The Efficacy and Safety of Efsubaglutide Alfa in Overweight/Obesity（SPARKLE）

A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Efsubaglutide Alfa Injection in Subjects With Overweight or Obesity

This is a multicenter, double-blind, randomized, placebo-controlled phase Ⅱ study to evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of YN-011 in subjects with overweight (27 kg/m2 ≤ BMI < 30 kg/m2, with at least one comorbidity) or obesity (BMI ≥ 30 kg/m2, with or without comorbidities). The entire study period will consist of a 2-week screening period, a 22-week double-blind treatment period, and a 4-week off-treatment follow-up period

Inclusion Criteria:

1. Willing to comply with protocol required visit schedule and visit requirements and provide written informed consent form (ICF);
2. Male or female subjects, aged 18 to 75 years (both inclusive) at the time of signing the ICF;
3. Obese: BMI ≥ 30.0 kg/m2, with or without comorbidities; Or overweight: 27.0 kg/m2 ≤ BMI < 30.0 kg/m2, with at least one of the following weight-related comorbidities: pre-diabetes, hypertension, dyslipidemia, fatty liver, osteoarthritis, or obesity-induced obstructive sleep apnea syndrome (If the subject has only fatty liver as a comorbidity, imaging results within the 3 months prior to screening are required for fatty liver);
4. A self-reported change in body weight less than 5.0% controlled with diet and exercise within 3 months before screening;
5. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use highly effective contraception methods throughout the study (from the signing of ICF to 3 months after the last dose of investigational medicinal products).

Exclusion Criteria:

