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)
Chinese (zh)
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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 CN202280045316.5A priority Critical patent/CN117597135A/zh
Priority to JP2023579334A priority patent/JP2024524273A/ja
Priority to US18/573,602 priority patent/US20240293513A1/en
Priority to EP22827666.3A priority patent/EP4360641A4/en
Priority to KR1020247003005A priority patent/KR20240027053A/ko
Priority to CA3224043A priority patent/CA3224043A1/en
Priority to AU2022298841A priority patent/AU2022298841A1/en
Publication of WO2022268174A1 publication Critical patent/WO2022268174A1/zh
Anticipated expiration legal-status Critical
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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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PCT/CN2022/100878 2021-06-25 2022-06-23 Mazdutide的应用 Ceased WO2022268174A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN202280045316.5A CN117597135A (zh) 2021-06-25 2022-06-23 Mazdutide的应用
JP2023579334A JP2024524273A (ja) 2021-06-25 2022-06-23 マズチドの使用
US18/573,602 US20240293513A1 (en) 2021-06-25 2022-06-23 Use of mazdutide
EP22827666.3A EP4360641A4 (en) 2021-06-25 2022-06-23 USE OF MAZDUTIDE
KR1020247003005A KR20240027053A (ko) 2021-06-25 2022-06-23 마즈두타이드의 용도
CA3224043A CA3224043A1 (en) 2021-06-25 2022-06-23 Use of mazdutide
AU2022298841A AU2022298841A1 (en) 2021-06-25 2022-06-23 Use of mazdutide

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CN202110711050.0 2021-06-25
CN202110711050 2021-06-25

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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
WO2025073288A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating adolescent obesity
WO2025073289A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating diabetes and 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
TWI700291B (zh) * 2015-06-22 2020-08-01 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
KR20250021331A (ko) * 2022-06-01 2025-02-12 이노벤트 바이오로직스 (쑤저우) 컴퍼니, 리미티드 mazdutide를 사용하는 치료 방법

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
WO2025073288A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating adolescent obesity
WO2025073289A1 (en) * 2023-10-03 2025-04-10 Innovent Biologics (Suzhou) Co., Ltd. Methods of treating diabetes and 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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