Use of mazdutide

Abstract

Disclosed is an application of mazdutide. Specifically disclosed is an application of a compound as shown in formula (I) in preparation of a medicine for reducing uric acid level of a patient; mazdutide has a significant uric acid-lowering effect.

Description

[0001] Priority and related applications

[0002] This application claims priority to Chinese patent application 202110711050.0, filed on June 25, 2021, entitled “Application of OXM3”, the entire contents of which, including its appendices, are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicine, and more specifically, to the field of uric acid lowering. This invention relates to the application of mazdutide. Background Technology

[0004] High uric acid is a metabolic disease caused by a disorder in the metabolism of purines, leading to an increase in uric acid in the blood. The daily production and excretion of uric acid in the body are roughly equal. In terms of production, one-third comes from food, and two-thirds are synthesized within the body. Excretion occurs through two main pathways: one-third is excreted through the intestines, and two-thirds through the kidneys. Any disruption in any of these pathways will result in elevated uric acid levels.

[0005] High uric acid levels are related to obesity and diabetes. Obesity is a metabolic disorder that causes hyperinsulinemia and insulin resistance, leading to elevated levels of circulating adipokines. Type 2 diabetes is a disease primarily characterized by glucose metabolism disorders, resulting from insulin resistance and a progressive decline in pancreatic β-cell function, leading to chronic hyperglycemia. Both are related to insulin metabolism, and insulin's metabolism of glucose and fat is influenced by many adipocytes, further enhancing insulin resistance. This ultimately leads to increased uric acid production and reabsorption by the renal tubules, resulting in elevated uric acid levels. Besides obesity and diabetes, high uric acid can cause other complications such as uremia, atherosclerosis, and hypertension. Excessively high uric acid can also trigger other diseases, such as hyperuricemia and gout. Hyperuricemia (as defined in the Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019)) and gout are independent risk factors for chronic kidney disease, hypertension, cardiovascular and cerebrovascular diseases, and diabetes, and are independent predictors of premature death (see Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options[J]. BMC Med, 2017, 15(1): 123).

[0006] GLP-1R / GCGR dual agonist

[0007] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the intestines that has multiple mechanisms aimed at lowering blood sugar and reducing weight, including glucose-dependent insulin secretion, inhibition of glucagon secretion, delay of gastric emptying, and suppression of central appetite.

[0008] Glucagon is a hormone secreted by pancreatic α cells, consisting of a single-chain polypeptide of 29 amino acids. Glucagon exerts its physiological effects by specifically binding to glucagon receptors (GCGRs) on the surface of target cells in the liver and kidneys, activating intracellular adenylate cyclase, increasing intracellular cAMP levels. Glucagon is a catabolism-promoting hormone; short-term injections of glucagon can promote glycogenolysis and gluconeogenesis, leading to elevated blood glucose levels. However, studies have found that long-term glucagon injections activating GCGR can reduce appetite, stimulate fatty acid breakdown, and significantly increase energy expenditure in adipose tissue (see Campbell JE, Drucker DJ. Nature Reviews Endocrinology, 2015, 11(6):329-338).

[0009] Endogenous gastric acid regulator oxyntomodulin (OXM) is a peptide hormone secreted by L cells in the human gut after nutrient ingestion. OXM is a dual agonist of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), combining the anorexia and hypoglycemic effects of GLP-1R agonists with the energy expenditure-increasing effect mediated by GCGR (see Pocai A. Unraveling Oxyntomodulin, GLP1's enigmatic brother. J Endocrinol. 2012; 15:335-346; Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonisteliminates obesity in rodents. Nat Chem Biol. 2009; 5:749-757.), and may be more effective than GLP-1R agonists in treating obesity and lowering blood glucose. Simultaneously, injection of OXM into humans significantly reduced body weight and appetite, and increased energy expenditure. Studies have found that slow infusion of OXM in GLP-1R knockout mice (GLP-1R- / -) resulted in weight loss, but the decrease was smaller compared to wild-type (WT) mice. This suggests that the weight-loss effect of OXM requires simultaneous activation of both GLP-1R and GCGR receptors (Kosinski JR, Huber J, Carrington PE, et al. The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin. Obesity. 2012; 20:1566-1571.). Preclinical data from rodents indicate that GLP-1R / GCGR agonists are more effective at reducing body weight compared to GLP-1R agonists.Similarly, Lao et al. reported that their dual GLP-1R / GCGR agonist showed a greater weight loss effect in diet-induced obese rhesus monkeys (refer to Lao J, Hansen BC, DiMarchi R, et al. Effect of GLP1R / GCGR dual agonist in monkeys. Diabetes. 2013; 62(suppl 1): A257; Ralf Elvert, Andreas W. Herling. Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non-human primate. Diabetes Obes Metab. 2018; 20: 1836-1851.). In animal studies following OXM treatment, activation of the central nervous system's GCGR may have improved systemic glucose metabolism (see Mighiu PI, Yue JT, Filippi BM & Lam TK 2012 Hypothalamic glucagon signaling regulates glucose production. Diabetes 61(Suppl 1)A55. Nauck MA 2012 The design of the liraglutide clinical trial programme. Diabetes, Obesity and Metabolism 14(Suppl 2)4–12.). The hypoglycemic effect of OXM may primarily be achieved through weight reduction, increased insulin secretion, and inhibition of hepatic glucose production by activating the central nervous system's GCGR.

