119-OR: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Ultra-Long-Acting GLP-1 Receptor Agonist (ZT002) in Healthy Subjects

Introduction: ZT002, a novel ultra-long-acting GLP-1RA, is designed for monthly or biweekly subcutaneous administration and has non-inferior efficacies and a safety profile to semaglutide. Preclinical pharmacokinetics (PK) studies in multiple species (mouse, rat, minipig, monkey) demonstrated ZT002 had a 2-4 fold longer half-life than semaglutide. This first-in-human study assessed the safety, tolerability, PK, and pharmacodynamics (PD) of single ascending doses (SAD) of ZT002 in healthy subjects.

Methods: This phase 1, randomized, double-blind, placebo-controlled, SAD trial was conducted in Australia. Overtly healthy adults 18-55 years with the body mass index of 22.0-35.0 kg/m² were randomized (6:2) to receive ZT002 (0.03, 0.09, 0.13 and 0.26 mg/kg) or placebo.

Results: A total of 32 subjects [N=20 (male)/12 (female); median age=28 years; median BMI=26.7 kg/m²)] participated in the SAD trial. There were no serious adverse events, deaths or treatment-emergent adverse events (TEAEs) that led to withdrawal. The most common TEAEs related to the study drug were gastrointestinal (nausea and vomiting), and the majority were considered mild and transient. The PK profile was dose-proportional over the dose range with a mean half-life of 260-273 hours, supporting a monthly or biweekly injection. Weight loss from baseline at Day 15 was dose-responsive across the 4 cohorts, and the mean reduction in body weight (BW) from baseline on Day 14 was 2.01 kg in subjects with 0.26mg/kg ZT002 and clinically meaningful weight reduction, in comparison to the placebo, was maintained up to Day 71.

Conclusion: This SAD trial of ZT002 demonstrated acceptable safety, tolerability profile, and superior PK profiles. Significant reductions in BW were observed in healthy subjects. Further clinical development of ZT002 as a monthly or biweekly injectable therapy for obesity and type 2 diabetes mellitus (T2DM) is underway.