose titration, the drug or dose is adjusted based on the patient's real-time vital signs. In embodiments of this disclosure, the GLP-1 / GIP peptide is administered via titration, with the titration proceeding slowly from a low dose to a maintenance dose.

[0720] The term "maintenance dose" refers to a fixed dose used to maintain a stable therapeutic effect over a long period of time after dose titration has been completed.

[0721] In some embodiments of this disclosure for treating hypertension, overweight with hypertension, or obesity with hypertension, a first titration dose (e.g., 2.5 mg / week) of GLP-1 / GIP peptide is administered to the subject in need for a period of time via titration, followed by a maintenance dose (e.g., 5 mg / week).

[0722] In some embodiments of this disclosure for treating hypertension, overweight with hypertension, or obesity with hypertension, the drug is administered via titration. A first titrated dose (e.g., 2.5 mg / week) of GLP-1 / GIP peptide is given to the subject in need for a period of time, followed by a second titrated dose (e.g., 5 mg / week) of GLP-1 / GIP peptide for a period of time, and then a maintenance dose (e.g., 10 mg / week) is given to the subject in need.

[0723] In some embodiments of this disclosure for treating hypertension, overweight with hypertension, or obesity with hypertension, the drug is administered via titration. A first titrated dose of GLP-1 / GIP peptide (e.g., 2.5 mg / week) is given to the subject in need for a period of time, followed by a second titrated dose of GLP-1 / GIP peptide (e.g., 5 mg / week) for a period of time, followed by a third titrated dose of GLP-1 / GIP peptide (e.g., 10 mg / week) for a period of time, and finally a maintenance dose (e.g., 15 mg / week) is given to the subject in need.

[0724] In some embodiments of the present disclosure for treating hypertension, overweight with hypertension, or obesity with hypertension, the drug is administered by titration. A first titrated dose of GLP-1 / GIP peptide is given to the subject in need for a period of time, followed by a second titrated dose of GLP-1 / GIP peptide for a period of time, and then a maintenance dose is given to the subject in need; wherein the first titrated dose < the second titrated dose < the maintenance dose.

[0725] In some embodiments of this disclosure for treating hypertension, overweight with hypertension, or obesity with hypertension, the drug is administered via titration. A first titrated dose of GLP-1 / GIP peptide is given to the subject in need for a period of time, followed by a second titrated dose of GLP-1 / GIP peptide for a period of time, then a third titrated dose of GLP-1 / GIP peptide for a period of time, and finally a maintenance dose; wherein the first titrated dose < the second titrated dose < the third titrated dose < the maintenance dose.

[0726] The term "dosing frequency" refers to the interval between drug administrations, such as once daily (QD), twice daily (BID), once weekly (QW), etc. In embodiments of this disclosure, the drug administration frequency is once a week, twice a week, once every two weeks, once every three weeks, once a month, etc.

[0727] II. Examples

[0728] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0729] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0730] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0731] Example 1

[0732] A randomized, double-blind, placebo and active-drug parallel-controlled clinical study was conducted to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of BGM0504 injection in patients with type 2 diabetes after multiple administrations.

[0733] The investigational drug disclosed is BGM0504 injection, with a specification of 0.5mL:10mg (according to C). 235 H 368 N 50 O 71 (Design). Manufacturer: Borui Pharmaceutical (Suzhou) Co., Ltd.; Supplier: Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[0734] Placebo: BGM0504 injection simulation agent, manufactured by Borui Pharmaceutical (Suzhou) Co., Ltd., supplied by Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[0735] Positive control drug: Smegglutide injection Specification 1ml: 1.34mg, Manufacturer: Novo Nordisk Pharmaceuticals Ltd.

[0736] Administration method: Subcutaneous injection, once a week. Subcutaneous injection in the abdomen; avoid consecutive injections at the same site.

[0737] Study duration: For each dose group (including placebo): the screening period / baseline for each subject is up to 2 weeks, the first phase of the double-blind treatment period is 6 to 10 weeks (titration for 2 to 6 weeks for the 5 mg, 10 mg, and 15 mg dose groups followed by 4 weeks of continued administration of the target dose), the second phase of the double-blind treatment period is 8 weeks, and the safety follow-up is 2 weeks, for a total of up to 18 to 22 weeks (calculated based on the longest duration).

[0738] Positive control group: Each subject requires a screening period / baseline of up to 2 weeks, a titration period of 6 weeks, an open-label treatment period of 12 weeks, and a safety follow-up period of 2 weeks, for a total of up to 22 weeks (calculated based on the longest duration).

[0739] Indications: Clinically intended for use in combination with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM).

[0740] Main purpose:

[0741] To evaluate the safety and tolerability of the BGM0504 injection solution disclosed herein in patients with type 2 diabetes after multiple subcutaneous injections.

[0742] Secondary objective:

[0743] To evaluate the pharmacokinetic, pharmacodynamic and immunogenic characteristics of the BGM0504 injection solution disclosed herein after multiple subcutaneous injections in patients with type 2 diabetes.

[0744] A preliminary comparison was made between the efficacy and safety of BGM0504 injection and smegglutide injection in patients with type 2 diabetes after multiple subcutaneous injections.

[0745] Experimental Design:

[0746] 1. Experimental group design:

[0747] This study includes a dose escalation trial with three dosage groups: 5 mg, 10 mg, and 15 mg. Each dosage group is double-blind (experimental drug group and placebo group). Additionally, an open-label positive control group is planned to be established after the first phase of safety and tolerability evaluation in the 10 mg dosage group, tentatively scheduled to begin concurrently with the 15 mg dosage group trial.

[0748] This trial plans to enroll 64 patients with type 2 diabetes, both male and female. Each of the 5mg, 10mg, and 15mg dose groups will enroll 16 subjects (randomized in a 12:4 ratio to either the BGM0504 injection group or the placebo group disclosed herein); the positive control group will enroll 16 subjects, all of whom will receive smegglutide injection.

[0749] For details on the experimental grouping and dosing design, please refer to Table 1-1 Experimental Grouping.

[0750] Table 1-1 Experimental Groups

[0751] The studies will be conducted sequentially in ascending order of dose: 5 mg, 10 mg, and 15 mg. After all subjects in the 5 mg or 10 mg dose group complete the safety assessment at the end of Phase I of treatment, the researchers and sponsor will review the safety data for that dose group. If the current dose group is well-tolerated (i.e., the dose escalation termination criteria have not been met), the next higher dose group can be tested. If the 15 mg dose is still well-tolerated, the researchers and sponsor may discuss whether to conduct a higher dose trial or complete the study. If dose escalation continues, it must not exceed the maximum tolerated dose in Phase Ia. The positive control group will undergo an open-label trial, tentatively scheduled to be conducted concurrently with the 15 mg dose group.

[0752] Experimental Procedure: The experimental procedures for the 5mg, 10mg, and 15mg dose groups differed slightly from those for the positive control group, as follows:

[0753] (1) Trial procedure for 5mg, 10mg, and 15mg dosage groups

[0754] The trial process for the 5mg, 10mg, and 15mg dose groups in this study was divided into five phases: screening period, baseline period, first phase of treatment, second phase of treatment, and safety follow-up.

[0755] The double-blind treatment phase I and phase II were conducted sequentially: Phase I lasted 6–10 weeks (titration administration for 2–6 weeks, followed by target dose administration for 4 weeks), primarily evaluating the safety, tolerability, and PK / PD characteristics of the BGM0504 injection disclosed herein in patients with type 2 diabetes after titration administration followed by continuous administration of the target dose for 4 weeks; Phase II continued administration of the target dose for 8 weeks. Phases I and II together preliminarily evaluated the efficacy, safety, and immunogenicity of the BGM0504 injection disclosed herein for continuous administration for 14–18 weeks (titration administration for 2–6 weeks followed by target dose administration for 12 weeks) in the treatment of type 2 diabetes.

[0756] The first phase of treatment lasts 6–10 weeks, with medication administered weekly. Titration is performed gradually to reach the target dose. The initial titration schedule is as follows: for the 5 mg dose group, two titrations of 2.5 mg each are administered; for the 10 mg dose group, four titrations of 2.5 mg for two weeks and 5 mg for two weeks; and for the 15 mg dose group, six titrations of 2.5 mg for two weeks, 5 mg for two weeks, and 10 mg for two weeks (the titration dosage, frequency, or duration may be adjusted based on the results of the previous dose group. If adjustments are made, the treatment procedure will be sequentially continued after reaching the target dose). Once the target dose is reached, medication continues for another 4 weeks to complete the first phase of treatment. At the end of week 4 of target dose administration (provisionally week 4 of target dose administration corresponds to week 6 of actual administration for the 5 mg group, week 8 of actual administration for the 10 mg group, and week 10 of actual administration for the 15 mg group), a comprehensive safety check will be performed. If the investigator evaluates the safety and tolerability of the subject in the first phase of treatment as good, the subject may proceed to the second phase of treatment. Furthermore, the first phase of treatment will primarily collect pharmacokinetic (PK) and efficacy / prokinetic (PD) indicators. In the second phase of treatment, the target dose will continue to be administered for 8 weeks. At the end of weeks 8 and 12 of target dose administration (weeks 8 and 12 of target dose administration correspond to weeks 10 and 14 of actual administration for the 5 mg group, weeks 12 and 16 of actual administration for the 10 mg group, and weeks 14 and 18 of actual administration for the 15 mg group), HbA1c, fasting blood glucose, 2-hour postprandial blood glucose (only at week 12 of target dose administration), insulin, C-peptide, proinsulin, glucagon, ADA / NAb, and safety checks and weight measurements will be performed.

[0757] 2) Positive control group test procedure:

[0758] The positive control group is scheduled to begin its trial after the first phase of safety and tolerability evaluation in the 10mg dose group. This group will undergo a separate open-label trial. The trial process for this group consists of five phases: screening, baseline, titration, treatment, and safety follow-up.

[0759] The positive control group received the medication once weekly for 6 weeks, with a treatment period of 12 weeks. Titration was initially performed to the clinically recommended dose (1 mg), with 6 titrations administered at doses of 0.25 mg for 3 weeks and 0.5 mg for 3 weeks. After titration to 1 mg, administration continued for 12 weeks. The primary observations in this group were efficacy / PD indicators and safety indicators; no pharmacokinetic (PK) blood samples were collected in this group.

[0760] Sample size: 64 patients with type 2 diabetes mellitus (T2DM) are planned to be enrolled.

[0761] Inclusion criteria: To be eligible for this trial, candidates must meet all of the following inclusion criteria:

[0762] (1) (Consultation) Chinese adult patients with type 2 diabetes aged 18 to 65 years (inclusive), with both men and women in each dose group, and meeting any one of the following criteria:

[0763] 1) A treatment-naïve patient diagnosed with type 2 diabetes who has received at least 8 weeks of diet and exercise intervention and has not previously taken antidiabetic medications; or

[0764] 2) Patients with a previous diagnosis of type 2 diabetes who are currently in the diet and exercise intervention program and have not received diabetes medication within the 8 weeks prior to screening, may have their experimental drug treatment added to the lifestyle intervention program based on the investigator's evaluation of their condition.

[0765] (2) (Examination) During screening, male weight ≥ 50.0 kg, female weight ≥ 45.0 kg, body mass index (BMI): 19.5 kg / m2 ≤ BMI ≤ 35.0 kg / m2;

[0766] (3) (Examination) Screening / baseline glycated hemoglobin (HbA1c): 7.0% ≤ HbA1c ≤ 10%;

[0767] (4) (Examination) Screening / Baseline fasting blood glucose (FPG): FPG ≤ 13.3 mmol / L (if there are special factors affecting blood glucose, it can be retested once within 1 week);

[0768] (5) (Consultation) Those who have no plans to become pregnant within one month after signing the informed consent and who voluntarily take effective contraceptive measures to avoid pregnancy or causing their partner to become pregnant and who have no plans to donate sperm or eggs;

[0769] (6) (Consultation) Fully understand the purpose, nature, method and possible adverse reactions of the trial, be able to complete the trial according to the protocol requirements, voluntarily serve as a subject, and sign the informed consent form.

[0770] Note: The diagnosis and classification of type 2 diabetes adopt the World Health Organization's 1999 criteria, with HbA1c ≥ 6.5% added as a supplementary diagnostic criterion for diabetes.

[0771] Exclusion criteria: A device is excluded if it meets any one of the following exclusion criteria:

[0772] (1) (Medical history and examination) Diagnosed as non-type 2 diabetes: such as type 1 diabetes, special types of diabetes (such as hereditary defects in pancreatic β-cell function, hereditary defects in insulin action, pancreatic exocrine diseases, etc.);

[0773] (2) (Medical history taking) Screening for patients who have experienced severe acute diabetic complications within the past 12 months, such as diabetic ketoacidosis, hyperosmolar hyperglycemia, lactic acidosis, etc.

[0774] (3) (Medical history and examination) During screening, there are serious chronic complications of diabetes, such as diabetic nephropathy, proliferative retinopathy; peripheral vascular disease leading to amputation, chronic foot ulcers or intermittent claudication, painful diabetic neuropathy, etc.

[0775] (4) (Medical history) History of other serious endocrine system diseases that affect glucose metabolism, such as multiple endocrine adenomas, acromegaly syndrome, Cushing's syndrome;

[0776] (5) (Medical history) Screening for patients who have experienced grade 3 hypoglycemia within the past 6 months [see Appendix 3];

[0777] (6) (Medical history and examination) If the patient has had the following cardiovascular diseases in the 6 months prior to the screening period, such as heart failure (NYHA class III-IV), myocardial infarction, history of coronary artery bypass grafting or coronary stent implantation, or serious arrhythmia requiring treatment, such as second- or third-degree atrioventricular block, long QTC syndrome or QTc interval prolongation (QTcF ≥470ms for women or ≥450ms for men);

[0778] (7) (Consultation) Patients who have had hemorrhagic or ischemic stroke or transient ischemic attack within 6 months prior to screening are deemed unsuitable for participation in this clinical trial by the investigators.

[0779] (8) (Medical history) Patients who have had serious trauma or infection that may affect blood sugar control, or who have undergone major surgery within the past 3 months before screening;

[0780] (9) (Examination) Thyroid dysfunction that cannot be controlled with a stable drug dose during screening, or thyroid function test results that are clinically significant and require initiation of treatment during screening.

[0781] (10) (Examination) Subjects with uncontrolled hypertension (systolic blood pressure ≥160 mmHg and / or diastolic blood pressure ≥100 mmHg at the time of screening) or whose untreated blood pressure meets the above criteria at the time of screening;

[0782] (11) (Inquiry) Those with a history of acute or chronic pancreatitis or clinical evidence;

[0783] (12) (Medical history) History or family history of medullary thyroid carcinoma or multiple endocrine adenoma syndrome type 2;

[0784] (13) (Medical history and examination) Previous blood system diseases or medical history that may affect HbA1c test results or increase the risk to the subject: (such as aplastic anemia, myelodysplastic syndrome, etc.) or any disease that causes hemolysis or red blood cell instability (such as sickle cell, thalassemia, etc.);

[0785] (14) (Medical history and examination) Those with a history of serious diseases of the nervous system, respiratory system, immune system, liver, kidney or other systems or organs are deemed unsuitable for participation in the trial by the investigator.

[0786] (15) (Consultation and examination) Diagnosed with malignant tumors within 5 years prior to screening (excluding cured carcinoma in situ) or assessed as having potential malignant tumors at the time of screening;

[0787] (16) During the screening process, individuals with severe mental illness or language barriers may be unwilling or unable to fully understand and cooperate.

[0788] (17)(Inquiry) It is known that the patient has an allergic constitution (allergic to 3 or more kinds of food or drugs), or is allergic to GLP-1 receptor agonist drugs, or has a severe allergic disease (asthma, urticaria, eczema, dermatitis, etc.) at the time of screening.

[0789] (18) Prior to screening, any of the following medications were used:

[0790] 1) The cumulative insulin use time in the year prior to screening exceeds 14 days (the time for insulin treatment during gestational diabetes is not within this limit);

[0791] 2) Other medications that may affect glucose metabolism were used in the 8 weeks prior to screening, such as other hypoglycemic drugs, systemic glucocorticoids (excluding inhaled or topical), growth hormone, etc.

[0792] (19) Subjects whose laboratory test results at screening or baseline meet the following criteria:

[0793] 1) Fasting C-peptide < 0.81 ng / mL;

[0794] 2) A positive result for any of the following tests: insulin autoantibody (IAA), islet cell antibody (ICA), or glutamate decarboxylase antibody (GAD-Ab):

[0795] 3) ALT and AST ≥ 2.5 times the upper limit of normal (ULN) or total bilirubin ≥ 1.5 times the upper limit of normal (ULN);

[0796] 4) Serum amylase or serum lipase ≥ 1.5 times the upper limit of the normal range (ULN);

[0797] 5) Glomerular filtration rate (eGFR) ≤ 60 mL / min / 1.73 m2 (CKD-EPI formula) or urine protein positive 2+ or above;

[0798] 6) Serum calcitonin level ≥35 ng / L (pg / mL).

[0799] 7) Triglycerides ≥ 5.64 mmol / L (500 mg / dL);

[0800] 8) Hemoglobin (HGB) < 100 g / L;

[0801] 9) Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus load (HBV-DNA) higher than the local laboratory detection limit;

[0802] 10) Positive for hepatitis C antibody (HCV-Ab) and hepatitis C virus load (HCV-RNA) higher than the local laboratory detection limit;

[0803] 11) Positive for HIV antibody (HIV-Ab) or positive for Treponema pallidum antibody (TPAb);

[0804] (20) (Examination) Those with positive baseline urine drug screening results or alcohol breath test results;

[0805] (21) (Medical history) History of drug abuse;

[0806] (22)(Consultation) Screening those who have donated blood (including blood components) or lost a lot of blood (≥400mL, excluding menstrual blood in women) within the past 3 months, received blood transfusions or used blood products, and those who plan to donate blood within 1 month after the end of the study;

[0807] (23) (Consultation) Men who consumed more than 21 units of alcohol per week and women who consumed more than 14 units per week within the three months prior to screening (1 unit of alcohol ≈ 360 mL of beer or 45 mL of spirits with an alcohol content of 40% or 150 mL of wine), or those who could not abstain from alcohol during the trial period.

[0808] (24) (Consultation) Screening of individuals who have participated in any clinical study and received intervention with experimental drugs or medical devices within the previous 3 months;

[0809] (25) (Medical history taking) If you have consumed foods that affect liver drug enzymes (such as CYP3A4, CYP2D6 and CYP2E1) within 48 hours before the baseline examination, such as grapefruit or beverages containing grapefruit.

[0810] (26) (Inquiry) Patients with a history of fainting at the sight of blood or needles or who cannot tolerate intravenous blood collection;

[0811] (27) (Consultation / Examination) Female subjects who are pregnant or lactating;

[0812] (28) The researchers believe that the subject has any other factors that would make him or her unsuitable to participate in the trial.

[0813] Pharmacokinetic evaluation: No pharmacokinetic blood samples were collected from the positive control group.

[0814] (1) Blood sample collection time:

[0815] The following blood collection points are tentatively scheduled: within 1 hour before the 1st, 3rd, and 5th titrations (1 time for the 5mg dose group, 2 times for the 10mg dose group, and 3 times for the 15mg dose group); within 1 hour before the first target dose; and at 2, 4, 8, 12, 24, 36, 48, 72, 120, and 168 hours after the first target dose (i.e., before the second target dose); within 1 hour before the 3rd and 4th target doses; and at 2, 4, 8, 12, 24, 36, 48, 72, 120, and 168 hours after the fourth target dose (before the fifth target dose); and within 1 hour before the 9th and 12th target doses. A total of 26 blood collection points are tentatively planned for the 5mg dose group, 27 for the 10mg dose group, and 28 for the 15mg dose group.

[0816] (2) PK blood collection method:

[0817] Blood is collected using an indwelling venous catheter or venipuncture, with approximately 4 mL of blood collected each time. Before each blood collection, approximately 0.5 mL of blood containing the sealing solution in the indwelling catheter should be discarded.