[0010] These data suggest that OXM has the potential to become a well-tolerated anti-obesity drug and a hypoglycemic agent. However, there is currently no research on the effect of OXM on uric acid levels, although some uric acid-lowering drugs are available on the market, such as xanthine oxidase inhibitors (XOIs) and uricosuric drugs. Allopurinol, febuxostat, and benzbromarone are first-line drugs in China. In the United States, only allopurinol is a first-line drug. However, current uric acid-lowering drugs all have efficacy or safety issues, such as the high rate of severe hypersensitivity reactions to allopurinol, the cardiovascular risks of febuxostat, the side effects of benzbromarone, and low rates of achieving target serum uric acid levels. Therefore, current uric acid-lowering drugs used to treat gout cannot meet clinical needs. Therefore, there is an urgent need for a uric acid-lowering agent with strong safety and tolerability, and significant uric acid-lowering effect, especially in obese or diabetic patients. Summary of the Invention

[0011] To address the lack of safe, well-tolerated, and effective uric acid-lowering agents in existing technologies, this invention provides an application of mazdutide, which has a significant uric acid-lowering effect.

[0012] The mazdutide studied in this study is an OXM analogue. Mazdutide is a long-acting synthetic peptide similar to the mammalian gastrin oxyntomodulin (OXM), which utilizes a fatty acyl side chain to prolong its duration of action, allowing for once-weekly dosing. When administered exogenously, OXM can improve glucose tolerance and lead to weight loss (Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2013; 3(3):241-251.). In humans, this hormone is thought to exert its biological effects by activating glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) (refer to Tan TM, Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013; 62(4):1131-1138.). As an OXM analogue, mazdutide's effects are thought to be mediated by the binding and activation of GLP-1R and GCGR.

[0013] This invention provides the use of a compound (mazdutide) of formula (I) or a pharmaceutical salt thereof in the preparation of a drug for lowering uric acid levels in patients;

[0014]

[0015] The compound or its pharmaceutical salt is preferably one of the sole active ingredients or effective components of the drug.

[0016] The drug preferably further comprises hydroxymethylaminomethane and mannitol, and more preferably sucrose or propylene glycol.

[0017] Furthermore, prior to using the compound, the patient's serum uric acid level is preferably greater than 280 μmol / L.

[0018] Alternatively, the patient may have gout, hyperuricemia, uremia, atherosclerosis, hypertension, fatty liver, diabetes, obesity, or be overweight with complications.

[0019] In certain circumstances, patients not only have serum uric acid levels greater than 280 μmol / L, but also suffer from the above-mentioned conditions.

[0020] In a particular implementation, the uric acid level is greater than 420 μmol / L.

[0021] The present invention also provides a method for lowering a patient’s uric acid level, comprising: administering to the patient a compound as shown in formula (I) or a drug as defined above.

[0022] The present invention also provides a method for treating gout, comprising: administering to a patient a compound as shown in formula (I) or a drug as defined above.

[0023] Regarding the dosage of the above-mentioned drug, the drug is administered once a week at a dose of 1.0 to 10 mg; preferably, the drug is administered once a week at a dose of about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg.

[0024] In one embodiment, the drug is administered about once a week at least once every four weeks for a minimum of about four weeks, and after the escalation dose, at least one maintenance dose is administered about once a week for a minimum of about four weeks; wherein the escalation dose is selected from about 1.0 mg and about 2.0 mg; wherein the maintenance dose is selected from about 3.0 mg;

[0025] In one embodiment, the drug is administered about once a week at least once a week for a minimum of about four weeks, and after the escalation dose, at least one maintenance dose is administered about once a week for a minimum of about four weeks; wherein the escalation dose is selected from about 1.5 mg and about 3.0 mg; wherein the maintenance dose is selected from about 4.5 mg;

[0026] In one embodiment, the drug is administered about once a week at least once every four weeks for a minimum of about four weeks, and after the escalation dose, at least one maintenance dose is administered about once a week for a minimum of about four weeks; wherein the escalation dose is selected from about 2.0 mg and about 4.0 mg; wherein the maintenance dose is selected from about 6.0 mg.

[0027] In another aspect, the present invention provides a pharmaceutical composition for lowering uric acid levels in patients, comprising a compound as shown in formula (I) or a pharmaceutical salt thereof, and at least one pharmaceutically acceptable carrier.

[0028] Previous studies have shown that mazdutide has good safety and tolerability in single- or multiple-dose escalation trials in healthy individuals, and has also been found to lower uric acid levels in obese and diabetic patients.

[0029] A single-dose study in healthy subjects (I8P-MC-OXAA) has been completed: a single-center, double-blind, placebo-controlled randomized controlled study of mazdutide (SAD) with escalation doses of 0.03 mg, 0.1 mg, 0.3 mg, 1.0 mg, 2.5 mg, and 5.0 mg. The primary assessment was the safety, tolerability, and pharmacokinetic / potential disease (PK / PD) of mazdutide in healthy subjects. Results showed that dose escalation to 2.5 mg was well tolerated by all subjects, but 6 subjects experienced gastrointestinal adverse events (primarily nausea and vomiting) when escalating to 5 mg. Therefore, 2.5 mg can be considered the maximum tolerated dose (MTD) for a single dose.

