754-P: A First-in-Human Single Ascending Dose Study of GSBR-1290, a Novel Small Molecule GLP-1 Receptor Agonist, in Healthy Volunteers

Abstract

Introduction: Type 2 Diabetes Mellitus (T2DM) and obesity incidences are rising globally. The risk:benefit ratio of peptide GLP-1 receptor agonists (RAs) has been established; however, new therapeutic options are still needed. We report the results of a single ascending dose (SAD) study with GSBR-1290, a highly potent, orally bioavailable, fully biased small molecule GLP-1 RA. Methods: The study enrolled 48 healthy volunteers in 6 Cohorts, randomized 3:1 to receive GSBR-1290 (1, 10, 15, 30, 60, and 90 mg) or placebo, under fasting conditions. The safety, tolerability, and pharmacokinetics (PK) of a single dose of GSBR-1290 were investigated. The food effect on PK was also assessed in the 15 mg cohort. Results: Participants were well-balanced across the treatment groups: female (60%), white (66%), mean age (SD) 30 (8) years, and BMI (SD) 24.5 (3.0). All randomized subjects completed the study and there were no deaths or serious adverse events. Treatment-emergent adverse events (TEAEs) were reported for 32/36 participants (89%) following fasted administration of GSBR-1290 and for 7/12 participants (58%) following administration of placebo. The majority (94%) were mild or moderate in severity. As expected, the most common TEAEs were gastrointestinal-related and included nausea, vomiting, decreased appetite and diarrhea, consistent with other drugs in this class. No clinically significant changes in laboratory safety parameters were reported. PK (Cmax and AUC) of GSBR-1290 increased with dose, and a high fat meal was associated with a 20% decrease in the geometric mean AUC and a 36% decrease in Cmax. Conclusion: GSBR-1290 is a promising orally available GLP-1 RA and was well-tolerated in this SAD study in healthy volunteers. These data support further clinical development in a multiple ascending dose study in individuals with T2DM and obesity. Disclosure B.Coll: Employee; Amgen Inc., ShouTi Pharma Inc. J.J.Zhang: Employee; Structure Therapeutics Inc. S.J.Jacober: Consultant; Structure Therapeutics, Inc., Adocia, Employee; Sanofi-Aventis U.S., Applied Therapeutics Inc., Other Relationship; Eli Lilly and Company. C.Argent: None. L.Ibarra: Employee; Structure Therapeutics. M.Snyder: None. M.A.Bach: Employee; Structure Therapeutics, Stock/Shareholder; Johnson & Johnson. Funding Structure Therapeutics Inc.