[0818] (3) PK blood sample processing:

[0819] After blood collection, immediately and gently shake the blood collection tube several times to ensure thorough mixing of the blood and anticoagulant (EDTA-K2). Place the tube upright on a test tube rack in an ice bath until centrifugation. Within 60 minutes of blood collection, centrifuge the PK blood sample at approximately 2500g and 2–8°C (set temperature 4°C) for 10 minutes to separate the plasma for PK testing. Aliquot the remaining plasma into another cryopreservation tube for backup. All PK analysis samples must be stored at -60°C or below within 120 minutes of blood collection until delivery to the analytical unit. PK analysis samples must be stored at -60°C or below at the analytical unit until analysis is required. For detailed procedures and requirements, please refer to the PK blood sample processing manual.

[0820] (4) PK parameters:

[0821] Mainly includes: AUC inf AUC 0-t C max T max t 1 / 2 ,Kel,MRT,CL / F,Vd / F,AUC_%Extrap,C min，ss C max，ss C av，ss AUC 0-τ DF, RAUC, RC max .

[0822] (5) PK sample analysis method:

[0823] Approximately 4 mL of venous blood will be collected from each blood collection point. The content of BGM0504 and its possible major metabolites in the plasma will be quantitatively detected using a methodologically validated method (subsequent adjustments will be made based on the PK test in phase Ia).

[0824] Pharmacodynamic evaluation: In the positive control group, only baseline, and week 4, 8, and 12 of target dose administration were collected for efficacy evaluation of HbA1c, fasting blood glucose, fasting weight, and 2-hour postprandial blood glucose (week 12 only of target dose administration). (All time points below refer to the week of target dose administration; the time point for index collection can be before the next week of administration.)

[0825] (1) PD / Effectiveness Evaluation Indicators:

[0826] 1) Key performance indicators (PD) / effectiveness evaluation metrics:

[0827] HbA1c: Change in HbA1c from baseline at week 12 of target dose administration.

[0828] 2) Secondary PD / effectiveness evaluation indicators:

[0829] HbA1c: Changes in HbA1c from baseline at weeks 4 and 8 after target dose administration;

[0830] Fasting insulin: Changes in fasting insulin levels from baseline at weeks 4, 8, and 12 of target dose administration;

[0831] Fasting proinsulin: Changes in fasting proinsulin from baseline at weeks 4, 8, and 12 after target dose administration;

[0832] Fasting C-peptide: Changes in fasting C-peptide from baseline at weeks 4, 8, and 12 after target dose administration;

[0833] Fasting glucagon: Changes in fasting glucagon levels from baseline at weeks 4, 8, and 12 after target dose administration;

[0834] Fasting blood glucose: Changes in fasting blood glucose from baseline at weeks 4, 8, and 12 after target dose administration;

[0835] 2-hour postprandial blood glucose: Change in standard 2-hour postprandial blood glucose from baseline during week 12 of target dose administration;

[0836] Fasting body weight: Changes in fasting body weight from baseline at weeks 4, 8, and 12 after target dose administration;

[0837] The percentage of subjects with HbA1c < 7.0% and HbA1c < 6.5% at week 12 of target dose administration;

[0838] Changes in HOMA2-B and HOMA2-IR from baseline at week 12 of target dose administration.

[0839] (2) Collection of PD indicators:

[0840] The schedule for collecting PD / efficacy indicators for the three dosage groups of 5mg, 10mg, and 15mg is shown in Table 1-2. (In the table below, D42 / 56 / 70, D71 / 85 / 99, and D98 / 112 / 126 refer to the time for collecting biological samples for the corresponding PD indicators in the 5mg / 10mg / 15mg dosage groups, respectively).

[0841] Table 1-2 Timetable for biological sample collection of PD indicators

[0842] Before the study begins, biostatisticians develop a statistical analysis plan based on the clinical study protocol, including safety, efficacy, pharmacokinetic (PK), and immunogenicity analyses, and execute the statistical analysis according to the established plan. Unless otherwise specified, SAS 9.4 or later, or WinNonlin V8.3 or later, are used for statistical analysis. Unless otherwise specified, commonly used statistical methods in the field are employed for result analysis.

[0843] Preliminary results of a clinical trial of BGM0504 injection for the treatment of type 2 diabetes showed that subjects in the target dose groups of 5mg, 10mg, and 15mg of BGM0504 injection, administered once weekly for 14–18 weeks, exhibited good overall tolerability and safety. Subjects in each dose group showed significant improvements compared to baseline in blood glucose control indicators such as HbA1c, fasting blood glucose, and 2-hour postprandial blood glucose, as well as the HbA1c / weight composite target achievement rate, which were significantly better than the placebo group. Furthermore, the results demonstrated good comparability with the positive control drug, semaglutide injection.

[0844] Details are as follows:

[0845] 1. Glycated hemoglobin (HbA1c)

[0846] At week 4 of target dose administration, the mean reduction in HbA1c from baseline (excluding placebo) in the BGM0504 injection 5 mg, 10 mg, and 15 mg groups and the smegglutide injection group were 1.32%, 1.48%, 2.16%, and 1.03%, respectively.

[0847] At week 12 of target dose administration, the mean reduction in HbA1c from baseline (excluding placebo) in the BGM0504 injection 5 mg, 10 mg, and 15 mg groups and the smegglutide injection group were 1.99%, 2.21%, 2.76%, and 1.71%, respectively.

[0848] At week 12 of target dose administration, the proportions of subjects achieving HbA1c < 7.0% after treatment with BGM0504 injection (5 mg, 10 mg, 15 mg) and semaglutide injection were 76.9%, 81.8%, 91.7%, and 75%, respectively. Specifically, 27.3%, 50%, and 12.5% ​​of subjects in the 10 mg, 15 mg, and semaglutide injection groups, respectively, achieved normal glycation levels (HbA1c < 5.7%).

[0849] Example 2

[0850] A randomized, double-blind, placebo-controlled parallel clinical study evaluating the safety, tolerability, pharmacokinetic / pharmacodynamic characteristics, and efficacy of multiple-dose administration of BGM0504 injection in non-diabetic overweight or obese subjects.

[0851] Test drug: BGM0504 injection, specification 0.5mL:10mg (calculated as C235H368N50O71), manufacturer: Borui Pharmaceutical (Suzhou) Co., Ltd., supplier: Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[0852] Placebo: The BGM0504 injection analogue disclosed herein is manufactured by Borui Pharmaceutical (Suzhou) Co., Ltd. and provided by Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[0853] Administration method: Subcutaneous injection, once a week. Subcutaneous injection in the abdomen; avoid consecutive injections at the same site.

[0854] Study duration: Each subject will require a screening period / baseline of up to 2 weeks, a double-blind treatment phase 1 of 6 to 10 weeks (6 weeks for the 5 mg dose group, 8 weeks for the 10 mg dose group, and 10 weeks for the 15 mg dose group), a double-blind treatment phase 2 of 20 weeks, and a safety follow-up of 2 weeks, for a total of up to 30 to 34 weeks (calculated based on the longest duration).

[0855] Indications: For use as an adjunct to diet, exercise, and behavioral interventions in adult weight management, with an initial body mass index (BMI) of:

[0856] 28.0kg / m 2 Or above (obese) or;

[0857] 24.0≤BMI<28.0kg / m 2 (Overweight) and at least one weight-related comorbidity (such as prediabetes, hypertension, dyslipidemia, fatty liver, obstructive sleep apnea syndrome, etc.).

[0858] Main purpose:

[0859] The safety, tolerability, and PK / PD characteristics of the BGM0504 injection solution disclosed herein were evaluated in non-diabetic overweight or obese subjects after titration administration at the target dose for 4 weeks (Phase I).

[0860] Secondary objective:

[0861] The safety, efficacy, and immunogenicity of the BGM0504 injection solution disclosed herein were evaluated in non-diabetic overweight or obese subjects after 20 weeks of continuous subcutaneous administration (Phase II).

[0862] This study is a randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation clinical trial conducted in overweight or obese non-diabetic adults in China. The study was double-blind in each dose group, with a two-phase double-blind treatment period: Phase I (6–10 weeks) was administered sequentially with titration followed by 4 weeks of target dose administration. The Phase I aimed to evaluate the safety, tolerability, and pharmacokinetic / pharmacodynamic (PK / PD) characteristics of the disclosed BGM0504 injection in overweight or obese non-diabetic subjects after titration followed by continuous administration of the target dose for 4 weeks. Phase II continued administration of the target dose for 20 weeks to preliminarily evaluate the efficacy, safety, and immunogenicity of the disclosed BGM0504 injection for weight control.

[0863] The first phase of treatment lasts 6–10 weeks, with medication administered once weekly. Titration is performed gradually to the target dose. For the 5 mg dose group, titration is initiated with two doses of 2.5 mg each; for the 10 mg dose group, titration is initiated with four doses of 2.5 mg twice, followed by two doses of 5 mg; and for the 15 mg dose group, titration is initiated with six doses of 2.5 mg twice, followed by two doses of 5 mg, followed by two doses of 10 mg (the titration dose, frequency, or duration may be adjusted based on the results of the previous dose group. If adjustments are made, the treatment procedure will be sequentially continued after reaching the target dose). Once the target dose is reached, medication is continued for another 4 weeks to complete the first phase of treatment. A comprehensive safety assessment will be conducted at the end of the fourth week of target dose administration (tentatively, the end of the fourth week of target dose administration is the end of the sixth week of actual administration for the 5 mg dose group, the end of the eighth week of actual administration for the 10 mg dose group, and the end of the tenth week of actual administration for the 15 mg dose group). If the investigator evaluates the safety and tolerability of the subject in the first phase of treatment as good, the subject may proceed to the second phase of treatment.

[0864] During the second phase of treatment, fasting weight, waist circumference, and other efficacy indicators were measured at the end of weeks 8, 12, 16, 20, and 24 of the target dose administration (tentatively weeks 10, 14, 18, 22, and 26 for the 5 mg dose group, weeks 12, 16, 20, 24, and 28 for the 10 mg dose group, and weeks 14, 18, 22, 26, and 30 for the 15 mg dose group). A comprehensive safety assessment was also conducted. ADA / NAb ratios were measured at weeks 12 and 24 of the target dose administration.

[0865] This trial plans to enroll 120 non-diabetic overweight or obese subjects with an appropriate male-to-female ratio. Three dosage groups are proposed: a 5mg dose group, a 10mg dose group, and a 15mg dose group. Each dose group is planned to enroll 40 subjects, who will be randomly assigned in a 3:1 ratio to either the BGM0504 injection group or the placebo group. The tentative trial groupings are shown in Table 2-1 below.

[0866] Table 2-1 Experimental Groups

[0867] This trial will be conducted sequentially from low to high dose groups. After all subjects in the 5 mg or 10 mg dose group complete the safety check at the end of Phase I of treatment, the investigators and sponsors will review the safety data for Phase I of treatment for all subjects in that dose group. If the current dose group is well-tolerated (i.e., the dose escalation termination criteria have not been met), the trial for the next higher dose group can be initiated. If the 15 mg dose is still well-tolerated, the investigators and sponsors may discuss whether to conduct a higher dose trial or complete the study. If the dose is to be increased further, it must not exceed the maximum tolerated dose in Phase Ia.

[0868] This study consists of five phases: screening, baseline, Phase I of treatment, Phase II of treatment, and safety follow-up. The overall trial process is as follows:

[0869] 1. Screening period (D-14~D-1)

[0870] During the screening period, participants will complete the corresponding screening examinations. Researchers will conduct a preliminary evaluation of whether participants meet the enrollment requirements based on the examination results and other relevant information, and inform participants who pass the preliminary screening of the specific time to return to the research center and the precautions to be taken in the near future.

[0871] 2. Baseline period (D-1)

[0872] Subjects who passed the initial screening completed baseline examinations and baseline data collection (including fasting weight, waist circumference, ADA testing, etc.) on day 1. After the researchers confirmed that the subjects met the inclusion requirements, they were randomized.

[0873] 3. First phase of treatment (5mg group: D1–D42, 10mg group: D1–D56, 15mg group: D1–D70. Time window: ±1 day)

[0874] Subjects in the 5mg dose group received titration administration (2.5mg of BGM0504 injection or placebo) on the mornings of Days 1 and 8 (8:00–9:00). A post-administration safety check was required before leaving the research center on Day 1. Subjects returned to the research center on Day 14. A light diet was provided on the evening of Day 14, followed by at least 10 hours of fasting with no restrictions on water intake. The first target dose (the third actual dose) was administered on the morning of Day 15 (8:00–9:00) on an empty stomach. One to two hours after administration, subjects could eat breakfast as needed. Lunch and dinner were provided 4 hours after administration (12:00–13:00, after PK blood collection 4 hours post-administration) and 10 hours after administration (18:00–19:00), respectively. Subjects continued to be hospitalized for PK blood sample collection and safety monitoring. They could temporarily leave the research center after completing PK and PD blood sample collection 48 hours post-administration. Subsequently, subjects received weekly drug injections and underwent PK, PD, and other indicator collection and safety checks at specified times. Subjects were readmitted to the research center on day 35 and continued to be hospitalized for PK blood sample collection after the fourth target dose was administered the following day (the sixth actual dose). They could leave the research center after PK blood sample collection was completed 48 hours after the first dose was administered. During this period, the drug administration and blood collection requirements were the same as those for the first target dose administration (the third actual dose).

[0875] Subjects in the 10 mg dose group received titration once each on the mornings of days 1, 8, 15, and 22 (BGM0504 injection or placebo, with a dose of 2.5 mg on days 1 and 8, and 5 mg on days 15 and 22; the titration dose may be adjusted based on trial results). The procedure after titrating to the target dose in the 10 mg dose group was the same as that in the 5 mg dose group, but the timeframe was extended by two weeks (subjects checked into the research center on days 28 and 49).

[0876] Subjects in the 15 mg dose group received a titration once each on the mornings of days 1, 8, 15, 22, 29, and 36 (BGM0504 injection or placebo, with doses of 2.5 mg on days 1 and 8, 5 mg on days 15 and 22, and 10 mg on days 29 and 36; the titration dose may be adjusted based on trial results). The procedure after titrating to the target dose in the 15 mg dose group was the same as that in the 5 mg dose group, but the timeframe was extended by 4 weeks (subjects were admitted to the research center on days 42 and 63).

[0877] The first phase end visit was conducted on day 42 for the 5 mg dose group, day 56 for the 10 mg dose group, and day 70 for the 15 mg dose group. Safety checks included vital signs, physical examination, 12-lead electrocardiogram, laboratory tests, and ADA / NAb testing. Researchers evaluated the safety and tolerability of the subjects after 2–6 weeks of titration followed by 4 weeks of target dose administration. If safety and tolerability were satisfactory, the subjects could proceed to the second phase of treatment. Subjects who prematurely withdrew from the first phase should complete the early withdrawal visit (the content of which was the same as the first phase end visit) as soon as possible.

[0878] 4. Second phase of treatment (5mg dose group: D43~D182, 10mg dose group: D57~D196, 15mg dose group: D71~D210. Time window: ±1 day)

[0879] Subjects entering the second phase of treatment will continue to receive the target dose once weekly for 20 consecutive weeks. Fasting weight and waist circumference will be measured at the end of weeks 8, 12, 16, and 20 of the target dose administration (tentatively weeks 10, 14, 18, and 22 for the 5 mg dose group, weeks 12, 16, 20, and 24 for the 10 mg dose group, and weeks 14, 18, 22, and 26 for the 15 mg dose group), and a comprehensive safety check will be performed. ADA / NAb levels will be measured at the end of weeks 12 and 24 of the target dose administration.

[0880] Subjects in the 5 mg group will have their Phase II end-of-treatment visit on D182, the 10 mg group on D196, and the 15 mg group on D210. At these visits, efficacy indicators will be collected, ADA / NAb levels will be measured, and a comprehensive safety assessment will be conducted. Subjects who withdraw early after receiving Phase II treatment should complete their early withdrawal visit as soon as possible (the visit content is the same as the Phase II end-of-treatment visit).

[0881] 5. Safety follow-up (5 mg dose group: D196, 10 mg dose group: D210, 15 mg dose group: D224, early withdrawal: day 14 after the last dose. Safety follow-up time window: ±3 days)

[0882] All subjects receiving the medication should undergo safety follow-up as required. The safety follow-up time is D1 96±3 for the 5 mg dose group, D2 10±3 for the 10 mg dose group, and D2 24±3 for the 15 mg dose group. Subjects who withdraw from the trial early after receiving the medication should also complete the safety follow-up as early as possible on day 14±3 after early withdrawal.

[0883] Unplanned visits

[0884] If the investigator assesses that a subject has safety issues after taking the medication, they need to be followed up until the adverse events (AEs) disappear, improve, stabilize, return to baseline levels, or the subject is lost to follow-up (whichever occurs first). In this case, the method and frequency of follow-up are determined by the investigator based on the subject's actual AE situation.

[0885] Sample size: The study plans to enroll a total of 120 obese or overweight subjects with at least one comorbidity (including prediabetes, grade I hypertension, simple fatty liver, dyslipidemia, weight-bearing joint pain, and obstructive sleep apnea syndrome).

[0886] Inclusion criteria: To be eligible for this trial, candidates must meet all of the following inclusion criteria:

[0887] (1) Age 18 to 60 years old (inclusive), male or female;

[0888] (2) (Inquiry and Examination) Obese individuals: BMI ≥ 28.0 kg / m2; or overweight individuals: 24.0 ≤ BMI < 28.0 kg / m2 and accompanied by at least one of the following: i. Prediabetes (impaired fasting glucose and / or impaired glucose tolerance), grade I hypertension, simple fatty liver, dyslipidemia or one or more of the following; ii. Pain in weight-bearing joints; iii. Dyspnea caused by obesity or obstructive sleep apnea syndrome;

[0889] (3) (Inquiry) Before screening, the patient had been under diet and exercise control for at least 12 weeks, with a weight change of <5.0% (chief complaint), and was able to continue to control weight through diet and exercise in the same way during the trial period.

[0890] (4) After signing informed consent, the candidate has no plans to become pregnant within one month after the end of the study and voluntarily takes effective contraceptive measures to avoid pregnancy or causing their partner to become pregnant, and has no plans to donate sperm or eggs;

[0891] (5) Can understand the procedures and methods of this study, are willing to strictly abide by the clinical trial protocol to complete this trial, and voluntarily sign the informed consent form.

[0892] Note: The percentage change in weight is calculated as follows: (weight 12 weeks before screening - weight at screening) / weight 12 weeks before screening × 100%.

[0893] Exclusion criteria: A device is excluded if it meets any one of the following exclusion criteria:

[0894] (1)(Inquiry) It is known that the person has an allergic constitution (allergic to 3 or more kinds of food or drugs), or is allergic to GLP-1 receptor agonist drugs, or has a severe allergic disease (asthma, urticaria, eczema, dermatitis, etc.) at the time of screening.

[0895] (2) Prior to screening, any of the following medications or treatments were used:

[0896] 1) Those who have used a GLP-1 receptor agonist or a similar drug with the same target within the 12 weeks prior to screening;

[0897] 2) Screening for medications that affect weight used within the 12 weeks prior to screening, including: systemic glucocorticoids (intravenous or oral administration), growth hormone, tricyclic antidepressants, medications for mental illnesses, or sedatives (such as imipramine, amitriptyline, mirtazapine, etc.);

[0898] 3) Use of weight-loss drugs within 12 weeks prior to screening, such as: sibutramine hydrochloride, phenbutylamine, phenylpropanolamine, chlorpheniramine, phentermine, amphetamine, lorcaserin, phentermine / topiramate combination, naltrexone / bupropion combination, etc. (If orlistat or metformin is used, it should be used stably for at least 3 months prior to screening and continued in the original manner during the trial).

