WO2022268174A1 - Mazdutide的应用 - Google Patents

Mazdutide的应用 Download PDF

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WO2022268174A1
WO2022268174A1 PCT/CN2022/100878 CN2022100878W WO2022268174A1 WO 2022268174 A1 WO2022268174 A1 WO 2022268174A1 CN 2022100878 W CN2022100878 W CN 2022100878W WO 2022268174 A1 WO2022268174 A1 WO 2022268174A1
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dose
week
drug
administered
uric acid
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French (fr)
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安培
邓焕
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Innovent Biologics Suzhou Co Ltd
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Innovent Biologics Suzhou Co Ltd
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Priority to CA3224043A priority Critical patent/CA3224043A1/en
Priority to AU2022298841A priority patent/AU2022298841A1/en
Priority to CN202280045316.5A priority patent/CN117597135A/zh
Priority to JP2023579334A priority patent/JP2024524273A/ja
Priority to KR1020247003005A priority patent/KR20240027053A/ko
Priority to US18/573,602 priority patent/US20240293513A1/en
Priority to EP22827666.3A priority patent/EP4360641A4/en
Publication of WO2022268174A1 publication Critical patent/WO2022268174A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the invention belongs to the field of medicine, more specifically, the invention belongs to the field of reducing uric acid, and the invention relates to an application of mazdutide.
  • High uric acid is a metabolic disease caused by a substance called purine in the human body due to metabolic disorders, resulting in an increase in uric acid in the blood.
  • the daily production and excretion of uric acid in the body are approximately equal.
  • three points One is from food, two thirds are synthesized in the body, one third is excreted from the intestines, and two thirds are excreted from the kidneys. As long as there is any problem in any of the above-mentioned ways, it will cause uric acid to rise.
  • High uric acid has a certain relationship with obesity and diabetes.
  • Obesity is a state of metabolic disorder, which will cause the body to be accompanied by hyperinsulinemia and insulin resistance, resulting in an increase in the level of adipocytokines circulating in the human body; type 2 diabetes is a disease mainly characterized by blood glucose metabolism disorders. It is characterized by chronic hyperglycemia caused by insulin resistance and progressive decline in pancreatic beta-cell function. Both are related to insulin metabolism, and the metabolism of insulin on glucose and fat is affected by many fat cells, further strengthening insulin resistance, and finally leading to increased production of uric acid and increased reabsorption of uric acid by renal tubules, resulting in elevated uric acid.
  • Hyperuricemia (“Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019)" pointed out that no matter whether male or female, blood uric acid level exceeds 420 ⁇ mol/L twice on different days, which is called hyperuricemia) and gout is chronic Independent risk factors for diseases such as kidney disease, hypertension, cardiovascular and cerebrovascular diseases, and diabetes are independent predictors of premature death (refer to 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).
  • Glucagon-1ikepeptide-1 (GLP-1), a peptide hormone secreted by the gut, has multiple mechanisms aimed at lowering blood sugar and reducing body weight, including increased glucose-dependent insulin secretion , Inhibit the secretion of glucagon, delay gastric emptying and suppress the central appetite.
  • Glucagon is a hormone secreted by pancreatic ⁇ -cells, which consists of a single-chain polypeptide with a length of 29 amino acids. Glucagon activates intracellular adenylate cyclase (adenylatecyclase) by specifically binding to the glucagon receptor (GCGR) on the surface of target cells on the liver and liver and kidney, increasing the level of intracellular cAMP, and exerting Physiological Effects. Glucagon is a hormone that promotes catabolism. Short-term injection of glucagon can promote glycogenolysis and gluconeogenesis, which can increase blood sugar.
  • adenylatecyclase glucagon receptor
  • Endogenous oxyntomodulin is a peptide hormone secreted by human intestinal L cells after nutritional intake.
  • OXM is a dual agonist of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), combining the anorectic and hypoglycemic effects of GLP-1R agonists and GCGR-mediated Increased energy expenditure (refer to 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-1co-agonist eliminates obesity in rodents.
  • GLP-1R-/- GLP-1R knockout mice
  • WT wild-type mice
  • Activation of GCGR in the central nervous system may improve its systemic glucose metabolism in animal experiments after OXM treatment (reference Mighiu PI, YueJT, Filippi BM&Lam TK 2012 Hypothalamic glucose signaling regulates glucose production. Diabetes 61(Suppl 1) A55.Nauck MA 2012 The design of the liraglutide clinical trial program. Diabetes, Obesity and Metabolism 14 (Suppl 2) 4-12.).
  • the hypoglycemic effect of OXM may be mainly through reducing body weight, promoting insulin secretion, and activating GCGR in the central nervous system to inhibit hepatic glucose production, thereby achieving hypoglycemic effect.
  • OXM has the potential to be a well-tolerated anti-obesity and hypoglycemic drug, but there is no relevant research on the effect of OXM on uric acid levels, although there are some urate-lowering drugs on the market, such as xanthine oxidation Enzyme inhibitors (XOIs) and uricosuric drugs.
  • XOIs xanthine oxidation Enzyme inhibitors
  • allopurinol, febuxostat and benzbromarone are the first-line drugs in China. In the United States, only allopurinol is the first-line drug.
  • the current uric acid-lowering drugs all have efficacy or safety problems, such as the severe hypersensitivity reaction rate of allopurinol, the cardiovascular risk of febuxostat, the side effects of benzbromarone, and the low rate of blood uric acid compliance. Therefore, the current uric acid-lowering drugs for the treatment of gout cannot meet the clinical needs. Therefore, there is an urgent need for a uric acid-lowering preparation with strong safety and tolerance and obvious uric acid-lowering effect, especially for reducing uric acid in obese patients or diabetic patients.
  • the present invention provides an application of mazdutide, which has a significant uric acid-lowering effect.
  • the mazdutide in this study is an OXM analog mazdutide.
  • Mazdutide is a long-acting synthetic peptide similar to the mammalian oxyntomodulin (OXM), which utilizes fatty acyl side chains to prolong the duration of action, allowing once-weekly dosing.
  • OXM mammalian oxyntomodulin
  • this hormone is thought to exert its biological effects by activating the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) (see Tan TM, Coadministration of glucagon -like peptide-1 during glucose infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013; 62(4): 1131-1138.).
  • GLP-1R glucagon-like peptide-1 receptor
  • GCGR glucagon receptor
  • the present invention provides the application of a compound (mazdutide) as shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicines for reducing uric acid levels in patients;
  • the compound or a pharmaceutically acceptable salt thereof is preferably the only active ingredient or one of the active ingredients of the drug.
  • the drug preferably further comprises hydroxymethylaminomethane and mannitol, more preferably sucrose or propylene glycol.
  • the uric acid level in the patient's serum is preferably greater than 280 ⁇ mol/L.
  • the patient suffers from gout, hyperuricemia, uremia, atherosclerosis, hypertension, fatty liver, diabetes, obesity, or is overweight with complications.
  • the patient not only has a serum uric acid level greater than 280 ⁇ mol/L, but also suffers from the above conditions.
  • said uric acid level is greater than 420 ⁇ mol/L.
  • the present invention also provides a method for reducing uric acid level in a patient, which comprises: administering the compound represented by formula (I) or the drug as defined above to the patient.
  • the present invention also provides a method for treating gout, which comprises: administering the compound represented by formula (I) or the drug as defined above to a patient.
  • the drug is administered once a week at a dose of 1.0-10 mg; Doses of 4.5mg, 5mg, 6mg, 7.5mg, 9mg or 10mg are administered once a week;
  • the drug is administered about once a week in at least one ascending dose for a minimum of about four weeks and at least one maintenance dose is administered about once a week after the ascending dose for a minimum of about four weeks; wherein the ascending dose is selected from about 1.0 mg and about 2.0 mg ; wherein the maintenance dose is selected from about 3.0 mg;
  • the drug is administered at least one ascending dose about once a week for a minimum of about four weeks and at least one maintenance dose is administered about once a week after the ascending dose for a minimum of about four weeks; wherein the ascending dose is selected from about 1.5 mg and about 3.0 mg ; wherein the maintenance dose is selected from about 4.5 mg;
  • the drug is administered at least one ascending dose about once a week for a minimum of about four weeks and at least one maintenance dose is administered about once a week after the ascending dose for a minimum of about four weeks; wherein the ascending dose is selected from about 2.0 mg and about 4.0 mg ; wherein the maintenance dose is selected from about 6.0 mg.