[0030] As used in this article, "incremental dose" refers to a dose smaller than the highest effective dose required by the patient.

[0031] As used in this article, "maintenance dose" refers to the dose that is the highest effective dose required by the patient.

[0032] As used herein, "medicinal salt" is familiar to those skilled in the art. In one implementation, the medicinal salt is trifluoroacetate.

[0033] As used herein, "patient" refers to a mammal that requires treatment for a condition or ailment. In one implementation, a patient is a person suffering from a disease or ailment from which they would benefit from treatment with mazdutide.

[0034] As used herein, when associated with numbers, the term “about” can mean, for example, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5%.

[0035] The amino acids used in this article are those well-known to those skilled in the art, such as: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M), Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), Asp (D), Glu (E), Lys (K), Arg (R), and His (H).

[0036] Preliminary results from studies on overweight or obese patients show that mazdutide can lower uric acid levels in these patients (see details). Figure 2 Preliminary results from a study of patients with type 2 diabetes showed that mazdutide can also lower uric acid levels in this population (see Table 6 for details). Figure 3 ).

[0037] The positive and progressive effects of this invention are as follows:

[0038] Mazdutide has a significant effect on lowering uric acid, reducing uric acid levels in patients with high uric acid by more than 80 μmol / L. Attached Figure Description

[0039] Figure 1 For the purpose of studying experimental design diagrams.

[0040] Figure 2 This represents the change in uric acid relative to baseline after drug administration in overweight / obese individuals.

[0041] Figure 3 This represents the change in uric acid relative to baseline after drug administration in diabetic patients. Detailed Implementation

[0042] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0043] Example 1: Study of drugs and patients

[0044] The structure of Mazdutide is shown in equation (Ⅰ).

[0045]

[0046] Its sequence is shown in SEQ ID NO:1, and the specific sequence is as follows:

[0047] His-Xaa-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly; where Xaa is Aib (2-aminoisobutyric acid); and Lys at position 20 is represented by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the Lys side chain, thus being chemically modified, and the carboxyl group of the C-terminal Gly is amidated to a C-terminal primary amide.

[0048] 1.1 The physical and chemical characteristics of the studied drugs are shown in Table 1:

[0049] Table 1

[0050]

[0051] 1.2 Research drug specifications and manufacturers

[0052] Mazdutide is a formulation for injection, consisting of 2 mg mazdutide and the inactive ingredients tris(hydroxymethyl)aminomethane, mannitol, and sucrose. The contents of the vial are reconstituted with sterile water for injection to obtain a clear solution of mazdutide. Alternatively, it can be composed of mazdutide and the inactive ingredients tris(hydroxymethyl)aminomethane, mannitol, and propylene glycol; the preparation method is described in PCT / CN2022 / 089742.

[0053] The placebo is a mazdutide mimic, consisting of the inactive ingredient tris(hydroxymethyl)aminomethane, mannitol, and sucrose. The contents of the vial are reconstituted with sterile water for injection to obtain a clear solution containing the inactive ingredient.

[0054] This study used a formulation strength of 2 mg / vial, and the placebo strength was matched with the formulation strength.

[0055] Dulaglutide: 1.5mg / vial, manufactured by Vetter Pharma-Fertigung GmbH & Co. KG.

[0056] 1.3 Storage

[0057] Both the formulation and the placebo should be stored under refrigeration (2°C to 8°C).

[0058] 1.4 Administration method

[0059] Both mazdutide and placebo are administered subcutaneously once a week. Each dose must be prepared and administered by the study nurse. For details on preparation and use of the study drug, please refer to the drug instructions.

[0060] 1.5 Selection Criteria

[0061] I. Obese or overweight subjects must meet all of the following criteria to be eligible for inclusion in this study:

[0062] 1. Age 18 to 75 years old (inclusive), male or female;

[0063] 2. Obese individuals: BMI ≥ 28.0 kg / m² 2 Or overweight: 24 ≤ BMI < 28.0 kg / m² 2 And accompanied by at least one of the following: i. strong appetite, unbearable hunger before meals, and large food intake at each meal; ii. one or more of the following: prediabetes (impaired fasting glucose and / or impaired glucose tolerance), hypertension, dyslipidemia (see Appendix 4 for reference standards), and fatty liver (within 6 months prior to screening); iii. pain in weight-bearing joints; iv. difficulty breathing due to obesity or obstructive sleep apnea syndrome;

[0064] 3. Screening requires at least 12 weeks of diet and exercise control with a weight change of less than 5%.

[0065] Percentage change in weight = |(Weight at screening - Weight in the 12 weeks prior to screening) / Weight at screening| * 100%

[0066] 4. Be able to understand the procedures and methods of this study, be willing to strictly abide by the clinical trial protocol to complete this trial, and voluntarily sign the informed consent form.

[0067] II. To be eligible for inclusion in this study, diabetic participants must meet the following criteria:

[0068] 1. Diagnosed with type 2 diabetes for at least 6 months according to the 1999 WHO criteria.

[0069] 2. When signing the informed consent form, the applicant must be a male or female aged 18 to 75.