[0899] (3) (Check) During screening / baseline testing, if any of the following laboratory test indicators meet the following criteria:

[0900] 1) ALT or AST ≥ 2.5 times the upper limit of normal (ULN) or total bilirubin ≥ 1.5 times the upper limit of normal (ULN);

[0901] 2) Glomerular filtration rate (eGFR) ≤ 60 mL / min / 1.73 m2 (CKD-EPI formula) or urine protein positive 2+ or above;

[0902] 3) Serum calcitonin level ≥35ng / L (pg / mL).

[0903] 4) Fasting triglycerides ≥ 5.64 mmol / L (500 mg / dL);

[0904] 5) Hemoglobin (HGB) < 100 g / L;

[0905] 6) Serum amylase or serum lipase > 2.0 × ULN;

[0906] 7) Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus load (HBV-DNA) higher than the local laboratory detection limit;

[0907] 8) Positive for hepatitis C antibody (HCV-Ab) and hepatitis C virus load (HCV-RNA) higher than the local laboratory detection limit;

[0908] 9) Positive for HIV antibody (HIV-Ab) or positive for Treponema pallidum antibody (TPAb);

[0909] (4) (Examination) Screening / Baseline 12-lead ECG showing heart rate <50 bpm or >100 bpm, second- or third-degree atrioventricular block, long QT syndrome or QTcF >470 ms in women or >450 ms in men, pre-excitation syndrome or other significant arrhythmias;

[0910] (5) History or evidence of any of the following diseases:

[0911] 1)(Inquiry) Obesity caused by secondary diseases or drugs includes: elevated cortisol hormone (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, obesity caused by reducing / discontinuing weight loss drugs, etc.

[0912] 2)(Inquiry) Those who have previously undergone gastric weight loss surgery, or have undergone liposuction or fat removal surgery within 1 year prior to screening, or plan to undergo weight loss surgery, liposuction, or abdominal fat removal surgery or other surgeries that significantly affect weight during the study period.

[0913] 3)(Inquiry) History of myocardial infarction, unstable angina, acute / chronic heart failure, or coronary intervention, coronary artery bypass grafting, or other cardiac surgeries;

[0914] 4)(Questionnaire) Has a history of moderate to severe depression, or has a PHQ (Depression Screening Scale) score ≥15 at the time of screening, or has a history of other serious mental illnesses, or has suicidal tendencies or suicidal behavior.

[0915] 5)(Inquiry) Diagnosed with malignant tumors within 5 years prior to screening (excluding cured carcinoma in situ) or assessed as having potential malignant tumors at the time of screening;

[0916] 6) (Inquiry) Previous diagnosis of type 1 or type 2 diabetes;

[0917] 7)(Inquiry) History of acute or chronic pancreatitis, or history of pancreatic injury;

[0918] 8)(Inquiry) History of thyroid C-cell carcinoma, MEN (multiple endocrine neoplasia) 2A or 2B, or related family history;

[0919] 9) (Inquiry) Has experienced severe hypoglycemia or recurrent (≥2 times within 6 months) symptomatic hypoglycemia within the 6 months prior to screening;

[0920] 10)(Inquiry) Subjects who have experienced hemorrhagic or ischemic stroke or transient ischemic attack within 6 months prior to screening; 11)(Examination) Subjects with uncontrolled hypertension (systolic blood pressure ≥160 mmHg and / or diastolic blood pressure ≥100 mmHg at the time of screening) or whose untreated blood pressure meets the above criteria at the time of screening.

[0921] 12)(Examination) Thyroid dysfunction that cannot be controlled with a stable drug dose at the time of screening, or thyroid function test results that are clinically significant and require initiation of treatment at the time of screening.

[0922] 13)(Inquiry and Examination) Abdominal ultrasound during screening indicates the presence of gallstones or polyps, or clinical symptoms of gallbladder disease are present during screening.

[0923] (6) (Examination) Positive baseline urine drug screening or alcohol breath test result;

[0924] (7) (Inquiry) During the screening, there is a history of drug abuse or alcoholism (more than 14 units of alcohol per week, 1 unit = 17.7 mL of ethanol, that is, 1 unit = 357 mL of beer with 5% alcohol content or 43 mL of liquor with 40% alcohol content or 147 mL of wine with 12% alcohol content).

[0925] (8) (Inquiry) Individuals who have participated in clinical trials of drugs or medical devices and received interventions with investigational drugs (including placebos) or medical devices within the 12 weeks prior to screening;

[0926] (9) (Inquiry) Those who have donated blood or suffered massive blood loss (≥400mL, except for menstrual bleeding in women) or received blood transfusions within 12 weeks prior to screening, or those who plan to donate blood within 3 months before the end of the study;

[0927] (10) (Examination) of pregnant or lactating women;

[0928] (11) Individuals with combined mental illness or language disorders who are unwilling or unable to fully understand and cooperate;

[0929] (12) Other situations in which researchers deem it unsuitable for participation in the trial.

[0930] Safety evaluation: (D42 / 56 / 70, D71 / 85 / 99, D99 / 113 / 127, D127 / 141 / 155, D155 / 169 / 183, D182 / 196 / 210 refer to the times when the corresponding tests were performed in the 5mg / 10mg / 15mg dosage groups, respectively)

[0931] (1) Adverse events: from the first dose to the completion of safety follow-up;

[0932] (2) Vital signs: including pulse, respiration, blood pressure, and body temperature. These were assessed at screening, baseline, 4 hours after the first dose, before the first target dose, 24 hours after the first target dose, and at D42 / 56 / 70, D71 / 85 / 99, D99 / 113 / 127, D127 / 141 / 155, D155 / 169 / 183, and D182 / 196 / 210.

[0933] (3) 12-lead electrocardiogram: screening, baseline (acceptable test results within 3 days of our hospital), 4 hours after the first dose, before the first target dose, 24 hours after the first target dose, D42 / 56 / 70, D71 / 85 / 99, D99 / 113 / 127, D127 / 141 / 155, D155 / 169 / 183, D182 / 196 / 210;

[0934] (4) Physical examination: conducted during screening, D42 / 56 / 70, and D182 / 196 / 210;

[0935] (5) Laboratory tests: including complete blood count, blood biochemistry, urinalysis, coagulation function, serum lipase, and serum amylase. These tests are performed during screening, at baseline (results within 7 days of testing at our hospital are acceptable), and on days 42 / 56 / 70, 71 / 85 / 99, 99 / 113 / 127, 127 / 141 / 155, 155 / 169 / 183, and 182 / 196 / 210; calcitonin is administered during the screening period, on days 42 / 56 / 70, and 182 / 196 / 210.

[0936] (6) Pregnancy test: Only for women of childbearing age. Blood pregnancy test is performed during the screening period, at baseline (results within 7 days of the test being accepted at our hospital), and before discharge on D182 / 196 / 210; blood or urine pregnancy test is performed on D42 / 56 / 70, D71 / 85 / 99, D99 / 113 / 127, D127 / 141 / 155, D155 / 169 / 183, and D182 / 196 / 210.

[0937] (7) Hypoglycemic events: from the first dose to the completion of safety follow-up;

[0938] PK / PD evaluation: PK / PD evaluation is conducted in the first phase of treatment.

[0939] PK blood sample collection time

[0940] Within 1 hour before each titration [1 hour before the first target dose (5 mg), 2 hours before the first target dose (1st and 3rd dose titrations) for the 10 mg dose, and 3 hours before the first target dose (1st, 3rd, and 5th dose titrations) for the 15 mg dose], within 1 hour before the first target dose, and at 2, 4, 6, 8, 12, 24, 36, 48, 72, 120, and 168 hours after the first target dose (before the second target dose); within 1 hour before the third and fourth target doses; and at 2, 4, 6, 8, 12, 24, 36, 48, 72, 120, and 168 hours after the fourth target dose (before the fifth target dose). A total of 26 blood collection points are tentatively planned for the 5 mg dose group, 27 for the 10 mg dose group, and 28 for the 15 mg dose group.

[0941] PK blood collection method

[0942] Blood is collected using an indwelling venous catheter or venipuncture, with approximately 4 mL of blood collected each time. Before each blood collection, approximately 0.5 mL of blood containing the sealing solution in the indwelling catheter should be discarded.

[0943] PK blood sample processing

[0944] After blood collection, immediately and gently shake the blood collection tube several times to ensure thorough mixing of the blood and anticoagulant (EDTA-K2). Place the tube upright on a test tube rack in an ice bath until centrifugation. Within 60 minutes of blood collection, centrifuge the PK blood sample at approximately 2500g and 2–8°C (set temperature 4°C) for 10 minutes to separate the plasma for PK testing. Aliquot the remaining plasma into another cryopreservation tube for backup. All PK analysis samples must be stored at -60°C or below within 120 minutes of blood collection until delivery to the analytical unit. PK analysis samples must be stored at -60°C or below at the analytical unit until analysis is required. For detailed procedures and requirements, please refer to the PK blood sample processing manual.

[0945] PK parameters

[0946] Mainly includes: AUC inf AUC 0-t C max T max t 1 / 2 ,Kel,MRT,CL / F,Vd / F,AUC_%Extrap,C min，ss C max，ss C av，ss AUC 0-τ DF, RAUC, RC max .

[0947] PK Sample Analysis and Detection Methods

[0948] Approximately 4 mL of venous blood will be collected from each blood collection point. The content of BGM0504 and its possible major metabolites in the plasma will be quantitatively detected using a methodologically validated method (subsequent adjustments will be made based on the PK test in phase Ia).

[0949] PD index

[0950] The percentage change in fasting weight and waist circumference from baseline at week 4 of target dose administration, and the proportion of subjects whose weight decreased by ≥5%, ≥10%, ≥15%, or ≥20% from baseline.

[0951] (All time points below refer to the target dose administration week; the data collection time point can be before the next week's administration.)

[0952] Effectiveness evaluation indicators:

[0953] 1) Key effectiveness evaluation indicators:

[0954] Fasting body weight: The percentage change in fasting body weight from baseline at week 24 after target dose administration;

[0955] 2) Secondary effectiveness evaluation indicators:

[0956] Fasting weight: The percentage change in fasting weight from baseline at weeks 8, 12, 16, and 20 after administration of the target dose, and the absolute change in fasting weight from baseline at weeks 8, 12, 16, 20, and 24.

[0957] The proportion of subjects whose body weight decreased by ≥5%, ≥10%, ≥15%, or ≥20% relative to baseline at week 24 of target dose administration;

[0958] Waist circumference: The percentage change in waist circumference from baseline at weeks 12 and 24 after administration of the target dose;

[0959] BMI: Changes in BMI from baseline at weeks 12 and 24 after target dose administration;

[0960] Fasting insulin: Changes in fasting insulin levels from baseline at weeks 8, 12, and 24 after target dose administration;

[0961] Fasting blood glucose: Changes in fasting blood glucose from baseline at weeks 8, 12, and 24 after target dose administration;

[0962] Triglycerides (TG): Changes in triglyceride levels from baseline at weeks 8, 12, and 24 after target dose administration;

[0963] Cholesterol (TC): Changes in cholesterol levels from baseline at weeks 8, 12, and 24 after target dose administration;

[0964] Low-density lipoprotein (LDL-C): Changes in LDL-C from baseline at weeks 8, 12, and 24 after target dose administration;

[0965] Serum uric acid (UA): Changes in serum uric acid from baseline at weeks 8, 12, and 24 after target dose administration;

[0966] Systolic blood pressure (SBP); changes in systolic blood pressure from baseline at weeks 8, 12, and 24 after target dose administration;

[0967] Diastolic blood pressure (DBP): Changes in diastolic blood pressure from baseline at weeks 8, 12, and 24 after target dose administration;

[0968] Weight-to-Quality-of-Life Scale (IWQOL-Lite-CT) score: Change from baseline at week 24. Injection site local reaction: From first administration to completion of safety follow-up.

[0969] Before the study begins, biostatisticians develop a statistical analysis plan based on the clinical study protocol, including safety, efficacy, pharmacokinetic (PK) analysis, immunogenicity analysis, and other relevant content. The statistical analysis is then performed according to the established plan. Generally, commonly used statistical methods in the field are employed to analyze the results.

[0970] Example 3

[0971] This study is a multicenter, randomized, double-blind, parallel / open-label confirmatory clinical trial conducted in Chinese adults with type 2 diabetes mellitus (T2DM) whose glycemic control is inadequate with hypoglycemic therapy (metformin monotherapy or metformin and sulfonylureas). The aim of this study is to verify, in the aforementioned Chinese adults with type 2 diabetes mellitus (T2DM), that the clinical efficacy of BGM0504 injection (5 mg or 10 mg) in combination with metformin or metformin and sulfonylureas for 32 weeks is at least non-inferior to the positive control drug semaglutide injection (1.0 mg). Simultaneously, the clinical efficacy and safety of BGM0504 injection (5 mg or 10 mg) in combination with metformin or metformin and sulfonylureas for 52 weeks are evaluated.

[0972] 1. Experimental group design

[0973] This study included a 5mg and a 10mg dose group of BGM0504 injection, as disclosed herein, and a 1.0mg positive control group of smegglutide injection. The 5mg and 10mg dose groups of BGM0504 injection were designed in a double-blind inter-group design, while the positive control group was an open-label design.

[0974] This study plans to enroll 537 patients with type 2 diabetes whose glycemic control is inadequate after treatment with metformin monotherapy or metformin combined with sulfonylureas, regardless of gender. Eligible participants meeting the inclusion criteria will be stratified and randomized according to their baseline HbA1c data (<8.5% or ≥8.5%) and medication history (metformin monotherapy or metformin combined with sulfonylureas). They will be randomly assigned in a 1:1:1 ratio to either the 5mg dose group of BGM0504 injection, the 10mg dose group of BGM0504 injection, or the 1.0mg positive control group of semaglutide injection, i.e., the 5mg and 10mg dose groups, with 179 participants in each group.

[0975] The experimental grouping and dosing design are detailed in Table 3-1, which shows the experimental grouping and dosing methods:

[0976] Table 3-1 Experimental Groups and Administration Methods

[0977] Trial Procedure: The trial procedure for this study consists of a screening period of up to 2 weeks, a possible metformin dose titration period (up to 4 weeks) and a dose stabilization period of 8 weeks, a placebo induction period of 4 weeks, a core treatment period (including dose titration period) of 52 weeks, and a safety follow-up period of 2 weeks, for a total of up to approximately 72 weeks (calculated based on the longest duration).

[0978] Participants who sign the informed consent form (ICF) will complete the relevant examinations during the screening period (V1, up to 2 weeks). Researchers will conduct a preliminary evaluation of the participants' eligibility for enrollment based on the examination results and other relevant information, and inform preliminarily qualified participants of the specific return date to the research center and any upcoming precautions. Glycated hemoglobin (HbA1c) levels during the screening period will be tested at the local laboratory of the research center, and the value (7.5% ≤ HbA1c ≤ 11.0%) will be the primary criterion for determining whether to proceed to the next stage of the trial.

[0979] Depending on the metformin treatment received at the time of screening, qualified subjects will participate in the subsequent trial process in the following two situations: (1) Subjects who received metformin daily dose ≥1500mg or the maximum tolerated dose (<1500mg / day, but ≥1000mg / day) for ≥8 weeks at the time of screening can directly enter the 4-week induction period; (2) If the subject's metformin daily dose is <1500mg at the time of screening and has not yet reached the maximum tolerated dose, they will first enter a metformin dose titration period of 0-4 weeks (determined by the investigator according to the subject's condition and clinical treatment routine). Individualized titration rates will be administered over 4 weeks. During the metformin dose titration period (V1a, up to 4 weeks), the daily metformin dose will be titrated to 1500 mg or the maximum tolerated dose (<1500 mg / day but ≥1000 mg / day). Subjects will then enter a metformin dose stabilization period (V1b, 8 weeks) at this dose. During this period, the subject's metformin dosage should remain unchanged. Subjects who complete the 8-week metformin dose stabilization period and have good medication adherence (80%–120%) will enter a 4-week placebo carryover period. If sulfonylureas were used at the time of subject selection, regardless of which process is followed to enter the placebo carryover period, the sulfonylurea must have been stably administered for at least 8 weeks (with a fixed daily dose at least the minimum therapeutic dose specified in the drug's instructions). After entering the placebo carryover period, subjects should maintain their original stable daily doses of metformin and sulfonylureas (if applicable) as background treatment until the end of the trial. All subjects entering the placebo induction period (V2–V3, 4 weeks) received subcutaneous injections of the BGM0504 injection analogue in a single-blind manner, once weekly for 4 consecutive weeks, on the basis of background treatment with metformin or metformin combined with sulfonylureas. Prior to randomization (V3), HbA1c was measured at a central laboratory (as baseline HbA1c) and inclusion / exclusion criteria were verified (central laboratory HbA1c must be ≥7.0% and ≤10.5%). Eligible subjects were stratified and randomized according to their baseline HbA1c data (<8.5% or ≥8.5%) and medication history (metformin or metformin combined with sulfonylureas), and were randomly assigned in a 1:1:1 ratio to the BGM0504 injection 5 mg dose group, the BGM0504 injection 10 mg dose group, or the semaglutide injection 1.0 mg positive control group.

[0980] Successfully enrolled subjects will enter a 52-week core treatment period (V4–V15). In addition to background therapy with metformin or metformin combined with sulfonylureas, they will receive weekly subcutaneous injections of 5 mg or 10 mg of the disclosed BGM0504 injection or the positive control drug semaglutide injection 1.0 mg, as per the protocol, for 52 consecutive weeks (including dose titration). During the core treatment period, the semaglutide injection 1.0 mg positive control group will undergo an open-label trial, while the 5 mg and 10 mg dose groups of the disclosed BGM0504 injection will remain double-blind. The dosage of the investigational drugs, BGM0504 injection and semaglutide injection 1.0 mg positive control, followed the dose escalation principle specified in the protocol until the target dose was reached (i.e., for the BGM0504 injection 5 mg dose group, the target dose was started after titration of 2.5 mg for 4 weeks; for the BGM0504 injection 10 mg dose group, the target dose was started after titration of 2.5 mg for 4 weeks and 5 mg for 4 weeks; for the semaglutide injection 1.0 mg positive control group, the target dose of 1.0 mg was started after titration of 0.25 mg for 4 weeks and 0.5 mg for 4 weeks). If, during treatment, a participant still could not tolerate gastrointestinal adverse reactions (i.e., moderate to severe vomiting, moderate to severe diarrhea, or severe nausea) despite symptomatic treatment, and the investigator believed that the participant could not tolerate further exposure, the medication could be temporarily suspended (see Section 5.3 Suspension of Medication) or the dosage adjusted (see Section 5.4 Dosage Adjustment) after discussion with the sponsor.

[0981] All participants will return to the research center for visits at the end of the 4th (V5), 8th (V6), 12th (V7), 16th (V8), 20th (V9), 24th (V10), 28th (V11), 32nd (V12), 36th (V13), 44th (V14), and 52nd (V15) weeks after drug administration. Visits will collect efficacy indicators (HbA1c, fasting blood glucose, fasting insulin, fasting weight, etc., see 7.1 Efficacy Indicators) and conduct safety checks (including vital signs, physical examination, 12-lead ECG, laboratory tests, etc.). Blood samples for anti-drug antibody / neutralizing antibody (ADA / NAb) testing will be collected at the end of the 12th (V7), 24th (V10), 32nd (V12), and 52nd (V15) weeks (only for the BGM0504 injection 5mg and 10mg dose groups; no samples will be collected from the positive control group). The specific tests performed at each visit will vary slightly; see Appendix 1: Study Flowchart. Participants who received at least one dose of the study drug (BGM0504 injection or semaglutide injection) after randomization but withdrew from the study / discontinued treatment early should also complete the early withdrawal / discontinuation visit as soon as possible (see Section 6.6 for early withdrawal / discontinuation visits). Based on the participant's urine albumin / creatinine ratio (UACR) test results before randomization (V3), if the UACR ≥ 30 mg / g, the participant will undergo additional UACR retesting at V12 and V15 to explore changes in the urine albumin / creatinine ratio (UACR). (This will only be conducted at research centers equipped to perform urine albumin / creatinine ratio testing).