  • Another aspect of the present invention provides a pharmaceutical composition for reducing uric acid levels in patients, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • mazdutide has good safety and tolerability in single and multiple dose climbing tests in healthy people, and it has also been found to have a uric acid-lowering effect in obese patients and diabetic patients.
  • escalating doses refers to doses that are smaller than the highest effective dose required by the patient.
  • maintenance dose refers to the dose that is the highest effective dose required by the patient.
  • pharmaceutically acceptable salts are well known to the skilled artisan.
  • the pharmaceutically acceptable salt is trifluoroacetate.
  • patient refers to a mammal in need of treatment for a condition or disorder.
  • the patient is a human with a disease or condition that would benefit from treatment with mazdutide.
  • the term "about” when connected with a number can mean, for example, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1% or ⁇ 0.5%.
  • amino acids used herein are 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), His(H).
  • Mazdutide has a significant uric acid-lowering effect, and can reduce the uric acid level in patients with hyperuricemia by more than 80 ⁇ mol/L.
  • Figure 1 is a diagram of the experimental design of the research.
  • Figure 2 is the change value of uric acid relative to the baseline after administration in the overweight/obese population.
  • Figure 3 is the change value of uric acid relative to the baseline after administration in the diabetic population.
  • the Mazdutide preparation is mazdutide for injection, consisting of 2 mg of mazdutide and the inactive ingredients tris, mannitol and sucrose. Reconstitute the contents of the vial with sterile water for injection to obtain a clear solution of mazdutide. Or it is composed of mazdutide and inactive ingredients tris, mannitol and propylene glycol, and the preparation method can be found in PCT/CN2022/089742.
  • Placebo a mazdutide mimic, consisted of the inactive ingredients tris, mannitol, and sucrose. Reconstitute the contents of the vial with sterile water for injection to obtain a clear solution without active ingredients.
  • the strength of the preparation used was 2mg/bottle, and the strength of the placebo matched the preparation.
  • the formulation and placebo should be stored under refrigeration (2°C to 8°C).
  • Both mazdutide and placebo were administered by subcutaneous injection once weekly. Each administration needs to be prepared and injected by the research nurse. For the preparation and use of the research drug, please refer to the drug use instructions.
  • Age 18-75 both ends included, male or female;
  • the weight change is less than 5%
  • Diabetic subjects who meet the following criteria can be selected for this study:
  • Body mass index 20 ⁇ BMI ⁇ 35kg/m2 (BMI weight (kg)/height (m)2).
  • GLP-1 receptor GLP-1R
  • GLP-1R/GCGR agonists Previous use of GLP-1 receptor (GLP-1R) agonists or GLP-1R/GCGR agonists
  • Drugs that affect body weight have been used within 3 months before screening, including: systemic steroid hormones (intravenous, oral or intraarticular administration), metformin, SGLT2 inhibitors, thiazolidinediones (TZD) , tricyclic antidepressants, psychiatric drugs, or sedative drugs (such as imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, Olanzapine, valproic acid, valproic acid derivatives, lithium salt), etc.;
  • systemic steroid hormones intravenous, oral or intraarticular administration
  • metformin SGLT2 inhibitors
  • thiazolidinediones thiazolidinediones
  • tricyclic antidepressants such as imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpro
  • weight-loss drugs such as: sibutramine hydrochloride, orlistat, phentermine, phenylpropanolamine, mazindol, phentermine, and Fepradone, lorcaserin, phentermine/topiramate mixture, naltrexone/bupropion mixture, etc.;
  • Obesity caused by secondary diseases or drugs including: elevated cortisol hormones (eg Cushing's syndrome), obesity caused by pituitary and hypothalamus damage, obesity caused by reduction/stopping of weight loss drugs, etc.;
  • Hypertension that has not been stably controlled at screening after at least 4 weeks of antihypertensive drug treatment, defined as: systolic blood pressure > 140mmHg and/or diastolic blood pressure > 100mmHg;
  • Heart-related diseases such as angina pectoris, myocardial infarction, cardiomyopathy, acute and chronic heart failure, etc.
  • heart-related diseases such as angina pectoris, myocardial infarction, cardiomyopathy, acute and chronic heart failure, etc.
  • MEN multiple endocrine neoplasia 2A or 2B syndrome or related family history at the time of screening;
  • Chronic gastrointestinal diseases systemic diseases that may affect gastrointestinal motility during screening, or use of drugs that may change gastrointestinal motility, appetite or absorption within 3 months before screening;
  • HAV human immunodeficiency virus
  • HBV hepatitis B surface antigen
  • HCV hepatitis C
  • any one of the laboratory inspection indicators meets the following criteria (if there is a clear reason for retesting during screening, retesting can be done within one week, and the researcher needs to make a record of the reason for retesting):
  • the 12-lead electrocardiogram at the time of screening shows that the heart rate is ⁇ 50 beats/min or >90 beats/min;
  • Blood donation and/or blood loss ⁇ 400mL or bone marrow donation within 3 months before screening, or hemoglobinopathy, hemolytic anemia, sickle cell anemia, or hemoglobin ⁇ 110g/L (male) or ⁇ 100g /L (female);
  • Type 1 diabetes specific types of diabetes or gestational diabetes.
  • Ketoacidosis or lactic acidosis occurred 6 months before screening.
  • hypoglycemia There is a history of severe hypoglycemia within 6 months before screening, which is defined as the occurrence of neurological hypoglycemia symptoms and the need for assistance from others to recover, or the previous complete ignorance of hypoglycemia or insufficient awareness of hypoglycemia symptoms. Patients who, in the investigator's opinion, were unable to communicate and understand hypoglycemia symptoms and appropriate treatment should also be excluded from the study.
  • TIA transient ischemic attack
  • Abnormal 12-lead electrocardiograms (such as: QTcF > 450ms, PR interval ⁇ 120ms, or PR interval > 220ms, II degree) that the investigator believes will increase the risk of the subject or may cause confusion (QT) in ECG data analysis during screening.
  • ventricular conduction delay ventricular conduction delay
  • QRS cardiac conduction delay
  • drugs such as antiarrhythmic drugs class IA and class III, cisapride, macrolide antibiotics and psychotropic drugs (phenothiazines (methylthioridazine, chlorpromazine, misoridazine), butyrophenones (droperidol, haloperidol) and loperamide).
  • antiarrhythmic drugs class IA and class III cisapride
  • macrolide antibiotics and psychotropic drugs phenothiazines (methylthioridazine, chlorpromazine, misoridazine), butyrophenones (droperidol, haloperidol) and loperamide).
  • ALT and AST transaminase
  • ALP alkaline phosphatase
  • HIV antibody positive and syphilis antibody positive during HIV virus infection and/or screening 17. HIV antibody positive and syphilis antibody positive during HIV virus infection and/or screening.
  • hepatitis B and/or be positive for hepatitis B surface antigen at screening, or positive for hepatitis C (HCV) antibody.
  • HCV hepatitis C
  • MEN multiple endocrine neoplasia 2A or 2B syndrome, or related family history.
  • Blood donation ⁇ 400mL or excessive blood loss or bone marrow transplantation within 3 months before screening, or hemoglobinopathy, hemolytic anemia, sickle cell anemia, or hemoglobin ⁇ 110g/L (male) or ⁇ 100g/L L (female).
  • Hyperthyroidism or hypothyroidism confirmed by clinical evaluation and/or TSH abnormality that the investigator believes will increase the risk of the patient.
  • weight-reducing drugs 3 months before screening, such as liraglutide, orlistat, sibutramine hydrochloride, phenylpropanolamine, clomizindol, phentermine, Lorcaserin hydrochloride, phentermine, phentermine/topiramate, bupropion, naltrexone/bupropion.
  • glucocorticoids accumulate or continuous use > 2 weeks within 1 year before screening, or glucocorticoids used within 4 weeks before screening (except for external use, intraocular, intranasal, intra-articular, and inhalation administration).
