Abstract
Disclosure: Background: Post-bariatric hypoglycemia (PBH) is an increasingly recognized and often serious condition characterized by hyperinsulinemic hypoglycemia in individuals who have undergone bariatric surgery, believed to be driven by an excessive glucagon-like peptide-1 (GLP-1) response. PBH can cause debilitating hypoglycemic events associated with neuroglycopenia, including impaired cognition, loss of consciousness, and seizures. Avexitide is an investigational, first-in-class GLP-1 receptor antagonist designed to competitively inhibit GLP-1-mediated insulin secretion and stabilize glucose levels. In PREVENT, a phase 2, randomized, placebo-controlled crossover trial (N=18 enrolled, 17 evaluable), results showed a reduction in rates of Level 2 and Level 3 hypoglycemic events in participants with PBH after Roux-en-Y gastric bypass (RYGB) following treatment with avexitide 30 mg twice daily (BID) and 60 mg once daily (QD) compared with placebo. In a phase 2b, open-label, investigator-initiated, crossover trial (N=16), avexitide 45 mg BID and 90 mg QD reduced rates of Level 2 and Level 3 hypoglycemic events in participants following RYGB, vertical sleeve gastrectomy, and other upper-gastrointestinal surgeries. Avexitide was well-tolerated with no treatment-related serious adverse events or discontinuations. The phase 3 LUCIDITY trial, which will further evaluate avexitide in PBH, has a primary efficacy outcome of composite reduction of Level 2&3 hypoglycemic events. Objective: To understand the composite reduction of Level 2&3 hypoglycemic events in prior phase 2 trials of avexitide in PBH. Methods: For each avexitide dose, the rate of composite Level 2&3 events was calculated as the number of distinct events divided by number of days for a given treatment period then normalized to one week. A least-squares (LS) mean rate ratio vs placebo of hypoglycemia during the treatment period was then calculated. Results: In the PREVENT phase 2 trial, both avexitide regimens resulted in reductions in the composite rate of Level 2&3 events. The LS mean rate ratio vs placebo for avexitide 30 mg BID and 60 mg QD were 0.60 (95% confidence interval (CI): [0.357, 1.016]; p=0.0571) and 0.45 (95% CI: [0.281, 0.717]; p=0.0012), respectively. Composite data from the phase 2b trial with a 45mg BID and 90 mg QD dose will also be presented. Conclusions: Avexitide 30 mg BID and 60 mg QD led to a 40% and 55% reduction in the composite rate of Level 2&3 events, respectively. The impact of avexitide on composite rates of Level 2&3 hypoglycemia in the phase 2b trial, including at the higher 90 mg QD dose being tested in LUCIDITY, will be presented. Results of the complete analysis will provide valuable context given the planned LUCIDITY trial, which has topline data anticipated in 1H 2026. Presentation: Sunday, July 13, 2025