[0982] For participants whose ultrasound at screening indicated fatty liver and who also had elevated ALT and / or AST, additional NASH-related biomarkers (including ALT, AST, CK18 fragment, Pro-C3, FIB-4, and calculation of the AST / PLT ratio) will be measured before randomization (V3) and on V12 and V15. Liver elasticity will also be assessed to exploratoryly evaluate changes in liver elasticity and NASH-related biomarkers (only at research centers capable of performing liver elasticity testing). All participants receiving the medication should undergo safety follow-up as required, starting at the end of week 54 (V16). Participants who withdraw from the study / discontinue treatment early after receiving medication should also complete the early withdrawal / discontinuation visit as soon as possible. A safety follow-up visit (telephone visit) will be completed on day 14±3 after the last treatment. Any adverse events (AEs), hypoglycemic events, injection site reactions, and concomitant medications occurring between the most recent visit and the follow-up visit (if applicable) will be inquired about and recorded. Participants will be considered to have completed the trial after investigator evaluation. Throughout the study, if the investigator assesses that a participant has safety issues after taking the medication, they will be followed up until the adverse event (AE) has resolved, returned to baseline levels, reached a stable state, or been reasonably explained (e.g., lost to follow-up, death). In this case, the method and frequency of follow-up will be determined by the investigator based on the participant's actual AE situation.

[0983] In addition, researchers should educate participants on medication adherence and the relevant requirements for diabetes diet and exercise during the trial. Participants should comply with the requirements for diabetes diet and exercise. This study plans to include a total of 537 Chinese adult patients with type 2 diabetes whose glycemic control is inadequate with metformin monotherapy or metformin and sulfonylureas. Regardless of gender, participants will be randomly assigned in a 1:1:1 ratio to either the investigational drug BGM0504 injection 5mg group, the BGM0504 injection 10mg group, or the semaglutide injection 1.0mg positive control group, with 179 participants in each group. Participants must meet all of the following inclusion criteria to be eligible for this study:

[0984] (1) Chinese patients with type 2 diabetes aged 18 to 75 years (inclusive), regardless of gender, who meet either criterion 1 or 2) below. If metformin combined with sulfonylureas is used during screening, criterion 3) must also be met:

[0985] 1) At the time of screening, patients must have received stable metformin monotherapy for ≥8 weeks at a dose of ≥1500 mg / day or the maximum tolerated dose (<1500 mg / day but ≥1000 mg / day) (qualified patients can directly enter the placebo transition period); or

[0986] 2) Patients receiving metformin treatment at a dose <1500mg / day at the time of screening and who have not yet reached the maximum tolerated dose (after passing the screening, metformin dose titration and dose stabilization treatment period must be performed first);

[0987] 3) When entering the placebo transition period, sulfonylureas have been used for stable treatment for ≥8 weeks (with a fixed daily dose of at least the minimum therapeutic dose specified in the drug instructions).

[0988] (2) Body mass index (BMI) at screening: BMI≥23.0kg / m2; and weight stable (±5%) within 3 months prior to screening, and agree not to initiate any diet and / or exercise program for weight loss purposes during the study period, except for regular diet and exercise;

[0989] (3) Glycated hemoglobin (HbA1c) must meet the following criteria: at screening (V1) 7.5% ≤ HbA1c ≤ 11.0% (local laboratory), at baseline (V3) HbA1c: 7.0% ≤ HbA1c ≤ 10.5% (central laboratory);

[0990] (4) Willing and able to accurately use a home blood glucose meter for self-monitoring of blood glucose;

[0991] (5) Those who can understand and abide by the research process, voluntarily participate in the clinical research, have no plans to become pregnant within one month after signing the informed consent form and the last use of the investigational drug, and voluntarily take effective contraceptive measures to avoid pregnancy or causing their partner to become pregnant, and have no plans to donate sperm or eggs during the research period;

[0992] Note: The diagnosis and classification of type 2 diabetes adopts the 1999 World Health Organization criteria, with HbA1c ≥ 6.5% added as a supplementary diagnostic criterion for diabetes. Disqualification is granted if any of the following exclusion criteria are met:

[0993] (1) Type 1 diabetes, special types of diabetes (such as diabetes caused by pancreatic damage, Cushing's syndrome or diabetes caused by acromegaly, etc.);

[0994] (2) Individuals who received any of the following medications or treatments prior to screening (medical consultation):

[0995] 1) Patients who have used other hypoglycemic drugs besides background therapy or systemic glucocorticoids (excluding inhaled, topical, intraocular, and intranasal medications) in the 8 weeks prior to screening.

[0996] 2) Those who have used insulin within the year prior to screening, except for the following: ① use of insulin to treat gestational diabetes, ② short-term use (≤2 weeks) of insulin due to acute illness, hospitalization or elective surgery;

[0997] 3) Has not tolerated or had poor response to any other glucagon (GCG) and / or glucose-dependent insulinotropic peptide (GIP) and / or glucagon-like peptide-1 (GLP-1) receptor agonists.

[0998] 4) Those who have used or plan to use weight-loss drugs within the three months prior to screening;

[0999] (3) (Medical history) Patients whose dosage of antihypertensive or lipid-regulating drugs has not reached a stable state before screening;

[1000] (4) Individuals with any of the following medical histories or conditions during (medical history / examination) screening:

[1001] 1) Acute cholecystitis or chronic cholecystitis present at the time of screening; or symptomatic or treatment-required cholelithiasis present at the time of screening; or symptomatic or treatment-required gallbladder polyps present at the time of screening; or newly developed cholelithiasis within 6 months prior to screening.

[1002] 2) Screening is conducted with gastrointestinal motility disorders or obstructive diseases (such as gastroparesis, gastroesophageal reflux, etc.);

[1003] 3) Have suffered a serious injury or infection that may affect blood sugar control within the past month, or have undergone major surgery;

[1004] 4) History or condition of any of the following heart diseases within the past 6 months: such as decompensated heart failure (NYHA class III or IV); unstable angina, myocardial infarction, coronary artery bypass grafting or coronary stent implantation; medical treatment required or serious arrhythmia (such as long QT syndrome), and deemed unsuitable for participation in this clinical trial by the investigator;

[1005] 5) Patients who have suffered from hemorrhagic or ischemic stroke within the past 6 months and are deemed unsuitable to participate in this clinical trial by the investigator;

[1006] 6) Having unstable proliferative retinopathy or macular degeneration requiring treatment within the past 6 months, or having non-proliferative diabetic retinopathy requiring emergency treatment at the time of screening;

[1007] 7) Accompanied by severe diabetic peripheral neuropathy within the past 6 months;

[1008] 8) Has had diabetic ketoacidosis or hyperglycemic hyperosmolar state within the past 6 months;

[1009] 9) History of ≥2 severe hypoglycemic episodes within the past year; 10) Currently accompanied by uncontrolled hypertension (systolic blood pressure ≥160 mmHg and / or diastolic blood pressure ≥100 mmHg at screening / baseline);

[1010] 11) Currently accompanied by thyroid dysfunction that cannot be controlled with a stable (at least 3 months) medication dose, or clinically significant abnormalities in thyroid function test results at the time of screening (excluding subclinical hypothyroidism with TSH < 10 mIU / L that does not require treatment).

[1011] 12) Currently accompanied by severe kidney disease or glomerular filtration rate (eGFR, using CKD-EPI formula) ≤60mL / min / 1.73m2 or urinary protein ≥(++);

[1012] 13) Currently accompanied by other serious endocrine system diseases affecting glucose metabolism, such as multiple endocrine adenomas, etc.;

[1013] 14) Those currently suffering from severe mental illness or language impairment are unwilling or unable to fully understand and cooperate;

[1014] 15) Patients with a history of malignant tumors within the past 5 years (excluding patients with basal cell carcinoma and squamous cell carcinoma of the skin, cervical carcinoma in situ, prostate carcinoma in situ, or papillary thyroid carcinoma without recurrence after surgery), or currently being evaluated for potential malignant tumors;

[1015] 16) Previous / screening diagnosis of medullary thyroid carcinoma, MEN (multiple endocrine neoplasia) 2A or 2B, or relevant family history;

[1016] 17) History of acute or chronic pancreatitis (past or present);

[1017] 18) A history of or past blood disorders that may affect HbA1c test results or increase the risk to participants (such as aplastic anemia, myelodysplastic syndrome, etc.) or any disease that causes hemolysis or erythrocyte instability (such as sickle cell disease, thalassemia, etc.);

[1018] 19) Individuals with a history of known allergies (allergic to 3 or more types of food or drugs), or allergic to GLP-1 receptor agonists (including GLP-1 receptor agonists or drugs with a mechanism of activating GLP-1 receptors) or metformin hydrochloride, or those with severe allergic diseases (asthma, urticaria, eczema, dermatitis, etc.) at the time of screening.

[1019] (5) Those whose laboratory test results at screening or baseline meet the following criteria:

[1020] 1) Fasting C-peptide < 0.81 ng / mL;

[1021] 2) Fasting blood glucose >15.0 mmol / L at screening (V1) (local laboratory), or fasting blood glucose >15.0 mmol / L at baseline (V3) (central laboratory) (if there are special factors affecting blood glucose, the test can be repeated once within 1 week);

[1022] 3) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 times the upper limit of normal (ULN) or total bilirubin ≥ 1.5 times the upper limit of normal (ULN);

[1023] 4) Serum amylase or serum lipase ≥ 1.5 times the upper limit of the normal range (ULN);

[1024] 5) Serum calcitonin level ≥35ng / L (pg / mL).

[1025] 6) Triglycerides ≥ 5.64 mmol / L (500 mg / dL);

[1026] 7) Hemoglobin (HGB) < 100 g / L;

[1027] 8) Positive for hepatitis B surface antigen (HBsAg) and abnormal hepatitis B virus load (HBV-DNA) test value;

[1028] 9) Positive hepatitis C antibody (HCV-Ab) and abnormal hepatitis C virus load (HCV-RNA) test value;

[1029] 10) Positive for HIV antibody (HIV-Ab) or positive for Treponema pallidum antibody (TPAb);

[1030] (6) Suspected or confirmed history of alcohol or drug abuse;

[1031] (7) Individuals who have participated in any clinical study and received investigational drugs (excluding placebo recipients) or medical device interventions within the three months prior to screening;

[1032] (8) Female participants who are pregnant or lactating;

[1033] (9) Metformin adherence during stable treatment (if applicable) or placebo induction period: <80% or >120% for metformin, or <75% or >125% for placebo induction period;

[1034] (10) Other circumstances in which the researcher deems the individual unsuitable to participate in this study (e.g., poor adherence to sulfonylurea medications as assessed by the researcher).

[1035] Early termination of study treatment does not equate to withdrawal from the study. Researchers will need to discuss and consider terminating study treatment with the sponsor if any of the following situations occur, but participants will be allowed to continue with follow-up visits during the study. The main reasons for early termination of treatment in this study include the following:

[1036] (1) Participant decision: The participant requests early termination of treatment;

[1037] (2) If a participant experiences an increased risk of hypoglycemia, hypersensitivity reaction, SAE, acute or chronic pancreatitis, or other safety risks related to the study drug, and the investigator determines that the participant is not suitable to continue receiving treatment;

[1038] (3) Participants' BMI ≤ 18.5 kg / m 2 Researchers must take into account the participants' own wishes, fully consider the risks of continuing to receive the study drug treatment, and discuss with the sponsor whether it is necessary to terminate the treatment in advance.

[1039] (4) The participant's rescue treatment failed, or the participant refused to receive rescue treatment;

[1040] (5) The researchers and / or sponsors believe that, based on the participant’s disease condition or personal circumstances, continuing to administer the investigational drug would put the participant at unnecessary risk.

[1041] Participants who terminate treatment early should complete the early termination visit as soon as possible and undergo a safety follow-up 14±3 days after the last dose (if this overlaps with a subsequent planned visit, the visit and related procedures can be combined. If the early termination of treatment is ≥2 weeks after the participant's last injection of BGM0504 or placebo, the early termination visit and safety follow-up can be combined). Subsequent procedures should at least complete the content specified in V15 as originally planned. Participants have the right to request early withdrawal from the study or withdraw informed consent based on their own rights. Researchers also have the right to arrange for early withdrawal of participants based on their safety and compliance. Reasons for early withdrawal in this study include, but are not limited to, the following:

[1042] (1) Participants voluntarily request to withdraw from the study or withdraw their informed consent;

[1043] (2) Pregnancy in female participants;

[1044] (3) Participants have poor compliance and make significant deviations from the protocol that seriously affect the evaluation of drug safety or efficacy. The investigators determine that it is not appropriate to continue the study.

[1045] (4) Other reasons: The researchers believe that the participants are not suitable to continue participating in this clinical study.

[1046] For participants who withdraw from the study early, an early withdrawal visit should be conducted as soon as possible, and a safety follow-up should be performed as close as possible to 14±3 days after the last dose of medication (if the early withdrawal is ≥2 weeks after the participant's last injection of BGM0504 or placebo, the early withdrawal visit and safety follow-up can be combined).

[1047] The reasons for early termination / suspension of a study may include, but are not limited to, the following:

[1048] (1) Significant errors were found in the clinical trial protocol during the trial, making it difficult to evaluate the clinical efficacy and safety of the investigational drug;

[1049] (2) The applicant requests termination (e.g., due to funding or management reasons);

[1050] (3) The National Medical Products Administration or the Medical Ethics Committee requires the termination of the trial.

[1051] Test drug: BGM0504 injection disclosed in this paper, specifications: 0.5mL:2.5mg, 0.5mL:5mg, 0.5mL:10mg (according to C) 235 H 368 N 50 O 71 (Computer), Manufacturer: Borui Pharmaceutical (Suzhou) Co., Ltd., Supplier: Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[1052] Positive control drug: Siglimeplasticide injection Specifications: 1.34mg / ml, 1.5ml, 1.34mg / ml, 3ml; Manufacturer: Novo Nordisk (China) Pharmaceutical Co., Ltd.; Supplier: Borui Xinchuang Biopharmaceutical Technology (Wuxi) Co., Ltd.

[1053] Placebo: The BGM0504 injection analogue disclosed herein is manufactured by Borui Pharmaceutical (Suzhou) Co., Ltd. and provided by Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[1054] Background treatment medication: 1) Metformin hydrochloride tablets Specifications: 500mg / tablet; Manufacturer: Bristol-Myers Squibb (Shanghai) Co., Ltd.; Supplier: Borui Biotech (Wuxi) Co., Ltd. 2) Sulfonylureas: Drugs that have been stable before screening, to be provided by the subjects themselves.

[1055] Salvage therapy drug: Empagliflozin tablets (brand name: Specification: 10mg / tablet, Manufacturer: Shanghai Boehringer Ingelheim Pharmaceutical Co., Ltd., Supplier: Borui New Creation Biomedical Technology (Wuxi) Co., Ltd.

[1056] Administration method: investigational drug, placebo, and positive control drug:

[1057] Subcutaneous injection in the abdomen, once a week, avoiding consecutive injections at the same site.

[1058] Background treatment medications:

[1059] Metformin hydrochloride tablets: With or without dose titration, metformin hydrochloride tablets are administered at a fixed daily dose of 1500 mg or the maximum tolerated dose (<1500 mg / day but ≥1000 mg / day) starting at least 8 weeks before the start of the induction phase and continuing until the end of the treatment period. For subjects who received metformin monotherapy for ≥8 weeks at screening and whose metformin dose was ≥1500 mg / day or the maximum tolerated dose (<1500 mg / day but ≥1000 mg / day), if the metformin hydrochloride they were taking before screening was not the metformin hydrochloride tablets (0.5 g) uniformly provided in this study, If the test result is positive, the researchers at each center will adjust the dosage according to the patient's condition and previous metformin hydrochloride dosage form, strength, and dosage, and then uniformly convert it to metformin hydrochloride tablets (0.5g). ).

[1060] Sulfonylureas: If sulfonylureas are used in combination with other medications at the time of subject screening, the dosage of sulfonylureas should be stable (the fixed daily dose should be at least the minimum therapeutic dose specified in the drug's instructions) and should be used steadily from at least 8 weeks before the start of the lead-up period until the end of the core treatment period. Unless the investigator assesses that the participant needs to adjust the dosage of sulfonylureas or suspend / discontinue their use due to safety concerns, sulfonylureas should be provided by the participant.

[1061] Salvage therapy drugs:

[1062] Once the subjects met the criteria for initiating salvage therapy, they were given empagliflozin tablets for salvage treatment.

[1063] Therapeutic indicators: Primary estimation targets:

[1064] Efficacy endpoint: Change in HbA1c relative to baseline at 32 weeks of treatment

[1065] Secondary estimation target:

[1066] HbA1c: Changes in HbA1c relative to baseline at weeks 12, 24, 44, and 52 of treatment, and the proportion of participants with HbA1c <7.0%, HbA1c <6.5%, and HbA1c <5.7% at weeks 12, 24, 32, 44, and 52 of treatment. Fasting blood glucose: Changes in fasting blood glucose relative to baseline at weeks 12, 24, 32, 44, and 52 of treatment.

[1067] 2-hour postprandial blood glucose: Changes in standard 2-hour postprandial blood glucose relative to baseline at weeks 32 and 52 of treatment.

[1068] Weight: Changes in fasting weight relative to baseline at weeks 12, 24, 32, 44, and 52 of treatment, and the proportion of participants whose weight decreased by ≥5%, ≥10%, and ≥15% from baseline. HbA1c and weight: The proportion of participants whose HbA1c was <7.0% and whose weight decreased by ≥5% from baseline at weeks 32, 44, and 52 of treatment. BMI: Changes in BMI relative to baseline at weeks 12, 24, 32, 44, and 52 of treatment.

[1069] Waist circumference: Changes in waist circumference relative to baseline at 12, 24, 32, 44, and 52 weeks of treatment.

[1070] Fasting C-peptide: Changes in fasting C-peptide relative to baseline at weeks 12, 24, 32, 44, and 52 of treatment.

[1071] Blood lipids (TC, TG, LDL-C, HDL-C): Changes in blood lipids (TC, TG, LDL-C, HDL-C) relative to baseline values ​​at 12, 24, 32, 44, and 52 weeks of treatment.

[1072] Insulin sensitivity: Changes in HOMA2-B and HOMA2-IR relative to baseline at weeks 32, 44, and 52 of treatment.

[1073] Self-monitoring of blood glucose: Changes in daily 7-hour self-monitoring of blood glucose (SMBG) and postprandial glucose variability (PPGE) relative to baseline values ​​at weeks 12, 24, 32, 44, and 52 of treatment.

[1074] Blood pressure: Changes in systolic and diastolic blood pressure relative to baseline at 12, 24, 32, 44, and 52 weeks of treatment.

[1075] Serum uric acid: Changes in serum uric acid relative to baseline at 12, 24, 32, 44, and 52 weeks of treatment.

[1076] Exploratory indicators:

[1077] Changes in urinary albumin / creatinine ratio (UACR) relative to baseline at weeks 32 and 52 of treatment (only in subjects with UACR testing facilities and baseline UACR ≥ 30 mg / g).

[1078] Changes in liver stiffness, degree of fatty degeneration (CAP), and NASH-related biomarkers (ALT, AST, CK18 fragment, Pro-C3, FIB-4, AST / PLT ratio) relative to baseline at 32 and 52 weeks of treatment (conducted only at research centers equipped to perform ultrasound examinations of liver stiffness and fatty degeneration).

[1079] Safety indicators:

[1080] (1) Adverse events: from the screening period (V1) to the safety follow-up period (V16);

[1081] (2) Vital signs: including pulse, respiration, blood pressure, and body temperature. These were measured at the end of the screening period (V1), before randomization (V3), and at the end of the treatment periods on the following weekends: the 4th (V5), 8th (V6), 12th (V7), 16th (V8), 20th (V9), 24th (V10), 28th (V11), 32nd (V12), 36th (V13), 44th (V14), and 52nd (V15).