  • Central nervous system stimulants such as: methylphenidate hydrochloride
  • methylphenidate hydrochloride are being used at the time of screening, except for caffeinated beverages.
  • Female subjects with pregnancy potential except those who have been sterilized or menopause, if they are unwilling to inform their sexual partners that they will participate in the clinical research, and do not take effective contraceptive measures during the research period.
  • Embodiment 2 overall research design
  • This study plans to enroll 36 overweight or obese patients whose body weight change is less than 5% after diet and exercise control for at least 12 weeks.
  • the dosing regimens for subcutaneous injection of mazdutide or placebo in cohort 1, cohort 2 and cohort 3 are described as follows (as shown in Figure 1):
  • Cohort 1 Subjects start with a dose of 1.0 mg, administered once a week, and after 4 weeks of continuous administration, if the subject tolerates it well*, then increase the dose to 2.0 mg, administered once a week , and administered continuously for 4 weeks, and the tolerance of the subjects was observed again. If the tolerance was good*, the dose was continued to be increased to 3.0 mg, administered once a week, and administered continuously for 4 weeks. (increase by 1 mg every 4 weeks to the target dose).
  • Cohort 2 Subjects start with a dose of 1.5 mg, administered once a week, and after 4 weeks of continuous administration, if the subject tolerates it well*, then increase the dose to 3.0 mg, administered once a week , and administered continuously for 4 weeks, observe the tolerance of the subject again, if the tolerance is good*, then continue to increase the dose to 4.5mg, administered once a week, and continuously administered for 4 weeks (in the form of every 4 weeks Increase ramp rate of 1.5 mg to target dose).
  • Cohort 3 Subjects need to start administration after cohort 2 subjects have completed 1.5mg administration for 4 weeks and are well tolerated. If cohort 2 subjects cannot tolerate 1.5mg, cohort 3 subjects do not Then explore 2.0mg and higher doses. The initial dose of subjects in this cohort was 2.0 mg, administered once a week, and after 4 weeks of continuous administration, if the subjects tolerated it well*, the dose was increased to 4.0 mg, administered once a week, And continue to administer for 4 weeks, observe the tolerance of the subjects again, if the tolerance is good*, continue to increase the dose to 6.0mg, administer once a week, and continue administering for 4 weeks. (increase by 2 mg every 4 weeks to the target dose).
  • This study plans to enroll 42 patients with type 2 diabetes, and after at least 2 months of lifestyle intervention or stable dose of metformin ( ⁇ 1000mg/day or maximum tolerated dose) treatment, the glycated hemoglobin control is still not up to standard.
  • the active control drug dulaglutide in cohort 1, cohort 2 and cohort 3 was administered at 1.5 mg QW for 12 weeks, and the dosing regimens of mazdutide and placebo were described as follows:
  • Cohort 1 The initial dose of subjects is 1.0 mg, administered once a week, after 4 weeks of continuous administration, if the subjects are well tolerated, it will be increased to 2.0 mg, administered once a week, and After 4 weeks of continuous administration, observe the tolerance of the subject again, if the tolerance is good, continue to increase to 3.0 mg, administer once a week, and continue administering for 4 weeks. (increase by 1 mg every 4 weeks to the target dose).
  • Cohort 2 The initial dose of subjects is 1.5 mg, administered once a week, after 4 weeks of continuous administration, if the subjects are well tolerated, it will be increased to 3.0 mg, administered once a week, and Continuous administration for 4 weeks, observe the subject's tolerance again, if the subject's tolerance of 3.0 mg is poor and meets the tolerance standard, the subject needs to explore the next dose according to cohort 2 (backup 1) If the tolerance is good, continue to increase to 4.5mg, administer once a week, and continue to administer for 4 weeks. According to cohort 2 (backup 2) for the next dose exploration. (increase at a ramp rate of 1.5 mg every 4 weeks to target dose).