[0070] 3. Patients with type 2 diabetes whose blood glucose was still poorly controlled within the two months prior to screening, despite lifestyle interventions or treatment with a stable dose of metformin (≥1000 mg / day or maximum tolerated dose).

[0071] 4. During screening, the local laboratory test results showed that 7.5% ≤ HbA1c ≤ 11.0%.

[0072] 5. Body Mass Index (BMI) ≤ 20 ≤ 35 kg / m² 2 (BMI = weight (kg) / height (m))2 ).

[0073] 6. During the research period, the original diet and exercise lifestyle can be maintained stably.

[0074] 7. Subjects voluntarily signed the informed consent form and agreed to strictly follow the requirements of this protocol.

[0075] 1.6 Exclusion Criteria

[0076] I. Obese or overweight participants who meet any of the following criteria will be excluded from this study:

[0077] 1. Researchers suspect that the subject may be allergic to the study drug or ingredient, or that the subject has an allergic constitution;

[0078] 2. Use of any of the following medications or treatments prior to screening:

[0079] 1) Previous use of GLP-1 receptor (GLP-1R) agonists or GLP-1R / GCGR agonists;

[0080] 2) Screening for medications that affect weight used within the past 3 months, including: systemic corticosteroids (intravenous, oral, or intra-articular administration), metformin, SGLT2 inhibitors, thiazolidinediones (TZDs), tricyclic antidepressants, medications for mental illnesses, or sedatives (such as imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium salts, etc.);

[0081] 3) Those who have used Chinese herbal medicines or health products that affect their weight within the past 3 months will be screened.

[0082] 4) Screening for those who have used or are currently using weight loss drugs within the past 3 months, such as: sibutramine hydrochloride, orlistat, phenylbutazone, phenylpropanolamine, chlorpheniramine, phentermine, amphetamine, lorcaserin, phentermine / topiramate combination, naltrexone / bupropion combination, etc.

[0083] 5) Participated in other clinical trials (and received investigational drug treatment) within 3 months prior to screening;

[0084] 3. History or evidence of any of the following diseases prior to screening:

[0085] 1) Diagnosed with diabetes according to WHO 1999 criteria;

[0086] 2) At the time of screening, fasting venous blood glucose ≥7.0mmol / L or venous blood glucose ≥11.1mmol / L two hours after the 75g oral glucose tolerance test (OGTT) (subjects with fasting blood glucose between 6.1-7.0mmol / L at the time of screening need to have their venous blood glucose collected two hours after the OGTT glucose load for confirmation);

[0087] 3) Patients with a history of retinopathy or at the time of screening;

[0088] 4) Obesity caused by secondary diseases or drugs, 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.

[0089] 5) Has previously undergone weight loss surgery or acupuncture for weight loss within one year prior to screening;

[0090] 6) History of depression; or history of severe mental illness, such as schizophrenia, bipolar disorder, etc.

[0091] 7) Hypertension that is not stably controlled at the time of screening after at least 4 weeks of antihypertensive drug treatment is defined as: systolic blood pressure >140 mmHg and / or diastolic blood pressure >100 mmHg;

[0092] 8) During screening, systolic blood pressure <90 mmHg and / or diastolic blood pressure <50 mmHg;

[0093] 9) History of malignant tumors at the time of screening (excluding cured basal cell carcinoma of the skin and cervical carcinoma in situ);

[0094] 10) The patient has heart-related diseases (such as angina pectoris, myocardial infarction, cardiomyopathy, acute and chronic heart failure, etc.) at the time of screening;

[0095] 11) Had a hemorrhagic or ischemic stroke or transient ischemic attack within 6 months prior to screening.

[0096] 12) History of thyroid C-cell carcinoma, MEN (multiple endocrine neoplasia) 2A or 2B syndrome, or related family history at the time of screening;

[0097] 13) History of acute or chronic pancreatitis, gallbladder disease, or pancreatic injury at the time of screening;

[0098] 14) Chronic gastrointestinal diseases or systemic diseases that may affect gastrointestinal motility during screening, or use of drugs that may alter gastrointestinal motility, appetite, or absorption within 3 months prior to screening;

[0099] 15) There are limb deformities or defects, making it impossible to accurately determine indicators such as height and weight;

[0100] 16) Individuals who have undergone major or medium-sized surgery, severe trauma, or severe infection within one month prior to screening, and whom the researchers deem unsuitable to participate in this study;

[0101] 17) Has a history of suicidal tendencies or suicidal behavior;

[0102] 18) Any scheduled surgery during the trial, except for outpatient surgeries that the investigators determine will have no impact on the safety of the subjects or the trial results;

[0103] 19) Subjects who tested positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or syphilis antibody at the time of screening;

[0104] 20) History of alcohol abuse within one month prior to screening. Average weekly alcohol intake exceeding 21 units for men and 14 units for women, or unwillingness to abstain from alcohol consumption in the 24 hours prior to administration and throughout the study period (1 unit = 360 ml beer, or 150 ml red wine, or 45 ml spirits / baijiu);

[0105] 21) Positive urine screening results for drug and narcotics abuse during screening;

[0106] 4. Any laboratory test result meets the following criteria (if there is a clear reason for retesting during screening, retesting can be performed within one week, and the researcher must record the reason for retesting):