[1082] (3) 12-lead electrocardiogram: performed at the end of the week during the screening period (V1), before randomization (V3), and at the end of the treatment period on the weekends of the 4th (V5), 8th (V6), 12th (V7), 16th (V8), 20th (V9), 24th (V10), 28th (V11), 32nd (V12), 36th (V13), 44th (V14), and 52nd (V15);

[1083] (4) Physical examination: conducted at the end of the screening period (V1), and at the end of the 12th (V7), 24th (V10), 32nd (V12), and 52nd (V15) of the treatment period;

[1084] (5) Laboratory tests: including complete blood count, blood biochemistry, urinalysis, serum lipase, and serum amylase. The timing of the examination and visit is the same as the 12-lead electrocardiogram mentioned above; calcitonin and coagulation function tests are performed at the end of the screening period (V1), the 12th (V7), 24th (V10), 32nd (V12), and 52nd (V15) weeks of the treatment period;

[1085] (6) Pregnancy test: Only women of childbearing age are tested. The timing of the examination visit is the same as the 12-lead electrocardiogram mentioned above. Blood pregnancy tests are performed at the end of the screening period (V1), before randomization (V3), and at the end of the 52nd week of treatment (V15). Blood or urine pregnancy tests can be performed at other visits.

[1086] (7) Hypoglycemic events: from the screening period (V1) to the safety follow-up period (V16);

[1087] (8) Injection site reaction: from placebo induction period (V2-V3) to safety follow-up period (V16).

[1088] In addition, researchers may conduct additional planned visits or other necessary examinations based on the participants' actual conditions during the clinical study. Statistical analysis of the results data will be performed using statistical methods commonly used in the field.

[1089] Example 4

[1090] 1. Research Objectives

[1091] Main purpose

[1092] To evaluate the clinical efficacy of GLP-1 / GIP peptide injection at a dose of 15 mg for 52 weeks as an adjunct to diet, exercise, and behavioral interventions for weight management in overweight or obese adults with hypertension who are not diabetic in China.

[1093] Secondary objective:

[1094] To evaluate the preliminary clinical efficacy of GLP-1 / GIP peptide injection at a dose of 15 mg in lowering blood pressure.

[1095] To evaluate the clinical safety of GLP-1 / GIP peptide injection at a dose of 15 mg for 52 weeks as an adjunct to diet, exercise, and behavioral interventions for weight management in overweight or obese adults with hypertension who are not diabetic in China.

[1096] 2. Duration of the study

[1097] Each subject requires a screening period of up to 2 weeks, a core treatment period (including dose titration) of 52 weeks, and a safety follow-up period of 2 weeks, for a total of up to 56 weeks (calculated based on the longest duration).

[1098] 3. Research Design

[1099] This study is a single-arm, open-label, investigator-initiated clinical trial conducted in non-diabetic overweight or obese adults with hypertension in China. The aim was to evaluate the clinical efficacy of GLP-1 / GIP peptide injection at a dose of 15 mg for 52 weeks as an adjunct to diet, exercise, and behavioral interventions for weight management and preliminary antihypertensive efficacy in non-diabetic overweight or obese adults with hypertension in China. Simultaneously, the clinical safety of the GLP-1 / GIP peptide injection 15 mg group was evaluated after 52 weeks of treatment.

[1100] 3.1 Experimental Design

[1101] This study plans to enroll 100 (tentative) non-diabetic overweight or obese subjects with hypertension who have not responded well to weight loss through diet and exercise alone, including both men and women. A 15mg dose group of GLP-1 / GIP peptide injection will be included, and enrollment and administration will be based on the order of the eligible subject screening numbers.

[1102] 3.1.1 Research drugs

[1103] Test drug: GLP-1 / GIP peptide injection, specifications: 0.5mL:2.5mg, 0.5mL:5mg, 0.5mL:10mg, 0.5mL:15mg (according to C) 235 H 368 N 50 O 71(Computer), Manufacturer: Borui Pharmaceutical (Suzhou) Co., Ltd., Supplier: Borui Xinchuang Biomedical Technology (Wuxi) Co., Ltd.

[1104] 3.1.2 Administration method

[1105] Subcutaneous injection in the abdomen, once a week, avoiding consecutive injections at the same site.

[1106] For specific dosages of each group, please refer to Table 4-1.

[1107] Table 4-1

[1108] 3.2 Test Procedure

[1109] The trial process of this study is divided into three phases: a screening period of up to 2 weeks, a core treatment period (including a dose titration period of 10 weeks and a target dose stabilization period of 42 weeks) of 52 weeks, and a safety follow-up period of 2 weeks, for a total of approximately 56 weeks (calculated based on the longest duration).

[1110] Subjects who sign the informed consent form (ICF) will complete the relevant screening tests during the screening period (V1, up to 2 weeks). Researchers will conduct a preliminary evaluation of whether the subjects meet the enrollment requirements based on the test results and other relevant information, and inform the subjects who pass the preliminary screening of the specific time to return to the research center and the precautions to be taken in the near future.

[1111] Subjects who passed the initial screening returned to the research center at baseline (V2) to complete the baseline period examination. The researchers confirmed that the subjects met all the enrollment requirements. Subjects who met the enrollment requirements were administered the drug according to the order of their screening numbers and entered the investigational drug GLP-1 / GIP peptide injection group at a dose of 15 mg.

[1112] Successfully enrolled subjects will enter the core treatment period (V2–V10, W1–W52), receiving subcutaneous injections of GLP-1 / GIP peptide once weekly for 52 consecutive weeks, as per the protocol. The dosage of the investigational drug GLP-1 / GIP peptide injection will follow a slow dose-escalation protocol until the target dose is reached (i.e., for the 15 mg dose group, titrations of 2.5 mg over 2 weeks, 5 mg over 4 weeks, and 10 mg over 4 weeks, followed by the target dose of 15 mg). If, during the core treatment period, a subject is still unable to tolerate gastrointestinal reactions (i.e., moderate to severe vomiting, diarrhea, or severe nausea) despite symptomatic treatment, discontinuation of administration (once every four weeks) or dose adjustment may be considered (see the dose adjustment section for details).

[1113] All subjects will return to the research center for a visit at the end of the week on the 4th (V3), 8th (V4), 12th (V5), 16th (V6), 24th (V7), 32nd (V8), 40th (V9), and 52nd (V10) of the dosing period. The visit will include a safety check (including vital signs, physical examination, 12-lead electrocardiogram, laboratory tests, etc.) and collection of efficacy indicators (weight, waist circumference, BMI, blood lipids, blood pressure, blood uric acid, etc.).

[1114] During the trial, participants will maintain dietary, exercise, and behavioral interventions under the guidance of a nutritionist or qualified healthcare professional to help them adhere to a healthy, balanced diet. Participants are advised to maintain a daily calorie deficit of 500 kcal and engage in at least 150 minutes of moderate-intensity aerobic exercise per week.

[1115] Subjects who terminate treatment early after receiving medication should complete the early termination visit and safety follow-up as soon as possible, and subsequently complete at least the tasks specified in V10 as originally planned. Subjects who withdraw from the trial early after receiving medication should complete the early withdrawal visit as soon as possible.

[1116] All subjects who complete 52 weeks of treatment should undergo safety follow-up (V11) as required, with the safety follow-up scheduled at the end of week 54. Subjects who terminate treatment early or withdraw from the trial early after receiving medication should also undergo safety follow-up as early as possible, on day 14 ± 5 ​​after the last dose. Safety follow-up is conducted via telephone, and adverse events (AEs), hypoglycemic events, and concomitant medications that occurred between the most recent visit and the follow-up date are recorded and taken into account. Subjects are considered to have completed the trial after investigator evaluation.

[1117] If the investigator assesses that a subject has safety concerns after taking the medication, they must be followed up until the adverse event (AE) is resolved (without sequelae / with sequelae), improves, does not improve / does not alleviate / persists, is fatal, or is unknown. The method and frequency of follow-up will be determined by the investigator based on the subject's actual AE situation.

[1118] 3.3 Planned number of participants

[1119] The study plans to enroll 100 overweight or obese subjects with hypertension who have not achieved satisfactory weight loss through diet and exercise alone. The subjects will be enrolled in the 15mg dose group of the investigational drug GLP-1 / GIP peptide injection.

[1120] 3.4 Selection Criteria

[1121] To be eligible for this study, candidates must meet all of the following inclusion criteria:

[1122] (1) Age 18 to 65 (inclusive), male or female;

[1123] (2) (Medical history and examination) BMI ≥ 30.0 kg / m 2 Or BMI ≥ 26.0 kg / m² 2 And accompanied by at least one of the following: i. one or more of the following: prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, and dyslipidemia; ii. pain in weight-bearing joints; iii. dyspnea caused by obesity or obstructive sleep apnea syndrome;

[1124] (3) (Consultation) Before screening, the patient had been under diet and exercise control for at least 12 weeks, with a weight change of <5.0% (chief complaint), and was able to maintain the diet and exercise intervention as required by this study during the trial period to control weight.

[1125] (4) Subjects diagnosed with essential hypertension according to the diagnostic criteria of the Chinese Guidelines for the Prevention and Treatment of Hypertension (2024 Revised Edition) are required to have not received treatment at the time of screening (newly diagnosed essential hypertension or those with a history of hypertension who have not taken any antihypertensive drugs for at least 4 weeks before screening) or those currently taking antihypertensive drugs are required to have stable treatment for at least 2 weeks. Hypertensive subjects must meet any of the following conditions:

[1126] 1) Grade 1 or 2 hypertension: i.e., screening period / baseline sitting office systolic blood pressure (sitSBP) and sitting diastolic blood pressure (sitDBP): sitSBP: 140-179 mmHg and / or sitDBP: 90-109 mmHg;

[1127] Or 2) Isolated systolic hypertension: i.e., screening period / baseline sitSBP: 140-179 mmHg and sitDBP < 90 mmHg;

[1128] Or 3) Isolated diastolic hypertension: i.e., screening period / baseline sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg;

[1129] (5) Can understand and comply with the research process, voluntarily participate in the clinical research, and have no plans to become pregnant within one month after signing the informed consent and voluntarily take effective contraceptive measures to avoid pregnancy or causing their partner to become pregnant, and have no plans to donate sperm or eggs during the research period.

[1130] Note: The percentage change in weight is calculated as follows: (weight 12 weeks before screening - weight at screening) / weight 12 weeks before screening × 100%.

[1131] 3.5 Exclusion Criteria:

[1132] If any of the following exclusion criteria are met, the application will be excluded:

[1133] (1) Hypertension in special populations (refractory hypertension, hypertensive emergency, hypertensive subacute) and secondary hypertension (renal parenchymal hypertension, Cushing's syndrome, primary aldosteronism, pheochromocytoma, drug-induced hypertension, etc.).

[1134] (2) Subjects who are known to have a history of orthostatic hypotension or have experienced frequent hypotension after taking antihypertensive drugs;

[1135] (3) (Medical history taking) It is known that the patient has an allergic constitution (allergic to 3 or more kinds of food or drugs), or is allergic to GLP-1 receptor agonist drugs, or has a severe allergic disease (such as severe asthma, urticaria, eczema, etc.) at the time of screening.

[1136] (4) Use any of the following medications or treatments prior to screening (medical history):

[1137] 1) Those who have used a GLP-1 receptor agonist or a similar drug with the same target within the 12 weeks prior to screening;

[1138] 2) Screening for medications that affect weight used within the 12 weeks prior to screening, including: systemic glucocorticoids (intravenous or oral administration), tricyclic antidepressants, psychotropic drugs, or sedatives that affect weight (such as imipramine, amitriptyline, mirtazapine, paroxetine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium salts);

[1139] 3) Patients who have used weight control medications within the 12 weeks prior to screening, such as: sibutramine hydrochloride, phentermine, phenylpropanolamine, chlorpheniramine, phentermine, amphetamine, lorcaserin, phentermine / topiramate combination, naltrexone / bupropion combination, orlistat, etc.

[1140] (5) (Check) During screening / baseline testing, if any of the following laboratory test indicators meet the following criteria:

[1141] 1) Glycated hemoglobin (HbA1c) ≥ 6.5%, or fasting blood glucose ≥ 7.0 mmol / L, or 2-hour blood glucose ≥ 11.1 mmol / L in the oral glucose tolerance test (OGTT) (subjects with fasting blood glucose between 6.1 and 6.9 mmol / L need to undergo the OGTT test during screening);

[1142] 2) ALT or AST ≥ 2.5 times the upper limit of normal (ULN) or total bilirubin ≥ 1.5 times the upper limit of normal (ULN);

[1143] 3) Glomerular filtration rate (eGFR) ≤ 60 mL / min / 1.73 m 2 (CKD-EPI formula) or urine protein positive 2+ or above;

[1144] 4) Serum calcitonin level ≥35 ng / L (pg / mL);

[1145] 5) Thyroid-stimulating hormone (TSH) > 6.0 mIU / L or < 0.4 mIU / L;

[1146] 4) Fasting triglycerides ≥ 5.64 mmol / L (500 mg / dL);

[1147] 5) Hemoglobin (HGB) < 100 g / L;

[1148] 6) Serum amylase or serum lipase > 2.0 × ULN;

[1149] 7) Positive for hepatitis B surface antigen (HBsAg) and abnormal hepatitis B virus load (HBV-DNA) test value;

[1150] 8) Positive hepatitis C antibody (HCV-Ab) and abnormal hepatitis C virus load (HCV-RNA) test value;

[1151] 9) Positive for Treponema pallidum-specific antibody (TPAb) or positive for HIV-Ab;

[1152] (1)(Examination) Screening / Baseline 12-lead electrocardiogram showing heart rate <50 bpm or >100 bpm, second- or third-degree atrioventricular block, long QT syndrome or QTcF >470 ms in women or >450 ms in men or other electrocardiogram abnormalities that investigators judge require drug intervention.

[1153] (2) A history or evidence of any of the following diseases:

[1154] 1) (Consultation) Obesity may be caused by secondary diseases or medications, including: elevated cortisol levels (e.g., Cushing's syndrome), obesity caused by pituitary and hypothalamic damage, obesity caused by reducing / discontinuing weight loss drugs, etc.

[1155] 2) (Medical history / examination) Previous / screening diagnosis of type 1 or type 2 diabetes;

[1156] 3) (Medical history / examination) Previous / screening diagnosis of acute or chronic pancreatitis, or pancreatic injury;

[1157] 1) (Medical history / examination) Previous / screening diagnosis of thyroid C-cell carcinoma, MEN (multiple endocrine neoplasia) 2A or 2B, or relevant family history;

[1158] 2)(Consultation) Those who have previously undergone gastric weight loss surgery, or who plan to undergo weight loss surgery, liposuction, or abdominal fat removal surgery during the study period, or other surgeries that significantly affect their weight;

[1159] 3)(Questionnaire) History of moderate or severe depression, or a score of ≥15 on the PHQ-9 (Depression Screening Scale) questionnaire at the time of screening, or a history of other serious mental illness, or suicidal tendencies or suicidal behavior.

[1160] 4) (Consultation / Examination) Diagnosed with malignant tumors within 5 years prior to screening (excluding cured carcinoma in situ) or assessed as having potential malignant tumors at the time of screening;

[1161] 5)(Medical history) Screen for any of the following heart diseases within the past 6 months: such as decompensated heart failure (NYHA class III or IV); unstable angina, myocardial infarction, coronary artery bypass grafting or coronary stent implantation.

[1162] 6) Patients who have had hemorrhagic or ischemic stroke within the past 6 months and are deemed unsuitable for this clinical trial by the investigator;

[1163] 7) (Medical history) Screening for severe hypoglycemia or recurrent (≥2 times within 6 months) symptomatic hypoglycemia within the past 6 months;

[1164] 8) (Examination) Thyroid dysfunction that cannot be controlled with a stable drug dose during screening, or thyroid function test results that are clinically significant and require initiation of treatment during screening.

[1165] 9) Abdominal ultrasound during screening suggests the presence of gallstones or gallbladder polyps, or clinical symptoms of biliary tract disease or indications of cholestasis during screening.

[1166] 10) Clinically significant abnormalities in gastric emptying (e.g., severe gastroparesis or gastric outlet obstruction) were observed during screening.

[1167] (1) During the screening process, a history of drug abuse or alcoholism is suspected or confirmed.

[1168] (2) (Consultation) Screening individuals who have participated in clinical trials of drugs or medical devices and received interventions with investigational drugs (excluding placebo recipients) or medical devices within the previous 12 weeks;

[1169] (1) (Examination) of pregnant or lactating women;

[1170] (2) Individuals with combined mental illness or language disorders who are unwilling or unable to fully understand and cooperate;

[1171] Other situations where researchers deem it unsuitable for participation in the trial.

[1172] 3.6 Early termination of treatment

[1173] Participants have the right to request early termination of treatment based on their own interests. Researchers also have the right to discuss with the sponsor whether early termination of treatment is necessary, based on the safety and treatment rights of the participants. Reasons for early termination of treatment in this study include, but are not limited to, the following:

[1174] (1) The subject was unwilling to continue treatment;

[1175] (2) If a subject experiences an increased risk of hypoglycemia, hypersensitivity reaction, SAE, acute or chronic pancreatitis, or other safety risks related to the investigational drug, and the investigator determines that the subject is not suitable to continue treatment;

[1176] (3) Subjects with a BMI ≤ 18.5 kg / m² 2 Researchers must take into account the participants' own wishes, fully consider the risks of continuing to receive the study drug treatment, and discuss with the sponsor whether it is necessary to terminate the treatment early.

[1177] (4) The subject failed the salvage treatment for hypertension or refused the salvage treatment.

[1178] Early termination of study treatment is not considered withdrawal from the study. Subjects who terminate treatment early should complete the early termination visit as soon as possible and undergo a safety follow-up 14±5 days after the last treatment. Subsequent procedures should be completed as originally planned, at least as specified in V10.

[1179] 3.7 Early withdrawal from research

[1180] Participants have the right to withdraw from the trial early based on their own interests. Researchers also have the right to arrange for early withdrawal based on the participant's safety and compliance. Reasons for early withdrawal in this study include, but are not limited to, the following:

[1181] (1) If a subject meets the criteria for early termination of treatment but refuses to undergo follow-up visits, it is considered as early withdrawal from the trial;

[1182] (2) The subject voluntarily requested to withdraw from the trial;

[1183] (3) If the subjects have poor compliance and there is a major deviation from the protocol that seriously affects the evaluation of drug safety or efficacy, the investigators will determine that it is not appropriate to continue the trial.

[1184] (4) Other circumstances where the researchers deem it unsuitable for the individual to continue participating in this clinical trial.

[1185] For subjects who withdraw from the trial early, an early withdrawal visit should be conducted as soon as possible, and a safety follow-up should be performed as early as 14±5 days after the last treatment.

[1186] 3.8 Study Suspension / Termination Criteria

[1187] The reasons for early termination / suspension of a study may include, but are not limited to, the following:

[1188] (1) Significant errors were found in the clinical trial protocol during the trial, making it difficult to evaluate the clinical efficacy and safety of the investigational drug;

[1189] (2) The applicant requests termination (e.g., due to funding or management reasons);

[1190] The National Medical Products Administration or the Medical Ethics Committee requested the termination of the trial.

[1191] 3.9 Background treatment with antihypertensive drugs:

[1192] If a subject is using antihypertensive medication concurrently at screening, the dosage of that medication should remain stable until the end of the core treatment period. Unless required for safety or efficacy, the dosage or type of antihypertensive medication used by the subject may be adjusted upon investigator evaluation.

