Dose-escalation and Food Effect Study of ZT006 in Healthy, Overweight and Obese Participants

A Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ZT006 as Well as the Food Effect on the Pharmacokinetics of ZT006 in Healthy, Overweight and Obese Participants

ZT006 is an oral, long-acting glucagon-like peptide-1. This first-in-human study is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ZT006 in healthy, overweight and obese participants. The study comprises three parts, i.e. single dose-escalation, multiple dose-escalation, food effect on the pharmacokinetics of ZT006.

In the single dose-escalation study, participants will receive a single dose (ZT006 dose level 1 - 5 or corresponding placebo) of ZT006 under fasted condition. A higher dose can only be given after obtaining acceptable safety and tolerability data for at least 7 days after the previous dose. After study drug administration, there will be a 7-day in-house period for safety observation and pharmacokinetics samples collection. Participants will join ambulatory visits until 42 days post-dose.

In the multiple dose-escalation study, participants will receive a daily dose of ZT006 or corresponding placebo over 42 days in a dose up-titration fashion according to the following regimen:

• Cohort 1: dose level 1 - dose level 2 - dose level 3
• Cohort 2: dose level 1 - dose level 2 - dose level 3 - dose level 4
• Cohort 3: dose level 2 - dose level 3 - dose level 4
• Cohort 4: dose level 2 - dose level 3 - dose level 4 - dose level 5

Dosing of a cohort with higher drug exposure can only be done after evaluation of safety and tolerability data for at least 14 days after the first dose in the previous cohort. Participants will join ambulatory visits until 35 days after the last dose.

To evaluate the food effect on the pharmacokinetics of ZT006, participants who have received single dose of ZT006 or placebo of dose level 4 in the single dose-escalation study will receive another dose of ZT006 or placebo after a high fat, high caloric breakfast.

Inclusion Criteria:

• Considered to be generally healthy based on the medical history, physical examination, and the results of vital signs, 12-lead electrocardiogram and clinical laboratory tests (hematology, urinalysis, chemistry, coagulation), as judged by the investigator.
• Male or female, age between 18 - 55 years (both inclusive) at the time of signing of the informed consent.
• Body mass index (BMI) 19.0 - 35.0 kg/m²(both inclusive). Body weight >50.0 kg for male participants and >45.0 kg for female participants. BMI 19 - 28.0 kg/m²(both inclusive) for single-dose escalation study, BMI 19.0 - 28.0 kg/m²(both inclusive) for cohorts 1 and 2 of multiple-dose escalation study, BMI 24.0 - 35.0 kg/m²(both inclusive) for cohorts 3 and 4 of multiple-dose escalation study.
• Having dietary caloric restriction and increased physical activity for ≥3 months, with change in body weight (increase or decrease) no more than 5%, irrespective of medical records.

Exclusion Criteria:

• Known hypersensitivity to the study drug or excipients or GLP-1 receptor agonists.
• Medical history of hypoglycemia.
• History or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, or history of pancreatitis or symptomatic gallbladder disease.
• Previous diagnosis of endocrine disorders or monogenic mutations causing obesity, including but not limited to hypothalamic obesity, pituitary obesity, hypothyroidism-induced obesity, Cushing's syndrome, insulinoma, acromegaly, or hypogonadism.
• Use of GLP-1 receptor agonists within 30 days or 5 half-lives (whichever is longer) before the first dose of the investigational intervention.
• Glycated hemoglobin (HbA1c) > 6.0% or fasting plasma glucose < 3.9 mmol/L or > 6.1 mmol/L at screening, or diagnosed with diabetes mellitus of type 1 or type 2 diabetes or other specific types derived from other causes.
• Aspartate aminotransferase ≥ 2 × upper limit of normal (ULN), Alanine aminotransferase ≥ 2 × ULN, or total bilirubin ≥ 1.5 × ULN
• Calcitonin above ULN at screening.
• Other clinically significant diseases detected within 12 months before screening (including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, pulmonary, immunological, psychiatric, or cardiovascular diseases).
• Use of prescription drugs (excluding topical eye/nose drops and creams without systemic exposure risk), over-the-counter drugs, dietary supplements, vitamins, or herbal medicines (excluding routine vitamins) within 2 weeks before screening.
• Long-term use of medications directly affecting gastrointestinal motility prior to screening. Use of weight-loss medications (including but not limited to orlistat) within 3 months before dosing.