[0107] 1) Serum calcitonin ≥15 ng / L at screening;

[0108] 2) At the screening stage, alanine aminotransferase (ALT) ≥ 2.0 × ULN and / or aspartate aminotransferase (AST) ≥ 2.0 × ULN and / or total bilirubin ≥ 1.0 × ULN and / or alkaline phosphatase ≥ 2.0 × ULN;

[0109] 3) During screening, eGFR < 60 mL / min / 1.73 m 2 The CKD-EPI formula was used to estimate eGFR (see Table 2 below): CKD-EPI formula estimation: eGFR=a×[(serum creatinine (μmol / L) / b)] c ×(0.993) 年龄 :

[0110] Table 2

[0111]

[0112] 4) Abnormal thyroid function (FT3, FT4, or TSH) at the time of screening;

[0113] 5) Fasting triglycerides ≥ 5.64 mmol / L (500 mg / dL) at screening;

[0114] 6) At the time of screening, serum amylase or lipase > 2.0 × ULN;

[0115] 7) The international normalized ratio (INR) of prothrombin time was greater than the upper limit of the normal range during screening;

[0116] 5. During screening, a 12-lead electrocardiogram shows a heart rate <50 bpm or >90 bpm;

[0117] 6. Clinically significant 12-lead electrocardiogram (ECG) abnormalities at screening: second- or third-degree atrioventricular block without pacemaker implantation, long QT syndrome or QTcF > 450 ms (QTc Fridericia formula: QTcF = QT / (RR^0.33)), PR interval < 120 ms or PR interval > 220 ms, QRS > 120 ms, left or right bundle branch block, Wolff-Parkinson-White syndrome or serious arrhythmia requiring treatment;

[0118] 7. Pregnant or breastfeeding women, men or women of childbearing age who do not wish to use contraception throughout the study period;

[0119] 8. Those who have donated blood and / or lost blood ≥400mL within the 3 months prior to screening, or have donated bone marrow, or have hemoglobinopathies, hemolytic anemia, sickle cell anemia, or hemoglobin <110g / L (male) or <100g / L (female);

[0120] 9. The researchers believe that the subject has any other factors that may affect the efficacy or safety evaluation of this study and is therefore unsuitable to participate in this study.

[0121] II. Students with diabetes who meet any of the following criteria will be excluded from this study:

[0122] 1. Type 1 diabetes, special types of diabetes, or gestational diabetes.

[0123] 2. Had ketoacidosis or lactic acidosis in the 6 months prior to screening.

[0124] 3. Patients with a history of severe hypoglycemia within the previous 6 months were defined as those experiencing neurogenic hypoglycemia symptoms and requiring assistance from others for recovery, or those who were previously completely unaware of hypoglycemia or had insufficient understanding of its symptoms. Patients whom researchers believed could not communicate and understand hypoglycemic symptoms and appropriate treatment should also be excluded from the study.

[0125] 4. Candidates must have experienced any of the following within the past 6 months: acute myocardial infarction, unstable angina, coronary artery bypass grafting, percutaneous coronary intervention (excluding diagnostic angiography), transient ischemic attack (TIA), cerebrovascular accident, or acute or chronic heart failure.

[0126] 5. At the time of screening, researchers believed that abnormal 12-lead electrocardiograms (e.g., QTcF > 450 ms, PR interval < 120 ms, or PR interval > 220 ms, second- and third-degree atrioventricular block, ventricular conduction delay i.e., QRS > 120 ms, right bundle branch block, left bundle branch block, Wolff-Parkinson-White syndrome) would increase the risk to the subjects or may cause confusion in the analysis of electrocardiogram data (QT). Or, the subjects were taking any medications that may affect the QT interval of the heart (e.g., antiarrhythmic drugs of class IA and III, cisapride, macrolide antibiotics and psychotropic drugs (phenothiazines (methimazole, chlorpromazine, misopyridazine), butyrophenones (fluperidone, haloperidol and loperamide)).

[0127] 6. Previously diagnosed with long QT syndrome.

[0128] 7. Blood pressure that is not stably controlled at the time of screening: systolic blood pressure >140 mmHg or <90 mmHg, diastolic blood pressure >90 mmHg or <50 mmHg.

[0129] 8. Heart rate <50 bpm or >90 bpm during screening.

[0130] 9. Screening for patients with active or untreated malignant tumors within the past 5 years, or those in clinical remission of malignant tumors (excluding patients with basal cell carcinoma and squamous cell carcinoma of the skin, cervical carcinoma in situ, and papillary thyroid carcinoma without recurrence after surgery).

[0131] 10. A history of acute or chronic pancreatitis, or a serum lipase / amylase ratio twice the upper limit of normal at the time of screening, or fasting triglycerides > 5.65 mmol / L (500 mg / dL). If the patient is undergoing lipid-lowering therapy, the medication dose must be stable for 30 days prior to screening.

[0132] 11. Liver disease with clinical symptoms at the time of screening, acute or chronic hepatitis, or transaminase (ALT and AST) and alkaline phosphatase (ALP) > 2 times the upper limit of normal, and total bilirubin higher than the upper limit of normal at the time of screening.

[0133] 12. Calcitonin ≥15ng / L during screening.

