A Bridging Study of Efsubaglutide Alfa in Healthy Adults in Brazil

A Randomized, Double-Blind, Placebo-Controlled Bridging Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Efsubaglutide Alfa in Healthy Adult Participants in Brazil

This is a Phase I, randomized, double-blind, placebo-controlled, single-dose study in healthy adult participants in Brazil to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of YN-011. Participants will be randomized to receive a single subcutaneous dose of YN-011 1 mg, YN-011 3 mg, or matching placebo. The study includes screening, approximately 2 days of study-site confinement from the day before dosing to 24 hours after dosing, and outpatient follow-up for 4 weeks. Assessments include safety monitoring, PK blood sampling, PD evaluations, and immunogenicity testing.

This is a Phase I, randomized, double-blind, placebo-controlled, single-dose, parallel-group study in healthy adult participants in Brazil to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of YN-011 following subcutaneous administration.

The study will be conducted at a single clinical study site in Brazil and will enroll approximately 48 healthy adult participants. Participants will be randomized into 2 dose cohorts, a 1 mg cohort and a 3 mg cohort. Within each cohort, participants will be randomized in a 5:1 ratio to receive a single subcutaneous dose of YN-011 or matching placebo. Overall, the study will include 3 treatment groups: YN-011 1 mg, YN-011 3 mg, and placebo. The placebo will be matched in appearance and administered using the same device format in order to maintain blinding.

The main objectives of the study are to assess the safety and tolerability of YN-011 after single-dose administration in healthy adult participants, to characterize its PK profile, to evaluate selected PD effects, and to assess immunogenicity. Safety evaluations will include adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and other appropriate clinical assessments. PK assessments will characterize the concentration-time profile of YN-011 after dosing. PD assessments will evaluate the biologic effects of YN-011 after administration. Immunogenicity assessments will evaluate whether participants develop an immune response to YN-011.

The study includes a screening period of up to 4 weeks, a study-site confinement period of approximately 2 days, and an outpatient follow-up period of 4 weeks, for a maximum total study duration of approximately 8 weeks per participant. Participants will be admitted to the clinical study site on the day before dosing and will undergo pre-dose assessments to confirm continued eligibility. On Day 1, participants will receive a single subcutaneous injection of YN-011 1 mg, YN-011 3 mg, or matching placebo in the abdomen using a prefilled auto-injector.

During the confinement period, participants will remain under close clinical observation and will receive a controlled diet with specified fasting and fluid intake restrictions around dosing. After completion of the post-dose confinement period, participants will be discharged from the clinical study site and will return for scheduled outpatient follow-up visits for PK blood sampling, safety monitoring, PD evaluations, and immunogenicity assessments.

The results of this study are expected to provide clinical information on the safety, PK, PD, and immunogenicity profile of single-dose YN-011 in healthy adult participants in Brazil.

Inclusion Criteria:

1. Healthy male or female adults, aged 18-45 years (both inclusive) at the time of signing the informed consent form (ICF).
2. Body mass index (BMI) between 18-28 kg/m2 (both inclusive). Male participants must weigh no less than 50 kg, and female participants must weigh no less than 45 kg.
3. Voluntary participation in this study, as documented by the written signature of two copies of the ICF.
4. Negative serum pregnancy test for women of childbearing potential (WOCBP) during screening period. WOCBP and fertile male participants with WOCBP partners must use highly effective contraception methods without planning to become pregnant or to donate sperm or eggs throughout this study (from signing the ICF to at least 3 months after completion of this study).
5. Be able to maintain good communication with the investigators and comply with all requirements of protocol to complete all trial procedures.

Exclusion Criteria:

1. Known or suspected allergy to the investigational medicinal product, its components or drugs of the same class, or a clinically significant drug allergy, or a history of atopic allergic disease.

2. Previously or currently diagnosed diabetes mellitus (T1D or T2D) or prediabetes, according to the diagnostic criteria of the Brazilian Diabetes Society (SBD) guideline, defined by any of the following laboratory findings:

   • FPG ≥126 mg/dL or ≥7.0 mmol/L ;
   • FPG 100-125 mg/dL or 5.6 -6.9 mmol/L (prediabetes);
   • HbA1c ≥ 6.5% or ≥48 mmol/mol;
   • HbA1c 5.7-6.4% or 39-47 mmol/mol (prediabetes).