  • Cohort 2 (backup 1): If the subject cannot tolerate the dose of 3.0 mg, stop the drug for 1 week and lower it to 2.25 mg, and continue to administer the drug for 2 weeks, then observe the subject's tolerance again, if it is well tolerated , then continue to increase to 3.0mg, and continuous administration for 4 weeks.
  • Cohort 2 (backup 2): If the subject cannot tolerate the dose of 4.5 mg, the drug will be stopped for 1 week and reduced to 3.75 mg, and the drug will be continued for 2 weeks until the end of the trial.
  • Cohort 3 Subjects need to start after cohort 2 subjects complete the 1.5mg 4-week tolerance test. If cohort 2 subjects cannot tolerate 1.5mg, cohort 3 subjects will no longer explore 2.0mg or more high dose.
  • the initial dose of subjects in this cohort is 2.0 mg, administered once a week, and after 4 weeks of continuous administration, if the subjects tolerate it well, then it will be increased to 4.0 mg, administered once a week, and continuously After 4 weeks of administration, observe the tolerance of the subject again, if the tolerance is good, continue to increase to 6.0 mg, administer once a week, and continue administering for 4 weeks. (increase by 2 mg every 4 weeks to the target dose).
  • Example 4 The uric acid-lowering effect of mazdutide determined based on clinical safety studies
  • Fig. 2 is the change value mean value of each group after the administration relative to the pre-administration (baseline), as can be seen from Fig. 2, after the administration, the cohorts 1, 2, and 3 all have obvious reductions in uric acid levels, and are significantly superior in the placebo group.
  • Table 6 is the mean value of the change value of each group on the 85th day after administration relative to the pre-administration (baseline), as can be drawn from Table 6 and Figure 3, cohorts 1, 2, and 3 also have significantly lower uric acid levels than the placebo group and dulaglutide control group, in which cohorts 1 and 3 decreased most significantly.

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Abstract

公开了一种mazdutide的应用。具体公开了一种如式(I)所示的化合物在制备降低患者尿酸水平药物中的应用；mazdutide具有显著的降尿酸的效果。

Description

Mazdutide的应用
优先权和相关申请
本申请要求2021年6月25日提交的名称为“OXM3的应用”的中国专利申请202110711050.0的优先权，该申请包括附录在内的全部内容作为参考并入本申请。
技术领域
本发明属于医药领域，更具体地，本发明属于降尿酸的领域，本发明涉及一种mazdutide的应用。
背景技术
尿酸高是人体内有一种叫做嘌呤的物质因代谢发生紊乱，致使血液中尿酸增多而引起的一种代谢性疾病，体内尿酸每日的生成量和排泄量大约是相等，生成量方面，三分之一是由食物而来，三分之二是体内自行合成，排泄途径则是三分之一由肠道排出，三分之二从肾脏排泄。上述各种途径只要有任何一方面出问题，就会造成尿酸升高。
尿酸高和肥胖、糖尿病具有一定的关系。肥胖属于一种代谢紊乱的状态，同时会使机体伴有高胰岛素血症和胰岛素抵抗，导致人体内循环的脂肪细胞因子水平升高；2型糖尿病是一种以血糖代谢紊乱为主的疾病，其特点是由胰岛素抵抗、进行性胰岛β细胞功能下降导致的慢性血糖升高。两者都与胰岛素代谢有关而胰岛素对葡萄糖以及脂肪的代谢作用又被许多脂肪细胞影响，进一步加强胰岛素抵抗，最后导致尿酸的生成增加和肾小管对尿酸的重吸收增加，导致尿酸升高。除了肥胖和糖尿病以外，尿酸高还会引起其他的并发症，比如尿毒症、动脉粥样硬化、高血压等。尿酸过高，也会引发其他疾病，比如高尿酸血症、痛风。高尿酸血症(《中国高尿酸血症与痛风诊疗指南(2019)》指出，无论男性还是女性，非同日2次血尿酸水平超过420μmol/L，称之为高尿酸血症)和痛风是慢性肾病、高血压、心脑血管疾病及糖尿病等疾病的独立危险因素，是过早死亡的独立预测因子(参考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)。
GLP-1R/GCGR双激动剂
胰高血糖素样肽-1(Glucagon-1ikepeptide-1，GLP-1)是肠道分泌的一种肽类激素，具有多种旨在降低血糖和减轻体重的机制，包括葡萄糖依赖性胰岛素分泌增加、抑制胰高血糖素分泌、延缓胃排空以及抑制中枢食欲的作用。
胰高血糖素(Glucagon)是一种由胰岛α细胞分泌的激素，由一条长度为29个氨基酸的单链多肽组成。胰高血糖素通过特异性结合肝脏和肝肾上的靶细胞表面的胰高血糖素受体(GCGR)，激活细胞内的腺苷酸环化酶(adenylatecyclase)，提高细胞内的cAMP水平，发挥生理效应。胰高血糖素是一种促进分解代谢的激素，短期注射胰高血糖素能促进糖原分解和糖异生作用，使血糖升高。但是研究发现注射胰高血糖素长期激活GCGR能够降低食欲，刺激脂肪酸分解，显著提高脂肪组织的能量消耗(参考Campbell JE，Drucker DJ.Nature ReviewsEndocrinology，2015，11(6)：329-338)。
内源性胃泌酸调节素Oxyntomodulin(OXM)是营养摄入后由人肠道L细胞分泌的肽类激素。OXM是胰高血糖素样肽-1受体(GLP-1R)和胰高血糖素受体(GCGR)的双重激动剂，结合了GLP-1R激动剂的厌食和降糖作用以及GCGR介导的能量消耗增加作用(参考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-1co-agonist eliminates obesity in rodents.Nat Chem Biol.2009；5：749-757.)，可能比GLP-1R激动剂更有效地治疗肥胖和降低血糖。同时在人体内注射OXM可显著降低体重和食欲，并增加能量消耗。研究发现，GLP-1R敲除小鼠(GLP-1R-/-)缓慢输注OXM后体重有下降，但与野生型(WT)小鼠相比下降幅度较小。这表明OXM的减肥作用需要同时激活GLP1R和GCGR两种受体(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.)。来自啮齿动物的临床前数据表明，与GLP-1R激动剂相比，GLP-1R/GCGR激动剂能更有效地减轻体重。同样，Lao等报道，他们的双重GLP-1R/GCGR激动剂在饮食诱导的肥胖恒河猴中显示出更高的减肥效果(参考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.)。在OXM治疗后的动物试验中，中枢神经系统中GCGR的激活可能改善其全身葡萄糖代谢(参考Mighiu PI，YueJT，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.)。OXM的降糖效果可能主要通过降低体重，促进胰岛素分泌，以及激活中枢神经系统GCGR而抑制肝葡萄糖生成，从 而起到降糖效果。
这些数据表明，OXM具有成为耐受良好的抗肥胖药和降糖药物的潜力，但是关于OXM对于尿酸水平的影响目前还没有相关研究，虽然目前市场上也存在一些降尿酸药物，例如黄嘌呤氧化酶抑制剂(XOI)和促尿酸排泄药物。其中，别嘌醇、非布司他和苯溴马隆在中国属于一线用药。在美国，仅别嘌醇为一线用药。然而，目前的降尿酸药物都存在疗效或安全性问题，如别嘌呤醇的严重超敏反应率、非布司他的心血管风险、苯溴马隆的副作用、血尿酸达标率不高等问题。因此，目前用于痛风治疗的降尿酸药物不能满足临床需求。所以目前急需一种安全性和耐受性强、且降尿酸效果明显的降尿酸制剂，尤其在肥胖病人或糖尿病人中降低尿酸。
发明内容