[1193] 3.10 Combined Treatment

[1194] Prohibited combined treatment

[1195] Subjects are prohibited from using any other medications or non-pharmacological treatments that affect weight from the time they sign the ICF until the completion of the safety follow-up (V11). This includes, but is not limited to:

[1196] 1) Weight loss medications, such as: GLP-1 receptor agonists or similar drugs, sibutramine hydrochloride, phentermine, phenylpropanolamine, chlorpheniramine, phentermine, amphetamine, lorcaserin, phentermine / topiramate combination, naltrexone / bupropion combination, orlistat, etc. Also, other prescription drugs, over-the-counter drugs, traditional Chinese medicines, health supplements, meal replacement products, etc., for the purpose of weight loss.

[1197] 2) Other medications that affect weight, such as systemic corticosteroids used for a cumulative period of ≥14 days (excluding inhaled, topical, intraocular, and intranasal medications), tricyclic antidepressants, medications for mental illnesses, or sedatives (such as imipramine, amitriptyline, and mirtazapine).

[1198] 3) Non-drug treatments for weight loss, such as acupuncture, bariatric surgery, liposuction, and abdominal fat removal.

[1199] Permitted concomitant treatment

[1200] The concomitant treatments that the subjects were receiving at the time of screening and that met the enrollment requirements of the protocol were allowed to continue. If the investigator believed that the addition of concomitant treatments was necessary to ensure the clinical benefit and safety of the subjects and would not affect the evaluation of the investigation drug, the investigator may give the corresponding treatment based on clinical judgment.

[1201] All treatments (drug name, dosage, indication, treatment start time and end time) must be recorded in the original medical record and eCRF of subjects who are allowed to receive combined treatment.

[1202] 3.11 Dosage Adjustment

[1203] If, after reaching the target dose during the core treatment period, a subject still cannot tolerate gastrointestinal adverse reactions (i.e., moderate to severe vomiting, diarrhea, or severe nausea) two weeks after dietary adjustments, symptomatic treatment, and discontinuation of medication, and the investigator believes the subject cannot tolerate further dose exposure, a dose reduction may be considered after discussion with the sponsor. The dose may be reduced to 10 mg and maintained until the end of the trial. If gastrointestinal adverse reactions are still intolerable after dose adjustment, early termination of treatment or early withdrawal from the trial may be considered.

[1204] If the BMI of subjects in the 15mg dose group decreased to 18.5 kg / m² during treatment... 2 For doses of 10 mg or less, a dose reduction is permitted (if the investigator assesses that a dose reduction is necessary and discusses this with the sponsor, the dose to the subject may be reduced to 10 mg and maintained until the end of the trial).

[1205] 3.12 Study Endpoint

[1206] Main estimation target:

[1207] The percentage change in body weight from baseline at week 52 of drug administration;

[1208] Key secondary estimation targets:

[1209] Changes in systolic blood pressure from baseline at weeks 24 and 52 after drug administration;

[1210] Changes in diastolic blood pressure from baseline at weeks 24 and 52 after drug administration;

[1211] Blood pressure target achievement rate at week 52 of drug administration (Note: Blood pressure target achievement rate is defined as the proportion of subjects whose blood pressure drops to <140 / 90 mmHg or whose systolic blood pressure decreases by ≥20 mmHg and diastolic blood pressure decreases by ≥10 mmHg compared to baseline).

[1212] The proportion of subjects whose body weight decreased by ≥5% relative to baseline at week 52 of administration;

[1213] Secondary estimation target:

[1214] Systolic blood pressure (SBP); changes in systolic blood pressure from baseline at weeks 4, 8, 12, 32, and 40 after drug administration;

[1215] Diastolic blood pressure (DBP): Changes in diastolic blood pressure from baseline at weeks 4, 8, 12, 32, and 40 after drug administration;

[1216] The percentage of patients receiving salvage therapy with antihypertensive drugs at 52 weeks of treatment;

[1217] The proportion of subjects who reduced their antihypertensive medication intake at week 52 of treatment; (Note: Reduction in antihypertensive medication intake includes, but is not limited to, a reduction in the total daily intake and a reduction in the types of antihypertensive medications.)

[1218] Body weight: percentage change in body weight relative to baseline at weeks 12, 16, 24, 32, and 40 of drug administration; and the change in body weight from baseline at the above time points;

[1219] Weight: The proportion of subjects whose weight decreased by ≥5% relative to baseline at weeks 12, 24, 32, and 40 after administration; and the proportion of subjects whose weight decreased by ≥10%, ≥15%, and ≥20% relative to baseline at weeks 12, 24, 32, 40, and 52, respectively.

[1220] Waist circumference: The percentage change in waist circumference from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1221] BMI: The percentage change in BMI from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1222] High-density lipoprotein cholesterol (HDL-C): Changes in HDL-C from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1223] Triglycerides (TG): Changes in triglyceride levels from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1224] Total cholesterol (TC): Changes in total cholesterol from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1225] Low-density lipoprotein cholesterol (LDL-C): Changes in LDL-C from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1226] Serum uric acid (UA): Changes in serum uric acid from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1227] Fasting insulin: Changes in fasting insulin levels from baseline at week 52 of administration;

[1228] Fasting blood glucose: Change in fasting blood glucose from baseline at week 52 of drug administration;

[1229] Glycated hemoglobin: Change in glycated hemoglobin from baseline at week 52 of drug administration;

[1230] Pancreatic β-cell function and insulin resistance: Changes in HOMA2-B and HOMA2-IR from baseline at week 52 of drug administration;

[1231] Weight on quality of life scale (IWQOL-Lite-C High-density lipoprotein cholesterol (HDL-C): Changes in HDL-C from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1232] Triglycerides (TG): Changes in triglyceride levels from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1233] Total cholesterol (TC): Changes in total cholesterol from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1234] Low-density lipoprotein cholesterol (LDL-C): Changes in LDL-C from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1235] Serum uric acid (UA): Changes in serum uric acid from baseline at weeks 12, 24, 32, 40, and 52 after administration;

[1236] Fasting insulin: Changes in fasting insulin levels from baseline at week 52 of administration;

[1237] Fasting blood glucose: Change in fasting blood glucose from baseline at week 52 of drug administration;

[1238] Glycated hemoglobin: Change in glycated hemoglobin from baseline at week 52 of drug administration;

[1239] Pancreatic β-cell function and insulin resistance: Changes in HOMA2-B and HOMA2-IR from baseline at week 52 of drug administration;

[1240] Weight Impact on Quality of Life Scale (IWQOL-Lite-CT) score: Change in score from baseline at week 52.

[1241] 3.13 Sample Size Calculation

[1242] This is a single-arm, open-label clinical study. The primary objective was to evaluate the percentage change in weight relative to baseline at 52 weeks in overweight / obese adults as an adjunct to diet, exercise, and behavioral interventions, thus verifying the efficacy of GLP-1 / GIP peptide injection (15 mg). Assuming a 7% difference in percentage weight change from baseline between the experimental group and the external positive control (standard deviation 16.5%), a statistical significance level of α = 0.025 (one-sided), a power of 90%, and a PASS 15.0 estimate, the 15 mg injection group consisted of 61 subjects. Assuming a 4.8 mmHg difference in SBP from baseline between the experimental group and the external positive control (standard deviation 13), the sample size was 79 subjects. Considering a 20% dropout rate, approximately 100 subjects were needed to enroll in the 15 mg GLP-1 / GIP peptide injection group.

[1243] 4. Statistical Analysis

[1244] 4.1 Analyzing the dataset

[1245] Full Analysis Set (FAS): Includes all enrolled participants who have used the study drug at least once. Primarily used for demographic and baseline characteristic analysis, and for evaluating primary and secondary estimating objectives.

[1246] Safety analysis set (SS): Includes all subjects who have used the study drug at least once. This analysis set is used for the analysis of safety indicators.

[1247] 4.2 General Principles of Statistical Analysis

[1248] Unless otherwise specified, use SAS 9.4 or later for statistical analysis. For continuous data, descriptive statistics are generally performed, including the number of cases (n), arithmetic mean (Mean), standard deviation (SD), median, minimum (Min), and maximum (Max). For categorical data, the number of cases (n) and percentage (%) are generally provided.

[1249] 4.2.1 Missing Data Handling

[1250] Missing validity data is imputed using multiple imputation techniques for target estimation analysis. No imputation is performed on security data.

[1251] 4.2.2 Statistical Hypotheses

[1252] The superiority hypothesis test for the primary efficacy endpoint is as follows:

[1253] H0:μ E ≥-7%

[1254] H1:μ E <-7%

[1255] Where μ E This is the overall estimate of the difference between the experimental group and the external positive control. If the upper limit of the two-sided 95% CI of this difference is less than 0, the experimental group can be considered superior to the external positive control group.

[1256] 4.3 Statistical Analysis of Estimated Targets

[1257] Main target estimation analysis:

[1258] Target population: Overweight or obese Chinese adults with hypertension who do not have diabetes and meet the inclusion criteria but not the exclusion criteria.

[1259] Treatment: Administer GLP-1 / GIP peptide injection once a week for 52 weeks.

[1260] Target variable: percentage change in body weight from baseline at 52 weeks of treatment.

[1261] Population-level summary: Mean difference in the percentage change in relative body weight from baseline between the experimental group and the external positive control group after 52 weeks of core treatment.

[1262] Main target estimation analysis:

[1263] Analysis was conducted based on the primary estimated target population. A one-sample t-test was used to compare the percentage change in body weight from baseline at 52 weeks in the experimental group with that in the external positive control group, and the mean and 95% confidence interval of this difference were calculated. A statistically significant difference was considered to exist between the experimental drug group and the external positive control group if the upper limit of the two-sided 95% confidence interval was less than 0.

[1264] Secondary estimation target:

[1265] Target population: Overweight or obese subjects with hypertension who meet the inclusion criteria but not the exclusion criteria and whose weight loss through diet and exercise alone is ineffective.

[1266] Treatment: GLP-1 / GIP peptide injection was administered weekly for 52 weeks in an open state.

[1267] Target variables: Continuous target variables (including: percentage change in weight from baseline at weeks 12, 16, 24, 32, and 40 of administration, and the percentage change in weight from baseline at these time points; percentage change in waist circumference and BMI from baseline at weeks 12, 24, 32, 40, and 52 of administration; changes in systolic and diastolic blood pressure from baseline at weeks 4, 8, 12, 24, 32, 40, and 52 of administration; changes in high-density lipoprotein cholesterol, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and serum uric acid from baseline at weeks 12, 24, 32, 40, and 52 of administration; blank blood pressure at week 52 of administration). The study included changes in abdominal insulin, fasting blood glucose, glycated hemoglobin, HOMA2-B, HOMA2-IR, and weight on the quality of life scale from baseline, as well as dichotomous target variables (including: blood pressure target achievement rate at 52 weeks of treatment, the proportion of subjects using antihypertensive salvage therapy at 52 weeks of treatment, the proportion of subjects reducing antihypertensive medication at 52 weeks of treatment; the proportion of subjects whose weight decreased by ≥5% from baseline at weeks 12, 24, 32, 40, and 52 of treatment; and the proportion of subjects whose weight decreased by ≥10%, ≥15%, and ≥20% from baseline at weeks 12, 24, 32, 40, and 52 of treatment, respectively).

[1268] Population-level summary: the average difference or proportion of subjects among the above secondary target variables between the experimental group and the external positive control.

[1269] Secondary estimation target analysis:

[1270] For continuous target variables in secondary estimation objectives, the same analytical methods as those used in the primary estimation objective analysis were employed to calculate the mean and 95% confidence interval of the GLP-1 / GIP peptide injection group; for dichotomous target variables, the Clopper-Pearson method was used to calculate the 95% confidence interval of the rate.

[1271] 5. Results

[1272] The experimental results are shown in Tables 4-3 and 4-5, and Figure 31. As can be seen from the tables and figures, BGM0504 injection has a rapid onset and significant therapeutic effect on obesity accompanied by hypertension. Continuous administration of BGM0504 injection for 10 weeks resulted in an average reduction of approximately 9% in sitSBP and approximately 6% in sitDBP. After 20 weeks, the average reduction in sitSBP was approximately 11%, and the average reduction in sitDBP was approximately 7%. Hypertension significantly improved after approximately 10 weeks of continuous administration, and systolic and diastolic blood pressure stabilized after approximately 15-20 weeks of continuous administration, with no risk of hypotension observed.

[1273] Furthermore, BGM0504 injection exhibits superior antihypertensive effects in obese patients with stage II and III hypertension. Continuous administration of BGM0504 injection for 10 weeks reduced the sitSBP value by approximately 23% in an obese patient with stage II hypertension, and for 10 weeks reduced the sitSDP value by approximately 15%. Continuous administration of BGM0504 injection for approximately 12 weeks reduced the sitSDP value by approximately 13% in an obese patient with stage III hypertension, and for approximately 17 weeks reduced the sitSBP value by approximately 16%.

[1274] Table 4-3 Results of studies on obesity combined with hypertension

[1275] Table 4-4 Results of the study on obesity combined with grade II hypertension

[1276] Table 4-5 Results of the study on obesity combined with grade 3 hypertension

[1277] Test Example 1

[1278] This test case presents the results of a randomized, double-blind, placebo- and positive-drug parallel-controlled phase IIa clinical trial on the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of multiple doses of GLP-1 / GIP peptide injection in patients with type 2 diabetes, as described in Example 1.

[1279] 1. This study screened 127 subjects, planned to randomly enroll 64 subjects, and ultimately randomized 67 subjects (because 3 subjects withdrew from the trial after randomization without receiving the study drug, it was decided to use replacement random numbers to add 3 subjects). Of the 67 subjects randomly enrolled, 64 subjects received the study drug, 60 subjects completed the trial, and 7 subjects withdrew from the trial early. Seven subjects withdrew from the trial early, including: three (subject C114 in the 5mg dose group, subject C309 in the 15mg dose group, and subject C304 in the placebo group) who withdrew before receiving medication after randomization (all withdrew voluntarily); one (subject C102 in the 5mg dose group) who withdrew after completing the 7th target dose due to a sarcastic acute exacerbation (SAE), which was confirmed by the investigators to be related to medical history and possibly unrelated to the study drug; one (subject C301 in the 15mg dose group) who withdrew before the first target dose; and two (subjects C113 and C315 in the placebo group) who withdrew after completing the 4th and 10th target doses, respectively, due to fasting blood glucose exceeding the hyperglycemic threshold. The enrollment and completion statistics for each group are shown in Table 5-1 below.

[1280] The baseline characteristics of the subjects enrolled in the BGM0504 injection groups, placebo group, and positive control group were roughly the same, including age, weight, and BMI.

[1281] Table 5-1 Subject Distribution

[1282] Table 5-2 Analysis of Dataset Partitioning

[1283] 2. Analysis of PK Results

[1284] 2.1 Blood concentration-time curve of BGM0504

[1285] The plasma concentrations of BGM0504 in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection are summarized. The mean plasma concentration / mean concentration semi-logarithmic-time curves of BGM0504 are shown in Figures 1 and 2.

[1286] 2.2. Pharmacokinetic Parameter Results

[1287] BGM0504 injection at doses of 5 mg, 10 mg, and 15 mg was administered once weekly to subjects with type 2 diabetes mellitus (T2DM). Peak plasma BGM0504 levels were reached approximately 24 hours after the fourth target dose. The elimination half-life after the fourth target dose was approximately 109–160 hours. In T2DM subjects, at the same dose, C... maxThe AUC was slightly lower than that of healthy individuals, but the difference was not significant. The plasma concentrations before the 5th, 9th, and 12th doses of the target dose were similar, indicating that BGM0504 can reach steady-state plasma concentrations after four consecutive doses of the target dose in T2DM subjects. max AUC showed virtually no accumulation; C after the fourth target dose was administered. min,ss Approximately C max,ss It is estimated that 40% to 50% of the blood sugar levels will be stable with Q1W administration.

[1288] BGM0504 injection was administered once weekly in 5mg, 10mg, and 15mg dose groups. The main PK parameters of BGM0504 after the first and fourth target doses are shown in Table 5-3.

[1289] Table 5-3 Main pharmacokinetic parameters of BGM0504 in the plasma of subjects after the first and fourth target doses. Note 1) Data is from the Phase IIa clinical trial of BGM0504 injection for blood glucose lowering. Except for T in the table, max All values ​​are mean(SD), T max This represents the median value (minimum, maximum).

[1290] 2)t 1 / 2 =ln(2) / Kel, where Kel is the terminal elimination rate constant. Kel is calculated based on the slope of linear regression after logarithmic transformation of the last three points of the terminal elimination phase in the blood drug concentration from 0h before administration to 168h after administration.

[1291] 3) AUC 0-t The area under the concentration curve from 0 to 168 hours after the first target dose administration;

[1292] 4) The RAUC calculation method is based on the AUC of the fourth target dose administration. 0-168h AUC of the first target dose 0-168h ratio;

[1293] 5) Subject C301 in the 15mg dose group withdrew from the study early and did not have a PK blood sample collected after the target dose was administered. Subject C212 in the 10mg dose group had his dose reduced before the fourth target dose was administered and was not included in the PK analysis after the fourth target dose was administered.

[1294] 2.3. Pharmacokinetic dose-exposure ratio relationship

[1295] The PowerMode1 model was used to analyze the PK parameter-proportional dose-response relationship. If C max If the 90% CI of the AUC slope includes 1, it indicates that the PK parameter is linearly related to the dose.

[1296] The primary pharmacokinetic parameter C of BGM0504 after the first target dose administration max The point estimate of the slope and its 90% confidence interval are 0.9195 (0.794, 1.0460); AUC 0-168 The point estimate of the slope and its 90% confidence interval are 0.9004 (0.7217, 1.0790); AUC 0-inf The point estimate of the slope and its 90% confidence interval were 0.9353 (0.7869, 1.0840). C after the first target dose administration. max AUC 0-168 AUC 0-inf The effect increases with increasing dosage, exhibiting a typical linear relationship.

[1297] The main pharmacokinetic parameter C of BGM0504 after the fourth dose of target dose was reached. max,ss The point estimate of the slope and its 90% confidence interval are 0.6518 (0.4510, 0.8530); AUC 0-168 The point estimate of the slope and its 90% confidence interval are 0.7764 (0.5794, 0.9730); AUC 0-inf The point estimate and its 90% confidence interval were 0.9174 (0.687, 1.500). After the fourth dose reached a stable level, C... max AUC 0-168 AUC 0-inf It increases with increasing dose, where C max,ss AUC 0-168 It exhibits an atypical linear relationship, AUC 0-inf It exhibits a typical linear relationship.

[1298] Table 5-4 C-levels of plasma BGM0504 in subjects after administration of the investigational drug max AUC 0-168 AUC 0-inf Relationship with dosage (first target dose) - PKPS Note: Data is from BGM0504 injection solution stage IIa TFLs.

[1299] Table 5-5 C-levels of plasma BGM0504 in subjects after administration of the investigational drug max AUC 0-168 AUC 0-inf Relationship with dosage (4th target dose) - PKPS Note: Data is from BGM0504 injection solution stage IIa TFLs.

[1300] 2.4. Pharmacokinetics / Therapeutic Effect Analysis

[1301] All PD / validity data below are from the PDS analysis set, and the data in the PPS analysis set are consistent with them, so they will not be repeated here.

[1302] The main results of the PD / efficacy indicators after titration for 2–6 weeks and continued treatment at the target dose for 12 weeks in the BGM0504 injection 5mg, 10mg, 15mg dose groups, placebo group, and positive control semaglutide 1mg group were as follows:

[1303] 1) HbA1c, fasting blood glucose, and 2-hour postprandial blood glucose: After 12 weeks of treatment with the target dose of BGM0504 injection (5mg, 10mg, and 15mg), HbA1c, fasting blood glucose, and 2-hour postprandial blood glucose were significantly reduced, with statistically significant differences compared to baseline (P<0.05). The reduction in HbA1c, fasting blood glucose, and 2-hour postprandial blood glucose in each BGM0504 injection group was significantly greater than that in the placebo group, with statistically significant differences (P<0.05). Compared with the positive control group, the reduction in HbA1c in the BGM0504 injection (5mg, 10mg, and 15mg) groups was greater than that in the positive control group, with a statistically significant difference in the 15mg group compared to the positive control group (P<0.05). The reduction in fasting blood glucose and 2-hour postprandial blood glucose in each BGM0504 injection group tended to be similar to or greater than that in the positive control group. Regarding the rate of achieving blood glucose control targets, the percentage of subjects with HbA1c (%) <7.0%, <6.5%, and <5.7% in the BGM0504 injection 5mg, 10mg, and 15mg dose groups was higher than that in the placebo group. As the dosage increased, the proportion of subjects achieving blood glucose control targets showed an increasing trend. Among them, the percentage of subjects with HbA1c (%) <7.0%, <6.5%, and <5.7% in the BGM0504 injection 15mg dose group showed a certain advantage compared with other dose groups and the positive control group.