[0134] 13. At screening, the glomerular filtration rate (eGFR) was <60 mL / min / 1.73 m. 2 The modified MDRD formula was used to estimate eGFR: eGFR = 175 × [(serum creatinine (μmol / L) / 88.4)] - 1.234 × [age (years)] - 0.179 × 0.79 (female) or × 1 (male).

[0135] 14. Individuals with a history of mental illness or those identified at the time of screening are deemed unsuitable for participation in this study by the researchers.

[0136] 15. Diagnosis of gastroparesis or any form of obesity surgery, or gastric emptying abnormality that the investigator considers clinically significant.

[0137] 16. Known history of regular drug abuse.

[0138] 17. Positive HIV antibody and syphilis antibody at HIV infection and / or screening.

[0139] 18. Has a history of hepatitis B and / or was positive for hepatitis B surface antigen or hepatitis C (HCV) antibody at screening.

[0140] 19. History of Gilbert's syndrome.

[0141] 20. During screening, the INR is greater than the upper limit of the normal value.

[0142] 21. History of medullary C-cell thyroid carcinoma, MEN (multiple endocrine neoplasia) 2A or 2B syndrome, or related family history.

[0143] 22. The patient has a previous confirmed diagnosis of autonomic neuropathy, presenting with: urinary retention, resting tachycardia, orthostatic hypotension, and diabetic diarrhea.

[0144] 23. Screening for significant weight changes within the three months prior to screening, with a percentage change (>5%).

[0145] 24. Those who have donated blood ≥400mL within the three months prior to screening, or have experienced excessive blood loss, or have undergone bone marrow transplantation, or have hemoglobinopathies, hemolytic anemia, sickle cell anemia, or hemoglobin <110g / L (male) or <100g / L (female).

[0146] 25. Hyperthyroidism or hypothyroidism confirmed by clinical evaluation and / or abnormal TSH levels, which researchers believe will increase patient risk.

[0147] 26. Use of hypoglycemic drugs other than metformin within 2 months prior to screening.

[0148] 27. Use of weight-reducing drugs, such as liraglutide, orlistat, sibutramine hydrochloride, phenylpropanolamine, chlorpheniramine, phenbutylamine, lorcaserin hydrochloride, phentermine, phentermine / topiramate, amphetamine, naltrexone / bupropion, within 3 months prior to screening or planned for use during the trial.

[0149] 28. Long-term use of glucocorticoids within 1 year prior to screening (cumulative or continuous use > 2 weeks), or use of glucocorticoids within 4 weeks prior to screening (excluding topical, intraocular, intranasal, intra-articular, and inhaled administration).

[0150] 29. Central nervous system stimulants (e.g., methylphenidate hydrochloride) were being used during screening, except for caffeinated beverages.

[0151] 30. Known allergy to the test drug or its components.

[0152] 31. Participated in any clinical trial of a drug or medical device within 3 months prior to screening (defined as entering the randomization phase).

[0153] 32. Female participants who are sterilized or postmenopausal and have the potential to become pregnant, who do not wish to inform their sexual partners of their participation in this clinical study and do not use effective contraception during the study period. Male participants who do not wish to inform their female sexual partners of their participation in this clinical study and do not use effective contraception during the study period.

[0154] 33. Subjects who are pregnant or breastfeeding, or who plan to become pregnant or breastfeed during the study period.

[0155] 34. Any clinically significant laboratory abnormalities that the researchers believe may interfere with the interpretation of the efficacy and safety data in this study.

[0156] 35. The researcher believes that the subject has any other factors that may affect the assessment of subject cooperation, efficacy or safety in this study, such as the presence of mental illness.

[0157] 36. Men who consumed more than 21 units of alcohol per week and women who consumed more than 14 units per week, or who were unwilling to stop drinking alcohol in the 24 hours prior to administration and throughout the study period (1 unit = 360 ml beer, or 150 ml wine, or 45 ml spirits / drinks).

[0158] Example 2 Overall Study Design

[0159] I. For obesity or overweight

[0160] This study plans to enroll 36 overweight or obese patients who have achieved a weight change of less than 5% after at least 12 weeks of diet and exercise control. The double-blind treatment-phase study is divided into three cohorts: Cohort 1 (n=12), Cohort 2 (n=12), and Cohort 3 (n=12). Subjects in each cohort are randomly assigned in a 2:1 ratio to either the mazdutide treatment group (n=8) or the placebo group (n=4). The subcutaneous injection regimens for mazdutide or placebo in Cohort 1, Cohort 2, and Cohort 3 are described below (e.g., ...). Figure 1 As shown):

[0161] Cohort 1: Subjects started with a dose of 1.0 mg once weekly for 4 weeks. If the subjects tolerated the medication well*, the dose was increased to 2.0 mg once weekly for 4 weeks. Tolerance was then observed again. If the subjects tolerated the medication well*, the dose was increased to 3.0 mg once weekly for 4 weeks (increasing by 1 mg every 4 weeks to the target dose).

[0162] Cohort 2: Subjects started with a dose of 1.5 mg once a week for 4 weeks. If the subjects tolerated the medication well*, the dose was increased to 3.0 mg once a week for 4 weeks. Subjects were then observed for tolerance again. If the subjects tolerated the medication well*, the dose was increased to 4.5 mg once a week for 4 weeks (increasing by 1.5 mg every 4 weeks to the target dose).