为了解决现有技术中存在的缺少安全性和耐受性强、且降尿酸效果明显的降尿酸制剂等问题，本发明提供一种mazdutide的应用，该mazdutide具有显著的降尿酸的作用。
本研究的mazdutide是一种OXM类似物mazdutide。mazdutide是一种与哺乳动物胃泌酸调节素oxyntomodulin(OXM)类似的长效合成肽，其利用脂肪酰基侧链延长作用时间，允许每周给药一次。当外源给药时，OXM可以提高葡萄糖耐量并导致体重减轻(Pocai A.Action and therapeutic potential of oxyntomodulin.Mol Metab.2013；3(3)：241-251.)。在人类中，这种激素被认为通过激活胰高血糖素样肽-1受体(GLP-1R)和胰高血糖素受体(GCGR)来发挥其生物学效应(参考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.)。作为OXM类似物，mazdutide的作用被认为是通过GLP-1R和GCGR的结合和激活介导的。
本发明提供一种如式(I)所示的化合物(mazdutide)或其药用盐在制备降低患者尿酸水平的药物中的应用；
Figure PCTCN2022100878-appb-000001
所述化合物或其药用盐较佳地为所述药物的唯一活性成分或有效成分之一。
所述药物较佳地还包含羟甲基氨基甲烷和甘露醇，更佳地还包含蔗糖或丙二醇。
进一步地，在使用所述化合物之前，患者血清中的尿酸水平优选大于280μmol/L。
或者，所述患者患有痛风、高尿酸血症、尿毒症、动脉粥样硬化、高血压、脂肪肝、糖尿病、肥胖症、或超重伴有并发症。
在特定情况下，患者不仅血清中的尿酸水平大于280μmol/L，同时还患有以上病症。
在特定实施方案中，所述尿酸水平大于420μmol/L。
本发明还提供一种降低患者尿酸水平的方法，其包括：向患者施用如式(I)所示的化合物或如上所定义的药物。
本发明还提供一种治疗痛风的方法，其包括：向患者施用如式(I)所示的化合物或如上所定义的药物。
关于以上所述药物的施用剂量，所述药物以1.0～10mg的剂量每周给药一次；优选地，所述药物以约1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、4.0mg、4.5mg、5mg、6mg、7.5mg、9mg或10mg的剂量每周给药一次；
在一个实施方案中，所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.0mg和约2.0mg；其中维持剂量选自约3.0mg；
在一个实施方案中，所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.5mg和约3.0mg；其中维持剂量选自约4.5mg；
在一个实施方案中，所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约2.0mg和约4.0mg；其中维持剂量选自约6.0mg。
本发明的另一方面，提供一种用于降低患者尿酸水平的药物组合物，其包含如式(I)所示的化合物或其药用盐，以及至少一种药学上可接受的载体。
前期研究显示mazdutide在健康人群中的单多次剂量爬坡试验具有较好的安全性和耐受性，同时发现在肥胖病人和糖尿病患者中有降尿酸作用。
已完成健康人单次给药研究(I8P-MC-OXAA)：单中心、双盲、安慰剂随机对照SAD研究(爬坡剂量为0.03mg、0.1mg、0.3mg、1.0mg、2.5mg、5.0mg)，主要评估mazdutide在健康受试者中的安全性、耐受性、PK/PD。结果显示：剂量爬坡至2.5mg受试者均可以耐受，但爬坡至5mg时6例受试者均出现胃肠相关AE(主要为恶心、呕吐)，因此2.5mg可作为单次给药最大耐受剂量(MTD)。
如本文所用，“递增剂量”是指比患者所需的最高有效剂量更小的剂量。
如本文所用，“维持剂量”是指作为患者所需的最高有效剂量的剂量。
如本文所用，“药用盐”是技术人员熟知的。在一个实施方案中药用盐是三氟乙酸盐。
如本文所用，“患者”指需要治疗病状或病症的哺乳动物。在一个实施方案中，患者是患有将从mazdutide治疗获益的疾病或病状的人。
如本文所用，当与数字相连时，术语“约”可以表示例如±5％、±4％、±3％、±2％、±1％或±0.5％。
本文所用的氨基酸的指代是技术人员熟知的，如：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)、His(H)。
超重或肥胖患者的研究初步结果显示：mazdutide可降低患者的尿酸水平(详见图2)。2型糖尿病患者的研究初步结果显示：mazdutide也可降低该人群患者的尿酸水平(详见表6和图3)。
本发明的积极进步效果在于：
Mazdutide具有显著的降尿酸的作用，可将高尿酸患者体内尿酸水平降低80μmol/L以上。
附图说明
图1为研究试验设计图。
图2为超重/肥胖人群中给药后尿酸相对于基线的变化值。
图3为糖尿病人群中给药后尿酸相对于基线的变化值。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1研究药物与患者
Mazdutide的结构如式(I)
Figure PCTCN2022100878-appb-000002
其序列如SEQIDNO：1所示，具体序列为：
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；，其中Xaa为Aib(2-氨基异丁酸)；20位的Lys通过用([2-(2-氨基-乙氧基)-乙氧基]-乙酰基) 2-(γGlu) 1-CO-(CH 2) 18-CO 2H缀合于Lys侧链的ε-氨基从而被化学修饰，且C端Gly的羧基被酰胺化为C端伯酰胺。
1.1研究药物的物理和化学特征如表1所示：
表1
Figure PCTCN2022100878-appb-000003
1.2研究药物规格及生产商
Mazdutide制剂为注射用mazdutide，由2mg mazdutide和无活性成分三羟甲基氨基甲烷、甘露醇和蔗糖组成。用无菌注射用水复溶西林瓶内容物，得到mazdutide的澄清溶液。或由mazdutide和无活性成分三羟甲基氨基甲烷、甘露醇和丙二醇组成，制备方法见PCT/CN2022/089742。
安慰剂是mazdutide模拟剂，安慰剂由无活性成分三羟甲基氨基甲烷、甘露醇和蔗糖组成。用无菌注射用水复溶西林瓶内容物，得到无活性成分的澄清溶液。
本研究使用制剂规格为2mg/瓶，安慰剂规格与制剂相匹配。
度拉糖肽(Dulaglutide)：规格1.5mg/支，生产企业：Vetter Pharma-Fertigung GmbH&Co.KG。
1.3储存
制剂和安慰剂应在冷藏条件(2℃至8℃)下储存。
1.4给药方式
mazdutide和安慰剂均为皮下注射给药，每周一次。每次给药需由研究护士完成配制并注射，研究药物配制和使用详见药物使用说明。
1.5入选标准
一、肥胖或超重受试者符合以下所有标准，方可入选本研究：
1.年龄18～75周岁(包含两端)，男性或女性；
2.肥胖者：BMI≥28.0kg/m2；或超重者：24≤BMI＜28.0kg/m2并伴有以下至少一种表现：i.食欲旺盛，餐前饥饿难忍，每餐进食量较多；ii.合并糖尿病前期(空腹血糖受损和/或糖耐量异常)、高血压、血脂异常(参考标准详见附录4)、脂肪肝(筛选前6个月内)中的一种或几种；iii.合并负重关节疼痛；iv.肥胖引起呼吸困难或有阻塞性睡眠呼吸暂停综合征；
3.筛选时经单纯饮食运动控制至少12周，体重变化小于5％
体重变化百分比＝|(筛选时体重-筛选前12周体重)/筛选时体重|*100％
4.能够理解本研究的程序和方法，愿意严格遵守临床试验方案完成本试验，并自愿签署知情同意书。
二、糖尿病受试者符合以下标准，方可入选本研究：
1.根据1999年WHO标准确诊2型糖尿病至少6个月。
2.签署知情同意书时，18岁≤年龄≤75岁的男性或女性。
3.筛选前2个月内使用生活方式干预或稳定剂量二甲双胍(≥1000mg/日或最大耐受剂量)治疗血糖仍控制不佳2型糖尿病患者。
4.筛选时当地实验室检测7.5％≤HbA1c≤11.0％。
5.体重指数20≤BMI≤35kg/m2(BMI＝体重(kg)/身高(m)2)。
6.研究期间可以稳定维持原有的饮食运动生活方式。
7.受试者自愿签署知情同意书，并同意严格按本方案要求执行。
1.6排除标准
一、肥胖或超重受试者若符合以下任一标准，则将从本研究中剔除：
1.研究者怀疑受试者可能对研究药物或成分过敏或存在过敏体质的患者；
2.筛选前使用以下任何一种药物或治疗：
1)既往使用过GLP-1受体(GLP-1R)激动剂或GLP-1R/GCGR激动剂；
2)筛选前3个月内使用过对体重有影响的药物，包括：全身性的类固醇激素用药(静脉、口服或关节内给药)、二甲双胍、SGLT2抑制剂、噻唑烷二酮类(TZD)、三 环类抗抑郁药、精神疾病用药或镇静类药物(如丙咪嗪、阿米替林、米氮平、帕罗西汀、苯乙肼、氯丙嗪、硫利达嗪、氯氮平、奥氮平、丙戊酸、丙戊酸衍生物、锂盐)等；
3)筛选前3个月内使用过影响体重的中草药或保健品。
4)筛选前3个月内使用过或目前正在使用减肥药物，如：盐酸西布曲明、奥利司他、苯丁胺、苯丙醇胺、氯苯咪吲哚、芬特明、安非拉酮、氯卡色林、芬特明/托吡酯合剂、纳曲酮/安非他酮合剂等；
5)筛选前3个月内参加过其他临床试验(已接受试验药物治疗)；
3.筛选前有以下任何一种疾病的病史或证据：
1)WHO1999标准诊断为糖尿病患者；
2)筛选时空腹静脉血糖≥7.0mmol/L或75g口服葡萄糖耐量试验(OGTT)糖负荷后两小时静脉血糖≥11.1mmol/L(筛选时空腹血糖在6.1-7.0mmol/L受试者需采集OGTT糖负荷后两小时静脉血糖以确认)；
3)既往或筛选时存在视网膜病变的患者；
4)继发疾病或药物导致肥胖，包括：皮质醇激素升高(例如：库欣综合征)、垂体和下丘脑损伤导致的肥胖、减肥药物减量/停用导致的肥胖等；
5)既往有进行过减肥手术或筛选前1年内进行过针灸减肥等；
6)既往有过抑郁症病史；或既往有严重的精神疾病史，例如：精神分裂症，双相情感障碍等；