[1304] 2) Percentage change in weight and HbA1c / weight composite target achievement rate: No significant weight change was observed in the 5mg BGM0504 injection group before and after treatment. The 10mg and 15mg BGM0504 injection groups significantly reduced weight after 12 weeks of treatment at the target dose. The percentage and magnitude of weight reduction from baseline in the 10mg and 15mg BGM0504 injection groups were significantly greater than those in the placebo group (P < 0.01), while there was no significant difference between the positive control group and the placebo group (P = 0.09). The percentage and magnitude of weight reduction from baseline in the 10mg and 15mg BGM0504 injection groups were also greater than those in the positive control group, with a statistically significant difference between the 15mg group and the positive control group (P < 0.05). Regarding the HbA1c / weight composite target achievement rate, the 5mg, 10mg, and 15mg BGM0504 injection groups had higher achievement rates than the placebo group, with the 10mg and 15mg groups showing a certain advantage over the positive control group.

[1305] 3) Other secondary PD / effectiveness evaluation indicators

[1306] After 12 weeks of treatment with the target dose of BGM0504 injection at doses of 5mg, 10mg, and 15mg, HOMA2-B levels increased to varying degrees from baseline, with statistically significant differences compared to the placebo group, suggesting that BGM0504 exhibits a certain effect in improving β-cell function.

[1307] Detailed results of the primary and critical secondary PD / effectiveness based on PDS are shown in Tables 5-6 and 5-7.

[1308] The changes in mean HbA1c from baseline over time, mean fasting blood glucose from baseline over time, mean 2-hour postprandial blood glucose from baseline over time, and mean fasting body weight from baseline over time for each experimental group are shown in Figures 3 to 7.

[1309] Table 5-6 Summary of Major and Key Secondary PD / Effectiveness Results - PDS

[1310] Table 5-7 Summary of Results for Other Secondary PD / Effectiveness Evaluation Indicators - PDS

[1311] 3. Safety / Immunogenicity Evaluation

[1312] Of the 67 subjects enrolled in this study, 3 subjects did not receive medication after randomization. 64 subjects were included in the SS (Safety Surveillance) group for safety evaluation, including 13 subjects in the 5mg BGM0504 injection group, 11 subjects in the 10mg BGM0504 injection group, 12 subjects in the 15mg BGM0504 injection group, 16 subjects in the positive control group, and 12 subjects in the placebo group.

[1313] 3.1 Safety Conclusion

[1314] (1) Most adverse events (AEs) occurring at doses of 5mg to 15mg of BGM0504 injection were grade 1 to 2, and most recovered to "cured" without intervention. The adverse reactions that occurred were mostly gastrointestinal diseases, with a severity of grade 1, mainly occurring during the dose titration stage and the initial stage of reaching the target dose, and gradually became tolerable with continued administration. No hypoglycemic events or other unexpected adverse reactions occurred.

[1315] (2) In this study, some subjects developed ADA antibodies after using BGM0504 injection, but no neutralizing antibodies were produced, and no immunogenicity-related safety issues were found.

[1316] (3) BGM0504 injection at doses of 5mg, 10mg and 15mg all showed good safety and tolerability and can be used as experimental doses for Phase III studies in the field of T2DM.

[1317] 3.2 Immunogenicity Conclusion:

[1318] Some subjects tested positive for ADA antibodies after receiving BGM0504 injection, but no neutralizing antibodies were produced. No significant impact was observed on the safety, efficacy, or pharmacokinetic profile of the subjects.

[1319] 4. Summary

[1320] 4.1 PK Analysis

[1321] In this study, pharmacokinetic (PK) blood samples were collected from subjects in the 5 mg, 10 mg, and 15 mg BGM0504 injection groups after the first and fourth dose administration. The median T value of BGM0504 in plasma after the fourth dose administration was [data missing]. max It takes approximately 24 hours to reach its target concentration, with an elimination half-life of approximately 109–160 hours. The expected duration of action covers a clinical dosing interval (7 days), and the plasma concentrations are similar before the 5th, 9th, and 12th target doses, confirming that continuous dosing for 4 weeks can achieve steady-state plasma concentrations. After reaching steady-state concentrations, C... min,ss Approximately C max,ss The blood concentration remains at 40%–50% of the target level, maintaining a certain level before the next dose, and continuing to lower blood sugar throughout the dosing interval. Meanwhile, C is administered once weekly. maxThe AUC showed virtually no accumulation, and Q1-week dosing is expected to provide stable hypoglycemic efficacy. PK results of BGM0504 injection in patients with type 2 diabetes support its continued once-weekly dosing regimen in Phase III clinical trials for the treatment of type 2 diabetes.

[1322] Analysis of the PK results from the Phase Ia clinical trial of BGM0504 injection: In this study, the t-value of BGM0504 was... 1 / 2 The duration of a single dose was slightly longer than in healthy individuals (in this study, the time to administration of BGM0504 injection 5mg-15mg after the first target dose was t). 1 / 2 The duration of administration is 95h–122h, and the duration of administration for a single dose in healthy individuals is t. 1 / 2 (84–91 hours); in T2DM patients, the same dose of C max The AUC was slightly lower than that of healthy individuals, but the difference was not significant.

[1323] Combined with similar drugs such as telpotetide injection (trade name: Analysis of pharmacokinetic characteristics in patients with type 2 diabetes mellitus (T2DM):

[1324] 1) Regarding the half-life, in this study, the t-life of BGM0504 injection at doses of 5mg to 15mg was... 1 / 2 Similar to telpotetide (t of BGM0504 after the first and fourth target doses) 1 / 2 The half-life of telpoprit is approximately 95–122 h and 108–160 h, respectively, while the half-life of telpoprit is approximately 93–148 h.

[1325] 2) Regarding the time to peak concentration, in this study, the BGM0504 injection T max Approximately 24 hours later, with telpolide (T max The peak time is similar to that of 24 hours;

[1326] 3) Regarding peak concentration, in this study, the peak concentrations of BGM0504 injection at 5 mg, 10 mg, and 15 mg were slightly higher than those of telpotrebate at the same dose (C60, C ... max The concentrations were 764.8 ng / mL, 1327 ng / mL, and 1583.7 ng / mL, respectively, and the C of telpolide was... max (614 ng / mL, 1030 ng / mL and 1250 ng / mL);

[1327] 4) Regarding drug exposure, in this study, the exposure of BGM0504 injection at 5 mg, 10 mg, and 15 mg was slightly higher than that of telpotrebate at the same dose (AUC of BGM0504 after the fourth target dose of 5 mg, 10 mg, and 15 mg). 0-tThe AUC values ​​of telpolide were 88919 h*ng / mL, 166027 h*ng / mL, and 211135 h*ng / mL, respectively. 0-t The concentrations were 81900 h*ng / mL, 131000 h*ng / mL, and 164000 h*ng / mL. BGM0504 has a similar T value to telpolide. max t 1 / 2 But C max And with a slightly higher AUC, it is predicted that this product may have better hypoglycemic efficacy than telpolide at the same dose.

[1328] 4.2 Discussion of PD / Validity Results

[1329] 4.2.1 Changes in HbA1c (%)

[1330] In this study, BGM0504 injection was administered once weekly to patients with type 2 diabetes, titrated to the target dose, and continued for 12 weeks, demonstrating good effects in lowering blood sugar and reducing weight. After 12 weeks of treatment with the target dose, the changes in HbA1c (%) from baseline in the BGM0504 injection groups (5 mg, 10 mg, and 15 mg) were statistically significant compared to the placebo group. After excluding placebo, the HbA1c (%) values ​​were -2.00 (LSM -1.82 95% CI [-2.83, -0.81], P = 0.0011), -2.22 (LSM -2.05 95% CI [-3.27, -0.82], P = 0.0023), and -2.76 (LSM -2.56 95% CI [-3.58, -1.54], P < 0.0001), respectively. In contrast, the positive control group (semaglutide 1 mg) showed a HbA1c (%) value of -1.71 (LSM -1.86 95% CI [-2.83, -0.90], P = 0.0005) (see Figure 8).

[1331] Compared with the positive control drug semaglutide 1mg, the HbA1c (%) reduction from baseline in the BGM0504 injection 5mg, 10mg, and 15mg groups, excluding the difference in the positive control group, were -0.28 (1.09), -0.51 (1.25), and -1.05 (1.06), respectively. The difference between the 15mg group and the positive control group was statistically significant (LSM -0.6895%CI [-1.29, -0.06], P = 0.0327). The lack of statistical significance in the 5mg and 10mg groups compared with the positive control group may be related to the small sample size in this study.

[1332] Compared with the literature data reported in the Phase III clinical study (SUSTAIN-China study) of BGM0504 injection in Chinese patients with type 2 diabetes mellitus (T2DM), BGM0504 injection showed a significant advantage in reducing HbA1c (see Figure 9).

[1333] Compared with the results of the Phase III clinical trial SURPASS-1[9] of telpotetin in patients with T2DM, BGM0504 injection was slightly better at reducing HbA1c. After 40 weeks of treatment with telpotetin 5mg to 15mg, the change in HbA1c from baseline (excluding placebo effect) was -1.9% to -2.1% (see Figure 10).

[1334] (2) Changes in fasting blood glucose, 2-hour postprandial blood glucose, and body weight

[1335] Regarding key secondary efficacy evaluation indicators

[1336] 1) Fasting blood glucose: The changes in fasting blood glucose (mmol / L) relative to baseline in the BGM0504 injection groups (5mg, 10mg, and 15mg) were statistically different from those in the placebo group. After excluding placebo, the values ​​were -1.73 (LSM -1.63 95% CI [-3.00, -0.25], P = 0.0226) and -2.19 (LSM -1.95 95% CI [-3.88, -0.01], P = 0.0226), respectively. The values ​​for fasting blood glucose relative to baseline (excluding placebo effect) were -3.67 (LSM 3.1895% CI [-4.42, -1.93], P < 0.0001), while the values ​​for semaglutide 1 mg group were -2.47 (LSM -2.4995% CI [-3.73, -1.25], P = 0.0004). The changes in fasting blood glucose relative to baseline (excluding placebo effect) in the medium / high dose groups of BGM0504 injection were similar to or greater than those in the positive control group.

[1337] 2) Postprandial 2-hour blood glucose: The changes in blood glucose (mmol / L) at 2 hours after a meal relative to baseline (excluding placebo effect) in the BGM0504 injection 5mg, 10mg, and 15mg groups were statistically different from those in the placebo group, reaching -4.55 (LSM -4.93 95% CI [-7.78, -2.08], P = 0.0018), -4.54 (LSM -4.76 95% CI [-9.15, -0.37], P = 0.0351), and -6.10 (LSM -6.16 95% CI [-8.72, -3.59], P < 0.0001), respectively. These values ​​were similar to or even greater than those in the positive control semaglutide 1mg group (LSM -5.20 95% CI [-8.34, -2.06], P = 0.0023).

[1338] 3) Weight: The percentage change in fasting weight relative to baseline (excluding placebo effect) for the BGM0504 injection 5mg, 10mg, and 15mg groups were -0.25 (LSM -0.4095% CI [-3.82, 3.03], P = 0.8115), -5.75 (LSM -6.5895% CI [-10.95, -2.21], P = 0.0054), and -9.23 (LSM -9.5595% CI [-13.73, -5.38], P = 0.0001), respectively. The percentage change in weight in the medium / high dose groups was statistically significant compared to the placebo group. Compared to the semaglutide 1mg group (-2.42 (LSM -2.3495% CI [-5.09, 0.41], P = 0.0923), the medium / high dose groups showed greater weight loss. The changes in body weight from baseline (excluding placebo effect) in the 5mg, 10mg, and 15mg dose groups were 0.10kg, -3.92kg, and -7.34kg, respectively, while the semaglutide 1mg group was -1.81kg, which was lower than the medium / high dose groups.

[1339] 4) Percentage of subjects with HbA1c < 7%: The percentage of subjects with HbA1c < 7% in all BGM0504 injection groups and the semaglutide injection 1mg group was statistically different from that in the placebo group. The percentages in the BGM0504 injection 5mg, 10mg, and 15mg groups were 76.9% (95% CI [46.19–94.96], P = 0.0026), 81.8% (95% CI [48.22–97.72], P = 0.0018), and 91.7% (95% CI [61.52–99.79], P = 0.0002), respectively, which was higher than the 75.0% (95% CI [47.62–92.73], P = 0.0023) in the semaglutide 1mg group.

[1340] 5) Percentage of subjects with HbA1c < 7%: The percentage of subjects with HbA1c < 6.5% in the BGM0504 injection 10mg and 15mg dose groups and the semaglutide injection 1mg group was statistically different from that in the placebo group. The BGM0504 injection 5mg, 10mg and 15mg dose groups reached 53.8% (95% CI [25.13~80.78], P = 0.0530), 63.6% (95% CI [30.79~89.07], P = 0.0211) and 91.7% (95% CI [61.52~99.79], P = 0.0002), respectively. The high dose group was slightly better than the semaglutide 1mg group (75.0% (95% CI [47.62~92.73], P = 0.0023).

[1341] (3) Blood pressure changes

[1342] Statistical analysis was performed on the temporal changes of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in this study. Results

[1343] The 10mg and 15mg dose groups of BGM0504 injection showed a trend of gradually decreasing systolic blood pressure (SBP) and diastolic blood pressure (DBP) with the extension of the treatment period (see Figures 11 and 12). Furthermore, it was observed that within a comparable and shorter treatment period, the 10mg and 15mg dose groups of BGM0504 injection showed a greater reduction in SBP and DBP from baseline compared to the placebo group and the positive control group (see Figures 13 and 14), and no hypotension-related adverse reactions occurred. This indicates that BGM0504 injection demonstrated a good blood pressure-lowering effect while simultaneously lowering blood sugar.

[1344] In summary, BGM0504 injection showed good hypoglycemic, weight-reducing, and blood pressure-reducing effects within the dosage range of 5mg to 15mg in this study.

[1345] 4.3 Discussion of Safety Results

[1346] The incidence of TEAEs (transmissible adverse events) with BGM0504 injection (92%–100% in the 5mg–15mg dose groups) in this study was similar to the TEAE incidence (75%–93%) reported in the Phase II and III clinical trials of telpotentiol for lowering blood sugar, and both were mainly gastrointestinal AEs. The incidence of diarrhea in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection was 30.8%, 36.4%, and 33.3%, respectively, compared to 24%–32% in the Phase II study and 34%–45% in the Phase III study of telpotentiol. The incidence of nausea in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection was 7.7%, 0%, and 25.0%, respectively, compared to 20%–40% in the Phase II study and 20%–33% in the Phase III study of telpotentiol. The incidence of abdominal distension in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection was 23.1% and 27.3%, respectively. The incidence of vomiting was 0%, 18.2%, and 0% in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection, respectively, while it was 7.3%–26.4% in the Phase II study and 9.1%–14.9% in the Phase III study of telpoteptide. The incidence of decreased appetite was 7.7%, 9.1%, and 58.3% in the 5mg, 10mg, and 15mg dose groups of BGM0504 injection, respectively, while it was 20%–25.5% in the Phase II study and 32.2%–47.8% in the Phase III study of telpoteptide. At the same dosage, BGM0504 and telpolide have essentially the same safety profile (including the aforementioned gastrointestinal adverse events). The incidence of adverse reactions in each BGM0504 dosage group showed a slight increasing trend with increasing dosage, but these were mainly grade 1 to 2 adverse reactions, and the severity did not increase with increasing dosage. No adverse reactions such as gallbladder disease or pancreatitis, previously reported with similar targeted drugs, occurred in any of the BGM0504 injection dosage groups.

[1347] The BGM0504 injection groups (5mg, 10mg, and 15mg) were escalated to the target dose over 2, 4, and 6 weeks, respectively, while the semaglutide injection group was escalated to the target dose over 6 weeks. The safety profile of the BGM0504 injection groups in Phase II was comparable to that of the semaglutide injection group, and the gastrointestinal-related adverse reactions mainly occurred in the early stage of treatment (0-8 weeks), gradually becoming tolerated with increasing frequency of administration.

[1348] 4.4 Discussion of Immunogenicity Results

[1349] Because BGM0504 injection is a peptide drug with a structure that differs somewhat from that of human proteins, immunogenicity testing revealed that a small number of subjects began to develop ADA antibodies after 6–10 weeks of administration (4 weeks of treatment at the target dose) in the 5 mg, 10 mg, and 15 mg dose groups of BGM0504 injection. However, the proportion of ADA-positive subjects did not increase significantly with prolonged administration, a result similar to that observed with telpolide. NAb testing of ADA-positive blood samples in this study did not reveal the formation of NAb neutralizing antibodies. The presence of ADA antibodies in subjects did not affect the therapeutic effect, nor did it lead to any immunogenicity-related safety issues.

[1350] Test Example 2

[1351] This test case is the result of a randomized, double-blind, placebo-controlled, parallel-group phase II clinical trial evaluating the safety, tolerability, PK / PD characteristics, and efficacy of BGM0504 injection in non-diabetic overweight or obese subjects with multiple doses, as described in Example 2.

[1352] 1. A total of 204 subjects were screened in this study, and 120 subjects were planned to be randomly enrolled. 120 subjects were actually randomly enrolled. All 120 randomly enrolled subjects received the study drug, and 115 subjects completed the trial. Among them, 113 subjects completed the dosing as planned, while 7 subjects failed to complete the dosing as planned. The reasons are as follows: 5 subjects withdrew from the trial early and failed to complete all dosing (P130 in the 5mg dose group withdrew early after completing the 17-week target dose due to pregnancy; P140 in the placebo group withdrew early after completing the 1-week target dose due to work reasons; P218 in the placebo group voluntarily withdrew early after completing the 2-week target dose; P219 in the 10mg dose group voluntarily withdrew early after completing 4 titrations; and P335 in the 15mg dose group voluntarily withdrew early after completing the 23-week target dose). Subject P217 in the 10mg dose group did not complete the planned dosing regimen and was not included in the PDS. Subject P335 in the 15mg dose group withdrew early after completing 23 doses at a 10mg dose because the target dose of 15mg was not reached due to adverse events (AEs).

[1353] The distribution of subjects in each experimental group is detailed in Table 6-1.

[1354] Table 6-1 Summary of Participant Distribution

[1355] The baseline characteristics of the subjects enrolled in the BGM0504 injection groups and the placebo group were roughly balanced, including age, weight, and BMI. The specific division of the datasets for each group is shown in Table 6-2 below.

[1356] Table 6-2 Analysis of Dataset Partitioning

[1357] 2. Pharmacokinetic / Pharmacodynamic Analysis

[1358] 2.1 Blood concentration-time curve of BGM0504

[1359] The mean plasma concentration / mean concentration semi-logarithmic-time curves after administration of BGM0504 injection at doses of 5mg, 10mg, and 15mg are shown in Figures 11 and 12.