[0163] If subjects in cohort 2 experience intolerance at 3.0 mg or 4.5 mg, the dosage should be adjusted according to the standards in Table 3.

[0164] Table 3. Dosage and Adjustment Reference Table During Climbing

[0165]

[0166]

[0167] Remark:

[0168] *If subjects in Cohort 2 cannot tolerate 3 mg during the dose escalation process, the dose should be reduced to 2.25 mg after a one-week discontinuation period as in Cohort 2 (backup 1), and subsequent dose escalation should be carried out according to Cohort 2 (backup 1).

[0169] #If a subject in Cohort 2 cannot tolerate 4.5 mg during the escalation process, the dose should be reduced to 3.75 mg after one week of discontinuation as in Cohort 2, and maintained at this dose until the end of the trial;

[0170] Subjects in Cohort 3 should not be given medication until subjects in Cohort 2 have completed a 4-week tolerance study with 1.5 mg. If subjects in Cohort 2 cannot tolerate 1.5 mg, subjects in Cohort 3 will not be explored for 2.0 mg or higher doses.

[0171] Cohort 3: Subjects must have completed 4 weeks of 1.5 mg dosing with good tolerability in Cohort 2 before starting this cohort. If Cohort 2 subjects cannot tolerate 1.5 mg, Cohort 3 subjects will not be explored for 2.0 mg or higher doses. The starting dose for this cohort is 2.0 mg once weekly for 4 weeks. If the subjects tolerate it well*, the dose is increased to 4.0 mg once weekly for 4 weeks. Tolerance is then observed again. If tolerability is good*, the dose is increased to 6.0 mg once weekly for 4 weeks (increasing by 2 mg every 4 weeks to the target dose).

[0172] II. Regarding diabetes

[0173] This study planned to enroll 42 patients with type 2 diabetes whose glycated hemoglobin (HbA1c) control remained uncontrolled after at least 2 months of lifestyle intervention or stable-dose metformin (≥1000 mg / day or maximum tolerated dose). The study was divided into three cohorts: Cohort 1 (n=14), Cohort 2 (n=14), and Cohort 3 (n=14). Each cohort was randomly assigned in an 8:4:2 ratio to the mazdutide treatment group (n=8), the placebo group (n=4), and the Dulaglutide 1.5 mg treatment group (n=2). In Cohorts 1, 2, and 3, the active control drug Dulaglutide was administered at a dose of 1.5 mg once every 12 weeks (QW) for 12 weeks. The dosing regimens for mazdutide and placebo are described below:

[0174] Cohort 1: Subjects started with a dose of 1.0 mg once weekly for 4 weeks. If well tolerated, the dose was increased to 2.0 mg once weekly for another 4 weeks. Tolerance was then assessed again. If well tolerated, the dose was increased to 3.0 mg once weekly for another 4 weeks (increasing by 1 mg every 4 weeks to the target dose).

[0175] Cohort 2: Subjects started with a dose of 1.5 mg once weekly for 4 weeks. If well tolerated, the dose was increased to 3.0 mg once weekly for another 4 weeks. Tolerance was then observed again. If the 3.0 mg dose was poorly tolerated but met the tolerance criteria, the subject would proceed to the next dose trial in Cohort 2 (backup 1). If well tolerated, the dose was increased to 4.5 mg once weekly for another 4 weeks. If the 4.5 mg dose was poorly tolerated but met the tolerance criteria, the subject would proceed to the next dose trial in Cohort 2 (backup 2). (The dose was increased by 1.5 mg every 4 weeks until the target dose was reached).

[0176] Cohort 2 (backup 1): If a subject could not tolerate the 3.0 mg dose, the drug was discontinued for 1 week and the dose was reduced to 2.25 mg. After 2 weeks of continuous administration, the subject's tolerance was observed again. If the subject was well tolerated, the dose was increased to 3.0 mg and administered for 4 weeks.

[0177] Backup 2: If a subject could not tolerate the 4.5 mg dose, the drug was discontinued for 1 week and the dose was reduced to 3.75 mg, and continued for 2 weeks until the end of the trial.

[0178] Cohort 3: Subjects must begin this cohort only after Cohort 2 subjects have completed a 4-week tolerance study with 1.5 mg. If Cohort 2 subjects cannot tolerate 1.5 mg, Cohort 3 subjects will not be explored at doses of 2.0 mg or higher. The starting dose for this cohort is 2.0 mg once weekly for 4 weeks. If well tolerated, the dose is increased to 4.0 mg once weekly for another 4 weeks. Tolerance is then observed again. If well tolerated, the dose is increased to 6.0 mg once weekly for another 4 weeks (increasing by 2 mg every 4 weeks to the target dose).

[0179] Example 3 Safety Study and Assessment

[0180] For obese or overweight patients: As of March 15, 2021, a total of 36 patients were enrolled and included in the analysis. The overall safety and tolerability of this study were good. No SAEs, dose-termination-related AEs, hypoglycemic events, severe adverse events, acute pancreatitis, or subjects discontinuing treatment or withdrawing from the study due to adverse events occurred. No injection site reactions were observed; only two subjects in cohort 1 experienced mild urticaria. Gastrointestinal adverse reactions were the most common (15 / 24 cases, 62.5%), with the highest incidence being decreased appetite (29.2%), diarrhea (25%), and nausea (16.7%). The higher incidence of gastrointestinal reactions compared to placebo is consistent with the drug's mechanism of action. Furthermore, the mean heart rate was increased in the mazdutide group compared to the placebo group, but no serious cardiac-related adverse events were observed.