7)经至少4周降压药物治疗后筛选时仍未稳定控制的高血压，定义为：收缩压＞140mmHg和/或舒张压＞100mmHg；
8)筛选时收缩压＜90mmHg和/或舒张压＜50mmHg；
9)筛选时存在恶性肿瘤病史(已治愈的皮肤基底细胞癌和宫颈原位癌除外)；
10)筛选时存在心脏相关疾病(如心绞痛、心肌梗死、心肌病、急慢性心力衰竭等)；
11)筛选前6个月内发生出血性或缺血性脑卒中或短暂性脑缺血发作；
12)筛选时有甲状腺C细胞癌史、MEN(多发性内分泌腺瘤病)2A或2B综合征病史或相关家族史；
13)筛选时有急慢性胰腺炎病史，胆囊病史，胰腺损伤史；
14)筛选时有可能影响胃肠动力的慢性胃肠疾病、全身性疾病，或筛选前3个月内使用可能改变胃肠动力、食欲或吸收的药物；
15)存在肢体畸形或残缺，无法准确确定身高、体重等指标；
16)筛选前1个月内有大中型手术、严重外伤、严重感染，研究者判断不适合参加本研究者；
17)既往有自杀倾向或自杀行为；
18)试验期间有预期手术，但研究者判断对受试者安全和试验结果无影响的门诊手术除外；
19)在筛选时人免疫缺陷病毒(HIV)抗体或乙肝表面抗原(HBsAg)或丙型肝炎(HCV)抗体或梅毒抗体阳性的受试者；
20)筛选前1个月内有酒精滥用病史。平均每周酒精摄入男性超过21个单位，女性超过14个单位，或用药日前24小时及整个研究期间不愿意停止饮酒(1单位＝360ml啤酒，或150ml红酒，或45ml蒸馏酒/白酒)；
21)筛选时滥用药品和毒品的尿液筛查检测阳性；
4.有任何一项实验室检查指标符合下列标准(筛选时如有明确复测理由可在一周内复测，研究者需做好复测理由的记录)：
1)筛选时血清降钙素≥15ng/L；
2)筛选时谷丙转氨酶≥2.0×ULN和/或谷草转氨酶≥2.0×ULN和/或总胆红素≥1.0×ULN和/或碱性磷酸酶≥2.0×ULN；
3)筛选时eGFR＜60mL/min/1.73m 2，应用CKD-EPI公式估算(见下表2)：CKD-EPI公式估算：eGFR＝a×[(血肌酐(μmol/L)/b)] c×(0.993) 年龄：
表2
Figure PCTCN2022100878-appb-000004
4)筛选时甲状腺功能(FT3、FT4或TSH)异常；
5)筛选时空腹甘油三酯≥5.64mmol/L(500mg/dl)；
6)筛选时血淀粉酶或脂肪酶＞2.0×ULN；
7)筛选时凝血酶原时间的国际标准化比值(INR)大于正常值范围上限；
5.筛选时12导联心电图显示心率＜50次/分或＞90次/分；
6.筛选时具有临床意义的12导联心电图(ECGs)异常：未安装心脏起搏器的情况下出现的II度或III度房室传导阻滞、长QT综合征或QTcF＞450ms(QTc Fridericia公式计算公式：QTcF＝QT/(RR^0.33))、PR间期＜120ms或PR间期＞220ms、QRS＞120ms、左或右束支传导阻滞、预激综合征或需治疗的严重的心律失常；
7.妊娠或哺乳期女性，具有生育能力的男性或女性不愿意在整个研究期间避孕；
8.筛选前3个月内献血量和/或失血量≥400mL或进行过骨髓捐献，或存在血红蛋白病、溶血性贫血、镰状细胞性贫血、或血红蛋白＜110g/L(男性)或＜100g/L(女性)；
9.研者认为受试者具有任何可能影响本研究的疗效或安全性评价的其他因素存在，不适合参加本研究。
二、糖尿病受试者若符合以下任一标准，则将从本研究中剔除：
1. 1型糖尿病、特殊类型糖尿病或妊娠期糖尿病。
2.筛选前6个月发生过酮症酸中毒或乳酸酸中毒。
3.筛选前6个月内有重度低血糖发作病史，定义为出现神经低血糖症状且需要他人协助治疗才能恢复，或既往完全不知道低血糖或对低血糖症状认知不足。研究者认为患者无法沟通并理解低血糖症状及适当治疗的也应排除该研究。
4.筛选前6个月内发生过急性心肌梗死，不稳定性心绞痛，冠状动脉旁路移植术，经皮冠脉介入术(诊断性血管造影除外)，短暂性脑缺血发作(TIA)，脑血管意外，急慢性心力衰竭。
5.筛选时研究者认为增加受试者风险或可能引起心电图数据分析混淆(QT)的异常12导联心电图(如：QTcF＞450ms，PR间期＜120ms，或PR间期＞220ms，II度和III度房室传导阻滞，心室传导延迟即QRS＞120ms，右束支传导阻滞，左束支传导阻滞，预激综合征)；或正在服任何可能影响心脏QT间期的药物(如抗心律失常药物IA类及III类，西沙比利，大环内酯类抗生素及精神类药物(吩噻嗪类(甲巯哒嗪、氯丙嗪、米索哒嗪)、丁酰苯类(氟哌利多、氟哌啶醇)及洛哌丁胺)。
6.既往曾诊断为长QT间期综合征。
7.筛选时未稳定控制的血压，收缩压＞140mmHg或＜90mmHg，舒张压＞90mmHg或＜50mmHg。
8.筛选时心率＜50bpm或＞90bpm。
9.筛选前5年内存在活动性或未治疗的恶性肿瘤，或处于临床恶性肿瘤缓解期(皮肤基底细胞癌和鳞状细胞癌、宫颈原位癌、甲状腺乳头状癌术后无复发的患者除外)。
10.既往有急性或慢性胰腺炎病史，或筛选时血清脂肪酶/淀粉酶高于正常值上限2倍，或空腹甘油三酯＞5.65mmol/L(500mg/dl)。若患者在进行调脂治疗，必须筛选前药物剂量稳定30天。
11.筛选时存在临床症状的肝脏疾病，急慢性肝炎，或筛选时转氨酶(ALT和AST)和碱性磷酸酶(ALP)＞2倍正常值上限，总胆红素高于正常值上限。
12.筛选时降钙素≥15ng/L。
13.筛选时肾小球滤过率eGFR＜60mL/min/1.73m2，应用改良MDRD公式估算：eGFR＝175×[(血肌酐(μmol/L)/88.4)]-1.234×[年龄(岁)]-0.179×0.79(女)或×1(男)。
14.既往或筛选时存在精神疾病，研究者认为不适合参加本研究。
15.诊断为胃轻瘫或任何形式的肥胖外科手术，或研究者认为有临床意义的胃排空异常。
16.已知的规律性药物滥用病史。
17.HIV病毒感染和/或筛选时HIV抗体阳性，梅毒抗体阳性。
18.有乙肝病史和/或筛选时乙肝表面抗原阳性，或丙型肝炎(HCV)抗体阳性。
19.既往有Gilbert综合征。
20.筛选时INR大于正常值上限。
21.有甲状腺髓样C细胞癌史、MEN(多发性内分泌肿瘤)2A或2B综合征病史，或相关家族史。
22.既往明确诊断为自主神经病变，表现为：尿潴留，静息性心动过速，直立性低血压，糖尿病性腹泻。
23.筛选前3个月内存在明显体重变化，变化百分比(＞5％)。
24.筛选前3个月内献血量≥400mL或失血过多或进行过骨髓移植，或存在血红蛋白病，溶血性贫血，镰状细胞性贫血，或血红蛋白＜110g/L(男性)或＜100g/L(女性)。
25.研究者认为会增加患者风险的经临床评估和/或TSH异常证实的甲亢或甲减。
26.筛选前2个月内使用过除二甲双胍以外的降糖药物。
27.筛选前3个月使用或试验期间计划使用降低体重的药物，如利拉鲁肽，奥利司他，盐酸西布曲明，苯丙醇胺，氯苯咪吲哚，苯丁胺，盐酸氯卡色林，芬特明，芬特明/托吡酯，安非拉酮，纳曲酮/安非他酮。
28.筛选前1年内长期使用糖皮质激素(累计或连续使用＞2周)，或筛选前4周内使用过糖皮质激素(外用、眼内、鼻内、关节内、吸入给药除外)。
29.筛选时正在使用中枢神经兴奋剂(例如：盐酸哌醋甲酯)，含咖啡因的饮料除外。
30.已知对试验药物或成分过敏。
31.筛选前3个月内参与任何药物或医疗器械的临床试验(定义为进入随机用药阶段)。
32.除已经绝育或者停经的，具有怀孕潜质的女性受试者，如果不愿意告知其性伴侣其参加该项临床研究，并在研究期间不采取有效避孕措施的。男性受试者，不愿意告知 其女性性伴侣其参与该项临床研究，并在研究期间不采取有效避孕措施的。
33.妊娠期或者哺乳期，或者计划在研究期间怀孕或者哺乳的受试者。
34.研究者认为可能对本研究的疗效和安全性数据解释产生干扰的任何有显著临床意义的实验室异常值。
35.研究者认为受试者具有任何可能影响本研究的受试者配合、疗效或安全性评价的其他因素存在，例如：存在精神疾病。
36.平均每周酒精摄入男性超过21个单位，女性超过14个单位，或用药日前24小时及整个研究期间不愿意停止饮酒(1单位＝360ml啤酒，或150ml红酒，或45ml蒸馏酒/白酒)。
实施例2总体研究设计
一、针对肥胖或超重
本研究计划入组36例经饮食运动控制至少12周体重变化小于5％的超重或肥胖患者。双盲治疗期研究分成三个队列，分别为队列1(n＝12)、队列2(n＝12)、队列3(n＝12)，每个队列受试者按2∶1比例随机分成mazdutide治疗组(n＝8)、安慰剂组(n＝4)。队列1、队列2和队列3中mazdutide或安慰剂的皮下注射给药方案分别描述如下(如图1所示)：
队列1：受试者起始剂量为1.0mg，每周给药1次，连续给药4周后，如受试者耐受性良好*，则上调剂量至2.0mg，每周给药1次，并连续给药4周，再次观察受试者耐受情况，如耐受性良好*，则继续上调剂量至3.0mg，每周给药1次，并连续给药4周。(以每4周增加1mg的爬坡速度至目标剂量)。
队列2：受试者起始剂量为1.5mg，每周给药1次，连续给药4周后，如受试者耐受性良好*，则上调剂量至3.0mg，每周给药1次，并连续给药4周，再次观察受试者耐受情况，如耐受性良好*，则继续上调剂量至4.5mg，每周给药1次，并连续给药4周(以每4周增加1.5mg的爬坡速度至目标剂量)。
如果队列2中受试者在3.0mg或4.5mg出现不耐受情况需按表3中标准进行给药剂量的调整。
表3.爬坡过程剂量及其调整参照表
Figure PCTCN2022100878-appb-000005
Figure PCTCN2022100878-appb-000006
备注：
*如队列2组受试者在爬坡过程中无法耐受3mg，则需按队列2(backup1)中停药1周后下调至2.25mg，后续剂量爬坡按队列2(backup1)进行；
#如队列2组受试者在爬坡过程中无法耐受4.5mg，则需按队列2(backup2)中停药1周后下调至3.75mg，并维持该剂量直至试验结束；
&队列3组受试者需在队列2受试者完成1.5mg4周耐受试验后才开始给药，如队列2受试者无法耐受1.5mg，则队列3受试者不再探索2.0mg及更高剂量。