[1360] 2.2 Pharmacokinetic Parameter Results

[1361] BGM0504 injection at doses of 5 mg, 10 mg, and 15 mg was administered once weekly to non-diabetic overweight or obese subjects. Peak plasma BGM0504 levels were reached approximately 24–36 hours after the fourth subcutaneous injection of the target dose. The elimination half-life after the fourth subcutaneous injection of the target dose was approximately 100–114 hours. In non-diabetic overweight or obese subjects, the same dose resulted in C... max There was no significant difference in AUC; the plasma drug concentrations before the 3rd, 4th, and 5th target dose administrations were similar, indicating that BGM0504 can reach steady-state plasma drug concentrations after 4 consecutive target dose administrations in non-diabetic overweight or obese subjects, and C max AUC showed virtually no accumulation; C after the fourth target dose was administered. min,ss Approximately C max,ss 40% of the dose is expected to have a stable weight loss effect with Q1W administration.

[1362] BGM0504 injection was administered once weekly in 5mg, 10mg, and 15mg dose groups. The main PK parameters of BGM0504 after the first and fourth target dose administration are shown in Table 6-3.

[1363] Table 6-3 Main pharmacokinetic parameters of BGM0504 in the plasma of subjects after the first and fourth target doses. Note: 1) Data is from the Phase II clinical trial of BGM0504 injection for weight loss. Except for T in the table, max All values ​​are mean(SD), T max This represents the median value (minimum, maximum).

[1364] 2)t 1 / 2 =ln(2) / Kel, where Kel is the terminal elimination rate constant. Kel is calculated based on the slope of linear regression after logarithmic transformation of the last three points of the terminal elimination phase in the blood drug concentration from 0h before administration to 168h after administration.

[1365] 3) AUC 0-tThe area under the concentration curve from 0 to 168 hours after the first target dose administration;

[1366] 4) The RAUC calculation method is based on the AUC of the fourth target dose administration. 0-168h AUC of the first target dose 0-168h ratio;

[1367] 5) Subject P219 in the 10mg dose group withdrew from the trial after completing the titration period; blood data were missing 12 hours after the first target dose and 4 hours after the fourth target dose in subject P312 of the 15mg dose group; and blood data were missing 24 hours, 48 ​​hours, 120 hours, and 168 hours after the first target dose in subject P336 of the 15mg dose group. These three subjects affected the calculation of PK parameters and were not included in PKPS.

[1368] 6) Subject P335 in the original 15mg dose group experienced gastrointestinal adverse events during the titration period and did not reach the target dose of 15mg. After completing 23 doses at a dose of 10mg, he withdrew from the trial early and was analyzed according to the actual dose.

[1369] 2.3 Pharmacokinetic dose-exposure ratio relationship

[1370] The PowerMode1 model was used to analyze the PK parameter-proportional dose-response relationship. If C max If the 90% CI of the AUC slope includes 1, it indicates that the PK parameter is linearly related to the dose.

[1371] The primary pharmacokinetic parameter C of BGM0504 after the first target dose administration max The point estimate of the slope and its 90% confidence interval are 1.0324 (0.9400, 1.1250); AUC 0-168 The point estimate of the slope and its 90% confidence interval are 1.0300 (0.9390, 1.1210); AUC 0-inf The point estimate of the slope and its 90% confidence interval are 1.0503 (0.9469, 1.1540), as shown in Table 6-4. max AUC 0-168 AUC 0-inf All of them increase with increasing dosage, showing a typical linear relationship.

[1372] The main pharmacokinetic parameter C of BGM0504 after the fourth dose of target dose was reached. max,ss The point estimate of the slope and its 90% confidence interval are 0.9244 (0.8258, 1.0230); AUC 0-168 The point estimate of the slope and its 90% confidence interval are 0.9402 (0.8451, 1.0350); AUC 0-infThe point estimate and its 90% confidence interval are 0.9952 (0.8901, 1.1000), as shown in Table 6-5. C max,ss AUC 0-168 and AUC 0-inf All of them increase with increasing dosage, showing a typical linear relationship.

[1373] Table 6-4 C-levels of plasma BGM0504 in subjects after administration of the investigational drug max AUC 0-168h AUC 0-inf Relationship with dosage (first target dose) - PKPS

[1374] Table 6-5 C-levels of plasma BGM0504 in subjects after administration of the investigational drug max,ss AUC 0-168h AUC 0-inf Relationship with dosage (4th target dose) - PKPS

[1375] 3. Efficacy Analysis

[1376] 3.1 Pharmacodynamic Results

[1377] After titration for 2–6 weeks and continued treatment at the target dose for 4 weeks, the percentage changes in fasting body weight (excluding placebo) from baseline in the BGM0504 injection 5mg, 10mg, and 15mg dose groups were -5.23%, -6.98%, and -9.71%, respectively; and the percentage changes in waist circumference from baseline (excluding placebo) were -3.55%, -4.95%, and -5.69%, respectively. In the BGM0504 injection 5mg, 10mg, and 15mg dose groups, 60.0%, 83.3%, and 96.6% of subjects experienced a weight reduction of ≥5% from baseline, respectively; 0%, 30.0%, and 41.4% of subjects experienced a weight reduction of ≥10% from baseline, respectively; and 0% and 0% of subjects experienced a weight reduction of ≥15% from baseline, respectively.

[1378] Table 6-6 Summary of Pharmacodynamic Results - PDS

[1379] 3.2 Validity Results

[1380] After titration for 2–6 weeks and continued treatment at the target dose for 24 weeks, the primary efficacy endpoint (percentage change in fasting weight from baseline), and key secondary efficacy endpoints (relative change in fasting weight from baseline, waist circumference change from baseline, and the proportion of subjects with weight reductions of ≥5%, ≥10%, ≥15%, and ≥20% from baseline) in the BGM0504 injection 5mg, 10mg, and 15mg groups were all significantly better than those in the placebo group (P < 0.05). At 24 weeks of treatment at the target dose, the secondary efficacy endpoints (systolic and diastolic blood pressure) in the BGM0504 injection 5mg, 10mg, and 15mg groups were significantly reduced, and triglycerides, total cholesterol, LDL cholesterol, fasting insulin, fasting blood glucose, uric acid, and the weight-related quality of life scale score (excluding placebo) all showed varying degrees of improvement compared to baseline. Detailed results are shown in Tables 6-7 and 6-8. Figures 13 and 14 show the comparison of changes in body weight and waist circumference from baseline over time for each dosage group.

[1381] Subject P335 in the original 15mg dose group experienced a gastrointestinal adverse event during the titration period, failing to reach the target dose of 15mg. After completing 23 doses at a 10mg dose, the subject withdrew from the trial early. The efficacy analysis was performed according to the actual grouping of the subject, and the sensitivity analysis of key efficacy indicators was performed on the randomized groups. The results of the PDS-based sensitivity analysis were consistent with the results based on the PDS.

[1382] Table 6-7 Summary of Validity Results - PDS

[1383] Table 6-8 Summary of Other Minor Validity Results - PDS

[1384] 4. Safety / Immunogenicity Evaluation

[1385] Of the 120 subjects enrolled in this study, 120 were included in the SS (Safety Evaluation System) for safety assessment. Among them, 30 were in the 5mg BGM0504 injection group, 31 were in the 10mg BGM0504 injection group, 29 were in the 15mg BGM0504 injection group, and 30 were in the placebo group.

[1386] 4.1 Safety Conclusion

[1387] (1) The majority of adverse events (AEs) occurring at doses of 5mg, 10mg, and 15mg of BGM0504 injection were grade 1-2, and most recovered to "cured" without intervention. The adverse reactions that occurred were mostly gastrointestinal diseases, with a severity of grade 1, mainly occurring during the dose titration stage and the initial stage of reaching the target dose, and gradually became tolerable with continued administration. No hypoglycemic events or other unexpected adverse reactions occurred.

[1388] (2) BGM0504 injection at doses of 5mg, 10mg and 15mg showed good safety and tolerability and can be used as experimental doses in Phase III studies in the field of weight loss treatment.

[1389] 4.2 Immunogenicity C...

Claims

1. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) The minimum titration dose of GLP-1 / GIP peptide administered to the patient is approximately two weeks; and subsequently b) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The titration dose is approximately 50% of the maintenance dose.

2. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) The first titration dose of GLP-1 / GIP peptide was administered to the patient within approximately two weeks; and subsequently b) The patient was given a second titration dose of this GLP-1 / GIP peptide for a minimum of approximately two weeks; and subsequently c) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose is approximately 25% of the maintenance dose, and the second titration dose is approximately 50% of the maintenance dose.

3. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) The first titration dose of GLP-1 / GIP peptide was administered to the patient within approximately two weeks; and subsequently b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for a minimum of approximately two weeks; and subsequently... c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient for a minimum of approximately two weeks; and subsequently d) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose was approximately 16.67% of the maintenance dose, the second titration dose was approximately 33.33% of the maintenance dose, and the third titration dose was approximately 66.67% of the maintenance dose.

4. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) Administer titrated doses of GLP-1 / GIP peptide to the patients for 2–6 weeks; and subsequently b) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The titration dose is approximately 50% of the maintenance dose.

5. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently c) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose is approximately 25% of the maintenance dose, and the second titration dose is approximately 50% of the maintenance dose.

6. A method for treating type 2 diabetes or obesity in patients in need, comprising: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently d) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose was approximately 16.67% of the maintenance dose, the second titration dose was approximately 33.33% of the maintenance dose, and the third titration dose was approximately 66.67% of the maintenance dose.

7. Methods for treating type 2 diabetes or obesity in patients who need them, including: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

8. Methods for treating type 2 diabetes or obesity in patients who need them, including: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for four weeks; and subsequently c) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient.

9. Methods for treating type 2 diabetes or obesity in patients who need them, including: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for four weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently d) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

10. A method for treating type 2 diabetes in combination with sulfonylureas, comprising: a) Administer titrated doses of GLP-1 / GIP peptide to the patients for 2–6 weeks; and subsequently b) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The titration dose is approximately 50% of the maintenance dose.

11. A method for treating type 2 diabetes with a combination of sulfonylureas, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently c) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose is approximately 25% of the maintenance dose, and the second titration dose is approximately 50% of the maintenance dose.

12. A method for treating type 2 diabetes with a combination of sulfonylureas, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently b) Administer the second titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient for 2–6 weeks; and subsequently d) Administer a maintenance dose of this GLP-1 / GIP peptide to the patient; The first titration dose was approximately 16.67% of the maintenance dose, the second titration dose was approximately 33.33% of the maintenance dose, and the third titration dose was approximately 66.67% of the maintenance dose.

13. The method according to claim 10, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

14. The method according to claim 11, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for four weeks; and subsequently c) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient.

15. The method according to claim 12, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently b) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for four weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently d) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

16. A method for treating type 2 diabetes, comprising: a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

17. The method of claim 16, comprising: a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently c) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for a total of four weeks; and subsequently d) Administer a maintenance dose of 10 mg of this GLP-1 / GIP peptide to the patient.

18. The method of claim 16, comprising: a) Administer metformin or metformin combined with sulfonylureas to the patient for 1–12 weeks; and subsequently b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently c) Administer a second titration dose of this GLP-1 / GIP peptide of 5 mg / week to the patient for a total of four weeks; and subsequently d) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for four weeks; and subsequently e) Administer a maintenance dose of 15 mg / week of this GLP-1 / GIP peptide to the patient.

19. The method of claim 16, comprising: a) Administer metformin to the patient at the maximum tolerated dose of metformin for at least 8 weeks; and subsequently b) Administer the first titration dose of GLP-1 / GIP peptide to the patient at 2.5 mg / week for four weeks; and subsequently c) Administer a maintenance dose of 5 mg of this GLP-1 / GIP peptide to the patient.

20. A method for treating obesity, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to patients in need, 2.5 mg / week, for 2–6 weeks; and subsequently b) Administer the second titration dose of GLP-1 / GIP peptide to the patient, 5 mg / week, for 2–6 weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for 2–6 weeks; and subsequently d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patients at 15 mg / week for 2–6 weeks; and subsequently e) Administer a maintenance dose of 20 mg / week of this GLP-1 / GIP peptide to the patient.

21. The method according to claim 20, wherein, include: a) Administer the first titration dose of GLP-1 / GIP peptide to patients in need, 2.5 mg / week, for 2–6 weeks; and subsequently b) Administer the second titration dose of GLP-1 / GIP peptide to the patient, 5 mg / week, for 2–6 weeks; and subsequently c) Administer the third titration dose of this GLP-1 / GIP peptide to the patient at 10 mg / week for 2–6 weeks; and subsequently d) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patients at 15 mg / week for 2–6 weeks; and subsequently e) Administer the fourth titration dose of this GLP-1 / GIP peptide to the patient, 20 mg / week, for 2–6 weeks; and subsequently f) Administer a maintenance dose of 25 mg / week of this GLP-1 / GIP peptide to the patient.

22. The method according to any one of claims 1-21, wherein, The GLP-1 / GIP peptide structure is as follows:

23. The method according to any one of claims 1-22, wherein, GLP-1 / GIP peptide is used in a pharmaceutical composition comprising GLP-1 / GIP peptide, a stabilizer, and a buffer salt.

24. The method of claim 23, wherein, The stabilizer is selected from propylene glycol, mannitol, or glycerol; the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate.

25. The method of claim 23, wherein, The pharmaceutical composition comprises a GLP-1 / GIP peptide, a stabilizer, and a buffer salt, wherein the stabilizer is propylene glycol, the buffer salt is disodium hydrogen phosphate dodecahydrate, and the pH of the pharmaceutical composition is 7.0–8.4; and wherein, in the pharmaceutical composition, the concentration of the GLP-1 / GIP peptide is 5–30 mg / mL, the concentration of the propylene glycol is 10–20 mg / mL, and the concentration of the disodium hydrogen phosphate dodecahydrate is 7–23 mg / mL.

26. The method according to any one of claims 1-25, wherein, The injection is administered subcutaneously once a week.

27. Use of a GLP-1 / GIP peptide or a pharmaceutical composition containing the thereof for: (i) Prevention and / or treatment of hypertension; and (ii) Prepare drugs for the prevention and / or treatment of hypertension.

28. The use as described in claim 27, wherein, The hypertension mentioned refers to hypertension accompanied by being overweight or obesity.

29. The use as described in claim 27 or 28, wherein, The blood pressure of patients with hypertension is not lower than 140 mmHg.

30. The use as described in claim 29, wherein, The blood pressure of the hypertensive patients was 140–179 mmHg.

31. The use as described in claim 27 or 28, wherein, The blood pressure of patients with hypertension is not lower than 160 mmHg.

32. The use as described in claim 31, wherein, The blood pressure of the hypertensive patients was 160–179 mmHg.

33. The use as described in claim 27 or 28, wherein, The blood pressure of patients with hypertension is not lower than 180 mmHg.

34. The use as described in claim 27 or 28, wherein, The hypertensive patients mentioned above have a sitDBP of not less than 90 mmHg.

35. The use as described in claim 34, wherein, The patients with hypertension had a sitDBP of 90–109 mmHg.

36. The use as described in claim 27 or 28, wherein, The patient with hypertension has a sitDBP of not less than 100 mmHg.

37. The use as described in claim 36, wherein, The patients with hypertension had a sitDBP of 100–109 mmHg.

38. The use as described in claim 27 or 28, wherein, The patient with hypertension has a sitDBP of not less than 110 mmHg.

39. The use as described in claim 27 or 28, wherein, The patients with hypertension are classified as having grade I, II, or III hypertension.

40. The use as described in any one of claims 27 or 28, wherein, The patient with hypertension meets any of the following criteria: 1) Sit SBP: 140–179 mmHg or sit SBP not less than 180 mmHg; and / or sit DBP: 90–109 mmHg or sit DBP not less than 110 mmHg; or 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg; or 4) SitSBP: 140–159 mmHg and SitDBP < 90 mmHg; or 5) SitSBP: 160–179 mmHg and SitDBP < 90 mmHg; or 6) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP ≤ 99 mmHg; or 7) sitSBP < 140 mmHg and 100 mmHg ≤ sitDBP ≤ 109 mmHg; or 8) sitSBP ≥ 180 mmHg and sitDBP < 90 mmHg; or 9) sitSBP < 140 mmHg and sitDBP ≥ 110 mmHg.

41. The use as described in claim 27 or 28, wherein, The patients with hypertension meet any of the following criteria: 1) sitSBP: 140–179 mmHg; and / or sitDBP: 90–109 mmHg; or 2) SitSBP: 140–179 mmHg and SitDBP < 90 mmHg; or 3) sitSBP < 140 mmHg and 90 mmHg ≤ sitDBP < 110 mmHg.

42. The use as described in any one of claims 27-41, wherein, The patients who are overweight with hypertension or obese with hypertension have a BMI ≥ 24.0 kg / m². 2 .

43. The use as described in claim 42, wherein, The patients who are overweight with hypertension and / or obese with hypertension have a BMI ≥ 26.0 kg / m². 2 .

44. The use as described in claim 42, wherein, The overweight patients with hypertension and / or obese patients with hypertension exhibit any of the following symptoms: (a)BMI≥30.0kg / m 2 ; (b) BMI ≥ 26.0 kg / m 2 And accompanied by at least one of the following: i. prediabetes (impaired fasting glucose and / or impaired glucose tolerance), non-alcoholic fatty liver, dyslipidemia or one or more of these; ii. weight-bearing joint pain; and iii. obesity causing dyspnea or obstructive sleep apnea syndrome.

45. The use as described in any one of claims 27-44, wherein, The patients with hypertension mentioned are not patients with refractory hypertension, hypertensive emergencies, hypertensive urgency, and / or secondary hypertension.

46. ​​The use as described in any one of claims 27-44, wherein, The patients who are overweight with hypertension and / or obese with hypertension are not patients with type 1 or type 2 diabetes.

47. The use as described in any one of claims 27-44, wherein, The patients who are overweight with hypertension and / or obese with hypertension are not obese due to secondary diseases or medications.

48. The use as described in any one of claims 27-44, wherein, The GLP-1 / GIP peptide or pharmaceutical composition containing it is administered via parenteral administration.

49. The use as described in claim 48, wherein, The GLP-1 / GIP peptide or pharmaceutical composition containing it is administered by injection.

50. The use as described in claim 49, wherein, The GLP-1 / GIP peptide or a pharmaceutical composition containing it is administered once a week.

51. The use as described in claim 50, wherein, The dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5-15 mg per dose.

52. The use as described in claim 51, wherein, The dosage of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg / time, 5 mg / time, 10 mg / time, 12.5 mg / time, or 15 mg / time.

53. The use as described in claim 51, wherein, During the first two weeks, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg. During weeks 3 to 6, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg. During weeks 7–10, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and From week 11 onwards, the single-dose administration of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg; or During weeks 1 to 4, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 2.5 mg. During weeks 5 to 8, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 5.0 mg. During weeks 9–12, a single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 10.0 mg; and In week 13 and thereafter, the single dose of the GLP-1 / GIP peptide or a pharmaceutical composition containing it is 15.0 mg.

54. The use as described in any one of claims 27-53, wherein, The GLP-1 / GIP peptide structure is a compound of formula (I) below, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof; 55. The use as described in any one of claims 27-54, wherein, The pharmaceutical composition contains GLP-1 / GIP peptide, stabilizer, and buffer salt.

56. The use as described in claim 55, wherein, The stabilizer is a polyol; preferably, the stabilizer is selected from at least one of propylene glycol, mannitol, and glycerol; and / or, The buffer salt is selected from at least one of hydrogen phosphate, hydrogen phosphate hydrate, citrate, or citrate hydrate.

57. The use as described in claim 55 or 56, wherein, The concentration of the stabilizer in the pharmaceutical composition is 10–20 mg / mL; and / or The concentration of the buffer salt in the pharmaceutical composition is 7–23 mM.

58. The use as described in claim 55 or 56, wherein, The pH value of the pharmaceutical composition is 6.5 to 8.

5.

59. The use as described in claim 55 or 56, wherein, The pharmaceutical composition comprises 15–30 mg / mL GLP-1 / GIP peptide, 10–20 mg / mL propylene glycol, and 7–23 mM disodium hydrogen phosphate dodecahydrate, and the pH value of the pharmaceutical composition is 7.0–8.4.

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