768-P: A Phase 1b/2a Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of PB-718, a GLP-1R/GCGR Dual Agonist in Subjects with Obesity

Abstract

Introduction: PB-718 is a fixed dose combination of PB-119 (GLP-1 receptor agonist) and PB-722 (glucagon receptor agonist in clinical development. Compared with a single molecule approach, PB-718 may offer the balance between GLP-1 and GCGR through adjusting the molar ratio of PB-119 and PB-722 to achieve optimal efficacy and safety. Linear pharmacokinetics, good tolerability and promising effect of weight loss have been demonstrated in a phase 1 study conducted in US. Here we report a phase 1b/2a study in Obesity Methods: Thirty-six patients with obesity (BMI 30.5-40.0 kg/m2) without diabetes were randomized to this 3-sequential cohorts study (NCT06147544). In each cohort, 12 subjects were randomized (3:1) to receive PB-718 (PB-119/PB-722 600/1560 μg, 900/2340 μg or 1600/4160 μg) or placebo SC. injections once a week for 12-18 weeks. The primary endpoints were safety and PK profile. The secondary efficacy endpoints included changes in body weight (BW), BMI, lipids and HbA1c levels. Liver MRI-PDFF and body composition analysis were also assessed. Results: Both PB-119 and PB-722 demonstrated dose-proportional increases in AUC0-last and Cmax ,showing linear, and synergic pharmacokinetics. At 12 weeks, BW, FPG, HbA1c, Lipid, insulin level and HOMA-IR all decreased dose-dependently, and significant reduction in BW of over 4-6% were observed. Serum uric acid was also decreased. Liver fat content and visceral fat mass also showed significant and dose-related reduction with PB-718 treatment. Meanwhile, PB-718 groups lost more fat mass than lean mass. GI side effects were the most common AEs, and were all grade 1 in severity. Conclusions: PB-718 was safe, had predicted PK profile, and led to greater reductions in BW, HbA1c, blood lipids, uric acid, liver fat content and visceral fat mass. These data highlight the potential for PB-718 to provide additional benefit, and support the development of PB-718 as a promising treatment for obesity and NASH. Disclosure K. Ding: None.