[0181] For diabetic patients: As of April 26, 2021, a total of 42 patients were enrolled and included in the analysis. The overall safety and tolerability of the subjects in this study were good, with no adverse events leading to dose escalation termination, and no acute pancreatitis, severe hypoglycemia, allergic reactions, or injection site adverse reactions.

[0182] Example 4: The uric acid-lowering effect of mazdutide based on clinical safety studies.

[0183] 1. For obese subjects: As of March 15, 2021, a total of 36 subjects were enrolled and included in the analysis. Table 4 shows the uric acid levels of each group before drug administration, i.e., baseline values.

[0184] Table 4

[0185]

[0186] Figure 2 The mean change in each group after drug administration relative to the pre-administration (baseline) value is calculated by... Figure 2 It can be seen that after administration, cohorts 1, 2, and 3 all showed a significant reduction in uric acid levels, which was significantly better than that of the placebo group.

[0187] 2. For diabetic subjects: As of April 26, 2021, a total of 42 subjects were enrolled, and 36 subjects were included in the analysis. Table 5 shows the uric acid levels of each group before drug administration, i.e., baseline values.

[0188] Table 5

[0189]

[0190] Table 6 shows the mean changes in each group relative to baseline on day 85 after drug administration. Figure 3 It can be concluded that cohorts 1, 2, and 3 all had significantly lower uric acid levels than the placebo group and the dulaglutide control group, with the reduction being most significant in cohorts 1 and 3.

[0191] Table 6

[0192]

Claims

1. The use of a compound of formula (I) or a pharmaceutical salt thereof in the preparation of a medicament for lowering uric acid levels in patients. Equation (I) The patients in question have type 2 diabetes, are obese, or are overweight.

2. The application as described in claim 1, characterized in that, The compound or its pharmaceutical salt is the sole active ingredient or one of the effective ingredients of the drug.

3. The application as described in claim 1, characterized in that, The drug also contains hydroxymethylaminomethane and mannitol.

4. The application as described in claim 1, characterized in that, The uric acid level is greater than 280 μmol / L; where the uric acid level refers to the uric acid level in the patient's serum before the reduction.

5. The application as described in claim 4, characterized in that, The uric acid level is greater than 420 μmol / L.

6. The application as described in claim 1, characterized in that, The drug also contains sucrose or propylene glycol.

7. The application as described in claim 1, characterized in that, The compound or its pharmaceutical salt is administered once weekly at a dose of 1.0 to 10 mg.

8. The application as described in claim 7, characterized in that, The compound or its pharmaceutical salts are administered once weekly at doses of about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, or 10 mg.

9. The application as described in claim 8, characterized in that, The compound or its pharmaceutical salt is administered once weekly at a dose of about 2.0 mg, 3.0 mg, 4.0 mg, 6 mg or 9 mg.

10. The application as described in any one of claims 1-9, characterized in that, The compound or its pharmaceutical salt is administered once weekly at least once for a minimum of four weeks with an escalating dose and at least once weekly for a minimum of four weeks following the escalating dose; wherein the escalating dose is selected from about 1.0 mg and about 2.0 mg; wherein the maintenance dose is about 3.0 mg; or The compound or its pharmaceutical salt is administered once weekly at least once for a minimum of four weeks with an escalating dose and at least once weekly for a minimum of four weeks following the escalating dose; wherein the escalating dose is selected from about 1.5 mg and about 3.0 mg; wherein the maintenance dose is about 4.5 mg; or The compound or its pharmaceutical salt is administered once weekly for at least four weeks at an escalating dose and once weekly for at least four weeks at a maintenance dose; wherein the escalating dose is selected from about 2.0 mg and about 4.0 mg; and wherein the maintenance dose is about 6.0 mg.

11. The application as described in claim 10, characterized in that, The compound or its pharmaceutical salt is administered once weekly for at least four weeks at an escalating dose and once weekly for at least four weeks at a maintenance dose; wherein the escalating dose is selected from about 2.0 mg and about 4.0 mg; and wherein the maintenance dose is about 6.0 mg.

12. The application as described in claim 10, characterized in that, The compound or its pharmaceutical salt was administered at an escalating dose of 2.0 mg once weekly for four weeks, followed by a maintenance dose of 4.0 mg once weekly for a minimum of four weeks.

13. The application as described in claim 10, characterized in that, The compound or its pharmaceutical salt was administered at an escalating dose of 4.0 mg once weekly for four weeks, followed by a maintenance dose of 6.0 mg once weekly for a minimum of four weeks.

14. The application as described in claim 10, characterized in that, The compound or its pharmaceutical salt was administered at an escalating dose of 2.0 mg once weekly for four weeks, followed by an escalating dose of 4.0 mg once weekly for four weeks, and then a maintenance dose of 6.0 mg once weekly for a minimum of four weeks.

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