队列3：受试者需在队列2受试者完成1.5mg给药4周且耐受性良好后才能开始给药，如队列2受试者无法耐受1.5mg，则队列3受试者不再探索2.0mg及更高剂量。该队列受试者起始剂量为2.0mg，每周给药1次，连续给药4周后，如受试者耐受性良好*，则上调剂量至4.0mg，每周给药1次，并连续给药4周，再次观察受试者耐受情况，如耐受性良好*，则继续上调剂量至6.0mg，每周给药1次，并连续给药4周。(以每4周增加2mg的爬坡速度至目标剂量)。
二、针对糖尿病
本研究计划入组42例2型糖尿病的患者，并经过至少2个月生活方式干预或稳定剂量二甲双胍(≥1000mg/日或最大耐受剂量)治疗后糖化血红蛋白控制仍不达标者。本研究分成三个队列，分别为队列1(n＝14)、队列2(n＝14)、队列3(n＝14)，每个队列按8∶4∶2比例随机分成mazdutide治疗组(n＝8)、安慰剂组(n＝4)和Dulaglutide 1.5mg治疗组(n＝2)。队列1、队列2和队列3中活性对照药Dulaglutide给药方法均为1.5mg QW，持续给药12周，mazdutide和安慰剂的给药方案分别描述如下：
队列1：受试者起始剂量为1.0mg，每周给药1次，连续给药4周后，如受试者耐受性良好，则上调至2.0mg，每周给药1次，并连续给药4周后，再次观察受试者耐受情况，如耐受良好，则继续上调至3.0mg，每周给药1次，并连续给药4周。(以每4周增加1mg的爬坡速度至目标剂量)。
队列2：受试者起始剂量为1.5mg，每周给药1次，连续给药4周后，如受试者耐受 性良好，则上调至3.0mg，每周给药1次，并连续给药4周，再次观察受试者耐受情况，如受试者3.0mg耐受性较差，达到耐受标准，则该受试者需按队列2(backup 1)进行下一剂量探索；如耐受良好，则继续上调至4.5mg，每周给药1次，并连续给药4周，如受试者4.5mg耐受性较差，达到耐受标准，则该受试者需按队列2(backup 2)进行下一剂量探索。(以每4周增加1.5mg的爬坡速度至目标剂量)。
队列2(backup 1)：如受试者3.0mg剂量无法耐受，则停药1周并下调至2.25mg，并连续给药2周后，再次观察受试者耐受情况，如耐受良好，则继续上调至3.0mg，并连续给药4周。
队列2(backup 2)：如受试者4.5mg剂量无法耐受，则停药1周并下调至3.75mg，并连续给药2周直至试验结束。
队列3：受试者需在队列2受试者完成1.5mg 4周耐受试验后才开始，如队列2受试者无法耐受1.5mg，则队列3受试者不再探索2.0mg及更高剂量。该队列受试者起始剂量为2.0mg，每周给药1次，连续给药4周后，如受试者耐受性良好，则上调至4.0mg，每周给药1次，并连续给药4周后，再次观察受试者耐受情况，如耐受良好，则继续上调至6.0mg，每周给药1次，并连续给药4周。(以每4周增加2mg的爬坡速度至目标剂量)。
实施例3安全性研究评估
针对肥胖或超重患者：截止2021年3月15日，共入组36例，纳入分析36例。本研究患者整体安全性和耐受性良好，未发生SAE，未发生剂量终止相关AE，无低血糖事件，无重度不良事件，无急性胰腺炎发生，无受试者因不良事件中止给药或退出研究，无注射部位反应，仅有队列1组2例受试者出现过轻度荨麻疹。胃肠道不良反应是最常见的不良反应(15/24例，62.5％)，其中发生率最高的为食欲减退(29.2％)、腹泻(25％)、恶心(16.7％)。胃肠道反应发生比例高于安慰剂，这与该药物作用机制相符。此外，mazdutide试验组较安慰剂组平均心率有所增加，但未发现严重心脏疾病相关不良事件。
针对糖尿病患者：截止2021年4月26日，共入组42例，纳入分析42例。本研究受试者总体安全性和耐受性良好，未出现导致剂量爬坡终止的不良事件，无急性胰腺炎、重度低血糖、过敏反应或注射部位不良反应。
实施例4基于临床安全性研究确定的mazdutide的降低尿酸的作用
1.针对肥胖受试者：截止2021年3月15日，共入组36例，纳入分析36例。表4 为给药前各组的尿酸水平，即基线值。
表4
Figure PCTCN2022100878-appb-000007
图2为给药后各组相对于给药前(基线)的变化值均值，通过图2可以看出，给药后，队列1、2、3都有明显的尿酸水平的降低，且显著优于安慰剂组。
2.针对糖尿病受试者：截止2021年4月26日，共入组42例，纳入分析36例。表5为给药前各组的尿酸水平，即基线值。
表5
Figure PCTCN2022100878-appb-000008
表6为给药后第85天各组相对于给药前(基线)的变化值均值，由表6和图3可以得出，队列1、2、3同样有明显尿酸水平低于安慰剂组和度拉糖肽对照组，其中队列1和3降低最为显著。
表6
Figure PCTCN2022100878-appb-000009

Claims (17)

  1. 一种如式(I)所示的化合物或其药用盐在制备降低患者尿酸水平药物中的应用；
    Figure PCTCN2022100878-appb-100001
  2. 如权利要求1所述的应用，其特征在于，所述化合物或其药用盐为所述药物的唯一活性成分或有效成分之一。
  3. 如权利要求1或2所述的应用，其特征在于，所述药物还包含羟甲基氨基甲烷和甘露醇，优选地还包含蔗糖或丙二醇。
  4. 如权利要求1-3任一项所述的应用，其特征在于，所述尿酸水平大于280μmol/L，或/且所述患者患有痛风、高尿酸血症、尿毒症、动脉粥样硬化、高血压、脂肪肝、糖尿病、肥胖症、或超重伴有并发症，所述尿酸水平为降低前患者血清中的尿酸水平。
  5. 如权利要求4所述的应用，所述尿酸水平大于420μmol/L。
  6. 一种降低患者尿酸水平的方法，包括对患者给予有效量的如式(I)所示的化合物或其药用盐；
    Figure PCTCN2022100878-appb-100002
  7. 如权利要求6所述的方法，其特征在于，所述化合物或其药用盐为所述药物的唯一活性成分或有效成分之一。
  8. 如权利要求6或7所述的方法，其特征在于，所述药物还包含羟甲基氨基甲烷和甘露醇，优选地还包含蔗糖或丙二醇。
  9. 如权利要求6-8任一项所述的方法，其特征在于，所述尿酸水平大于280μmol/L，或/且所述患者患有痛风、高尿酸血症、尿毒症、动脉粥样硬化、高血压、脂肪肝、糖尿病、肥胖症、或超重伴有并发症，所述尿酸水平为降低前患者血清中的尿酸水平。
  10. 如权利要求9所述的方法，所述尿酸水平大于420μmol/L。
  11. 如权利要求6-8任一项所述的方法，其特征在于，所述药物以1.0～10mg的剂量每周给药一次；优选地，所述药物以约1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、4.0mg、4.5mg、5mg、6mg、7.5mg、9mg或10mg的剂量每周给药一次；
    更优选地，所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.0mg和约2.0mg；其中维持剂量选自约3.0mg；或
    所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.5mg和约3.0mg；其中维持剂量选自约4.5mg；或
    所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约2.0mg和约4.0mg；其中维持剂量选自约6.0mg。
  12. 一种用于降低患者尿酸水平的药物组合物，其包含如式(I)所示的化合物或其药用盐，以及至少一种药学上可接受的载体；
    Figure PCTCN2022100878-appb-100003
  13. 如权利要求12所述的药物组合物，其特征在于，所述化合物或其药用盐为所述药物的唯一活性成分或有效成分之一。
  14. 如权利要求12或13所述的药物组合物，其特征在于，所述药物还包含羟甲基氨基甲烷、甘露醇，优选地还包含蔗糖或丙二醇。
  15. 如权利要求12-14任一项所述的药物组合物，其特征在于，所述尿酸水平大于280μmol/L，或/且所述患者患有痛风、高尿酸血症、尿毒症、动脉粥样硬化、高血压、脂肪肝、糖尿病、肥胖症、或超重伴有并发症，所述尿酸水平为降低前患者血清中的尿酸水平。
  16. 如权利要求15所述的药物组合物，所述尿酸水平大于420μmol/L。
  17. 如权利要求12-14任一项所述的药物组合物，其特征在于，所述药物以1.0～10mg 的剂量每周给药一次；优选地，所述药物以约1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、4.0mg、4.5mg、5mg、6mg、7.5mg、9mg或10mg的剂量每周给药一次；
    更优选地，所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.0mg和约2.0mg；其中维持剂量选自约3.0mg；或
    所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约1.5mg和约3.0mg；其中维持剂量选自约4.5mg；或
    所述药物约每周一次施用至少一个递增剂量最短约四周并且在递增剂量后约每周一次施用至少一个维持剂量最短约四周；其中递增剂量选自约2.0mg和约4.0mg；其中维持剂量选自约6.0mg。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023231730A3 (zh) * 2022-06-01 2024-01-25 信达生物制药(苏州)有限公司 使用mazdutide的治疗方法
WO2025073289A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating diabetes and obesity
WO2025073288A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating adolescent obesity