3. History of clinically significant endocrine disorders that may affect glucose metabolism, body weight, or drug PK, including but not limited to Cushing's syndrome; acromegaly; pheochromocytoma; untreated or uncontrolled thyroid disorders (hyperthyroidism or hypothyroidism); polycystic ovary syndrome (PCOS) with metabolic abnormalities; adrenal insufficiency or other adrenal disorders; pituitary disorders affecting hormonal regulation.

4. History of acute or chronic pancreatitis, symptomatic gallbladder disease (those who have recovered from cholecystectomy and have no sequelae after treatment are allowable to be enrolled), pancreatic injury or other high-risk factors that may lead to pancreatitis, or screening serum amylase or lipase >2X upper limit of normal (ULN).

5. History of significant gastrointestinal (GI) disorders (e.g., gastroparesis, active ulcers within 6 months, or long-term use of medications that directly affect GI motility, or GI surgery within 6 months prior to screening.

6. History or presence of hepatic, renal, cardiovascular, neurological, psychiatric, psychological or immunological disorders.

7. Clinically significant abnormalities in physical examination, vital signs, laboratory tests, or 12-lead ECG at screening, and investigators consider that these abnormalities may affect participant's safety or study results. ECG abnormalities including but not limited to: second- or third-degree atrioventricular block; long QT syndrome or QTcF > 450 ms (males) or > 470 ms (females). (If the QTcF > 450 ms (males) or > 470 ms (females), two additional ECG measurements should be repeated, and the mean of the three values should be used to determine the participant's eligibility.); left bundle branch block;Wolff-Parkinson-White syndrome; Or other clinically significant 12-lead ECG abnormalities requiring treatment.

8. Use of any prescription or over-the-counter (OTC) medications, traditional Chinese medicine within 12 months prior to screening that may confound PK, PD, or safety assessments.

9. Personal or family history of thyroid C-cell tumors including medullary thyroid carcinoma (MTC), or multiple endocrine neoplasia type 2 (MEN2), or presence of hyperthyroidism or hypothyroidism that has not been controlled with a stable medication dose (defined as a stable dose for at least 3 months or longer).

10. Positive test results for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBSAg) and HBV-deoxyribonucleric adic (DNA) ≥ lab-specific ULN (for those with positive result on HBsAg, HBV-DNA test will be performed), hepatitis C antibody (HCV-Ab) and HCV-ribonucleric acid (RNA), participant can be eligible at the discretion of the investigator if HCV-Ab positive and HCV RNA negative, or Treponema pallidum antibody (TP-Ab).

11. Pregnant or breastfeeding women.

12. Donation or loss of ≥400 mL of blood within 3 months prior to screening.

13. History of drug abuse within 1 year prior to screening, or positive drug abuse screening test (including amphetamines (AMP), cocaine (COC), tetrahydrocannabinol (THC), morphine (MOP), benzodiazepines (BZO), and methamphetamines (MET), any one or more of which tested positive).

14. Consumption of more than 14 units of alcohol per week within 6 months prior to screening (1 unit of alcohol equivalent to 360 mL of beer or 45 mL of spirits with an alcohol content of 40% or 150 mL of wine), or consumption of alcohol-containing products within 48 hours before administration, or positive breath alcohol test before administration.

15. Participation in other clinical trials of vaccines, medical devices, or other drugs within 12 months prior to screening

16. Major surgery within 4 weeks prior to screening, or planned major surgery during the study.

17. Participant with systolic blood pressure (SBP) < 90 mmHg or > 140 mmHg, or diastolic blood pressure (DBP) < 50 mmHg or > 90 mmHg after resting in a sitting position, or heart rate (HR) < 50 beats per minute (BPM) or > 100 bpm at rest in sitting position at the screening.

18. Any other factors that may affect participation in this study at the discretion of the investigator.