1. Obesity caused by endocrine disease or monogenic mutation, including but not limited to hypothalamic obesity, pituitary obesity, hypothyroidism-related obesity, Cushing's syndrome, insulinoma, acromegaly or hypogonadism;
2. Known or suspected allergy to the investigational medicinal product, its components or drugs of the same class;
3. Previously diagnosed diabetes mellitus (including type 1 diabetes mellitus, type 2 diabetes mellitus, diabetes mellitus due to pancreatic damage, or other types of diabetes mellitus [except gestational diabetes mellitus]);
4. History of severe gastrointestinal disease (e.g., active ulcers), or gastrointestinal surgery (except for appendectomy, cholecystectomy, or other gastrointestinal endoscopic surgeries deemed by the investigator to have no significant impact on gastrointestinal motility), or clinically significant gastric emptying abnormalities (e.g., pyloric obstruction, gastroparesis), or long-term use of drugs with direct effects on gastrointestinal motility within 6 months before screening, or those who were not suitable for participating in this study at the investigator's discretion;
5. History of significant cardiovascular or cerebrovascular disease within 6 months before screening, including but not limited to:1) Myocardial infarction, coronary angioplasty or bypass grafting, heart valve disease or heart valve repair, clinically significant arrhythmias requiring treatment, angina, transient ischemic attack, cerebrovascular accident or others; 2)Congestive heart failure classified as Grade III or IV by the New York Heart Association (NYHA) (refer to Appendix 3);
6. History of acute or chronic pancreatitis, symptomatic gallbladder disease (subjects who have undergone cholecystectomy and have stable condition post-surgery are excluded), or pancreatic injury and other factors that may lead to high risk of pancreatitis;
7. Presence of hyperthyroidism; or hypothyroidism that has not been controlled with a stable medication dose (defined as a stable dose for 3 months or longer);
8. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2);
9. Subjects who have experienced two or more hypoglycemic events within 6 months prior to screening, defined as blood glucose < 2.8 mmol/L (50.4 mg/dl) or blood glucose not reaching < 2.8 mmol/L (50.4 mg/dl) but with significant hypoglycemia symptoms (manifested by sympathetic arousal [e.g., palpitations, anxiety, sweating, dizziness, shaking of the hands, feeling of hunger, etc.] and CNS symptoms [e.g., altered mentation, cognitive disturbances, seizures and coma]);
10. History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous-cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years; or there is a potential malignancy during screening;
11. History of severe infection or severe trauma within 3 months prior to screening, or undergoing major surgery or not fully recovering from surgery, and the investigator determines that the participant is unsuitable for this study;
12. History of significant active or unstable major depressive disorder or other severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) within 2 years prior to screening;
13. Previous suicidal tendency or suicidal behavior;
14. Suicidal ideation corresponding to type 4 or 5 on the C-SSRS at screening;
15. PHQ-9 questionnaire ≥ 15 points at screening;
16. Known active infections, e.g., bacterial, fungal and viral infections, including: 1)Human immunodeficiency virus (HIV) infection: defined as HIV antibody positive; 2)Syphilis infection: defined as treponema pallidum antibody (TP-Ab) positive; 3)Active hepatitis B virus (HBV): defined as hepatitis B surface antigen (HBsAg) positive and HBV-deoxyribonucleic acid (DNA) ≥ lab-specific upper limit of normal (ULN) (for those with positive result on HBsAg, HBV DNA test will be performed and those with positive HBV DNA results will be excluded); 4)Active hepatitis C virus (HCV): defined as HCV antibody (HCV-Ab) positive and HCV-ribonucleic acid (RNA) positive, if HCV-Ab positive and HCV RNA negative can be considered as eligible at the discretion of the Investigator;
17. Any of the laboratory test results at screening meet the following criteria (if there is a clear reason for re-test, the re-test can be performed once during the screening period, and the investigator should record the reason for re-test): 1)HbA1c ≥ 6.5% or fasting blood glucose ≥ 7.0 mmol/L (126 mg/dL) (fasting blood glucose will be tested at the local laboratory at the time of screening, plasma or serum glucose is acceptable); 2)Thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 0.4 mIU/L; 3)ALT or AST ≥ 3.0×ULN or total bilirubin (TBIL) ≥ 2× ULN; 4)Fasting TG > 5.65 mmol/L (500 mg/dl); 5)Blood amylase or lipase > 2.0×ULN; 6)Calcitonin ≥ 50 ng/L(pg/mL); 7)Estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73m2, calculated by the CKD-EPI formula (refer to Appendix 4); 8)International normalized ratio (INR) > ULN;
18. Abnormal 12-lead ECG: second- or third-degree atrioventricular block, long QT syndrome or QTcF > 450 ms (males) or > 470 ms (females) (refer to Appendix 5), left bundle branch block, Wolff-Parkinson-White syndrome, or other clinically significant abnormalities that require treatment;
19. Uncontrolled hypertension, defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg;
20. Use of any of the following medications or treatments within 3 months prior to screening: 1)Weight loss drugs, such as semaglutide, sibutramine hydrochloride, orlistat, phentermine, phenylpropanolamine, chlorpheniramine, phentermine, bupropion, lorcaserin, phentermine/topiramate mixture, naltrexone/bupropion mixture, etc.; 2)Chinese herbal medicine, health products, meal replacements affecting body weight; 3)Glucose-lowering drugs, such as metformin, SGLT2 inhibitors, GLP-1R agonists, thiazolidinediones (TZDs), etc; 4)Drugs that may affect body weight, including systemic steroids (Consecutively for 7 or more days), tricyclic antidepressants, psychiatric drugs or sedative drugs (such as imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium salts);
21. Previous bariatric surgery; acupuncture/cupping for weight loss, liposuction, and abdominal liposuction within 1 year prior to screening; or plan to undergo corresponding treatment during the study period;
22. Subjects who have participated in other clinical studies and received investigational drug therapy, vaccines or medical device intervention within 3 months before screening;
23. Blood donation or blood loss ≥ 400 mL within 3 months before screening, or those who have received blood transfusion;
24. Inability to be venipunctured and/or tolerate venous access;
25. Alcohol consumption of > 21 units per week for males and > 14 units per week for females within the 6 months before screening (1 unit=360 mL of beer or 45 mL of spirits with an alcohol content of ≥ 40% or 150 mL of wine);
26. Have a history or suspected abuse of drug, and the investigator determines that the subject is unsuitable for this study;
27. Have history of use of marijuana within 3 months before screening and unwillingness to abstain from marijuana use during the study;
28. Pregnant or lactating women;
29. Other conditions deemed unsuitable for participation in this study according to the judgment of the investigator..