WO2025098422A1 (zh) * 2023-11-07 2025-05-15 深圳信立泰药业股份有限公司 多重受体共激动剂化合物及其制备方法与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298757A1 (en) * 2005-06-13 2009-12-03 Imperial Innovations Limited Oxyntomodulin analogues and their effects on feeding behaviour

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI783244B (zh) * 2015-06-22 2022-11-11 美商美國禮來大藥廠 升糖素及glp-1共激動劑化合物
WO2019171352A2 (en) * 2018-03-08 2019-09-12 Janssen Pharmaceutica Nv Methods of treating severe non-diabetic obesity
CN119584980A (zh) * 2022-06-01 2025-03-07 信达生物制药(苏州)有限公司 使用mazdutide的治疗方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090298757A1 (en) * 2005-06-13 2009-12-03 Imperial Innovations Limited Oxyntomodulin analogues and their effects on feeding behaviour

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
BENSON CHARLES, THAM LAI-SAN, DU, GURBUZ SIREL, ROBINS DEBORAH, MATHER KIEREN, TANG CHENG, THOMAS MELISSA: "333-OR: Oxyntomodulin Analog LY3305677 (LY) Improves Glycemic Control and Weight Loss in Healthy Volunteers and Subjects with Type 2 Diabetes (T2D)", DIABETES, AMERICAN DIABETES ASSOCIATION, vol. 71, no. Supplement_1, 1 June 2022 (2022-06-01), XP009542082, ISSN: 0097-1472, DOI: 10.2337/db22-333-OR *
CAMPBELL JEDRUCKER DJ., NATURE REVIEWS ENDOCRINOLOGY, vol. 11, no. 6, 2015, pages 329 - 338
DAY JWOTTAWAY NPATTERSON JT ET AL.: "A New Glucagon and GLP-1 Co-Agonist Eliminates Obesity in Rodents", NAT CHEM BIOL., vol. 5, 2009, pages 749 - 757, XP002558889, DOI: 10.1038/nchembio.209
JI LINONG, JIANG HONGWEI, AN PEI, DENG HUAN, LIU MENG, LI LI, FENG LIQI, SONG BAILI, HAN-ZHANG HAN, MA QINGYANG, QIAN LEI: "IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study", ECLINICAL MEDICINE, vol. 39, 13 August 2021 (2021-08-13), pages 101088, XP093017460, ISSN: 2589-5370, DOI: 10.1016/j.eclinm.2021.101088 *
KOSINSKI JRHUBER JCARRINGTON PE ET AL.: "The Glucagon Receptor is Involved in Mediating the Body Weight-Lowering Effects of Oxyntomodulin", OBESITY, vol. 20, 2012, pages 1566 - 1571, XP055249612, DOI: 10.1038/oby.2012.67
LAO JHANSEN BCDIMARCHI R ET AL.: "Effect of GLP1R/GCGR Dual Agonist in Monkeys", DIABETES, vol. 62, 2013, pages 257
LI YUE, YANG CHAOQIAN, ZHANG XIAO, YANG YANFENG, XU LIPING, CHENG TUANJIE : "Current Situation of Related Research on Obesity and Hyperuricemia", WORLD LATEST MEDICINE INFORMATION, vol. 19, no. 98, 31 December 2019 (2019-12-31), pages 128 - 129, XP093017463, ISSN: 1671-3141, DOI: 10.19613/j.cnki.1671-3141.2019.98.056 *
MIGHIU PIYUE JTFILIPPI BMLAM TK: "Hypothalamic Glucagon Signaling Regulates Glucose Production", DIABETES, vol. 61, 2012, pages 55
NAUCK MA: "The Design of the Liraglutide Clinical Trial Programme, Diabetes", OBESITY AND METABOLISM, vol. 14, 2012, pages 4 - 12
POCAI A.: "Action and Therapeutic Potential of Oxyntomodulin", MOL METAB., vol. 3, no. 3, 2013, pages 241 - 251, XP055535735, DOI: 10.1016/j.molmet.2013.12.001
POCAI A: "Unraveling Oxyntomodulin, GLP1's Enigmatic Brother", J ENDOCRINOL., vol. 15, 2012, pages 335 - 346, XP055419392, DOI: 10.1530/JOE-12-0368
RALF ELVERTANDREAS 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., vol. 20, 2018, pages 1836 - 1851
See also references of EP4360641A4
TAN TM: "Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia", DIABETES, vol. 62, no. 4, 2013, pages 1131 - 1138, XP055594768, DOI: 10.2337/db12-0797
THAM LAI-SAN, THOMAS MELISSA K., BENSON CHARLES, BRAY ROSS, TANG CHENG CAI, LOGHIN CORINA: "106-OR: A First-in-Human Single Ascending Dose Study of Oxyntomodulin Analog LY3305677 in Healthy Subjects.", DIABETES, AMERICAN DIABETES ASSOCIATION, US, vol. 70, no. Supplement_1, 1 June 2021 (2021-06-01), US , XP009542081, ISSN: 0012-1797, DOI: 10.2337/db21-106-OR *
WANG HONGSHA, GUO WEIYING: "Relationships between Hyperuricemia and Hyperglycemia, Hypertension, and Obesity", ZHONGGUO LAONIANXUE ZAZHI, ZHONGGUO LAONIANXUE ZAZHI BIANJIBU, vol. 36, no. 11, 30 November 2016 (2016-11-30), pages 5729 - 5732, XP093017468, ISSN: 1005-9202, DOI: 10.3969/j.issn.1005-9202.2016.22.112 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023231730A3 (zh) * 2022-06-01 2024-01-25 信达生物制药(苏州)有限公司 使用mazdutide的治疗方法
WO2025073289A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating diabetes and obesity
WO2025073288A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating adolescent obesity
WO2025098422A1 (zh) * 2023-11-07 2025-05-15 深圳信立泰药业股份有限公司 多重受体共激动剂化合物及其制备方法与应用

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