OR20-5 28-Day Dosing with Avexitide Improves Hyperinsulinemic Hypoglycemia in Patients with Severe, Refractory Post-Bariatric Hypoglycemia: The PREVENT Study

Avexitide (formerly exendin 9-39) is a first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist in development as a liquid formulation for subcutaneous (SC) injection for treatment of post-bariatric hypoglycemia (PBH). PBH, a rare disease with high unmet medical need and no approved pharmacologic therapy, develops as a late complication of bariatric surgery. Patients with PBH exhibit exaggerated GLP-1 levels with dysregulated secretion of insulin and symptomatic hypoglycemia 1-3 hours after meals, putting them at risk for severe neuroglycopenic outcomes such as loss of consciousness, seizures, falls and motor vehicle accidents. Previous studies involving in-clinic SC injection of avexitide in patients with PBH have demonstrated attenuation of the insulinotropic effect of GLP-1 and prevention of hypoglycemia. PREVENT (NCT03373435), a Phase 2, multi-center, placebo-controlled study is the first to investigate the safety and durability of effect of 28-day outpatient dosing of SC avexitide in patients with severe, refractory PBH. Eighteen patients enrolled across five U.S. academic centers received placebo SC injections for 14 days in a single-blinded manner followed by avexitide SC 30 mg twice daily (BID) injections for 14 days and 60 mg once daily (QD) injections for 14 days, for a total of 28 days active dosing, in a double-blinded to dose, cross-over design. The primary efficacy endpoint of improved postprandial glucose nadir during mixed meal tolerance testing (MMTT) was achieved with avexitide 30 mg BID (57.1 vs 47.1 mg/dL; p = 0.001) and 60 mg QD (59.2 vs 47.1 mg/dL; p=0.0002), with fewer patients requiring glycemic rescue during each of the active dosing regimens than during placebo dosing. The secondary endpoint of reduced postprandial insulin peak during MMTT was achieved with avexitide 30 mg BID (349.5 vs 454.5 μIU/mL; p < 0.03) and 60 mg QD (357.2 vs 454.5 μIU/mL; p = 0.04). Metabolic and clinical improvements were monitored in the outpatient setting with electronic diaries and continuous glucose monitoring (CGM). Patients experienced fewer episodes of hypoglycemia (hypoglycemia symptoms confirmed by self-monitored blood glucose (SMBG) concentrations of <70 mg/dL) and severe hypoglycemia (neuroglycopenic symptoms confirmed by SMBG concentrations <55 mg/dL) during both dosing regimens of avexitide as compared to placebo. These results were corroborated by CGM data. Overall, avexitide was well-tolerated. There were no treatment-related serious adverse events and no participant withdrawals. PREVENT study findings support the continued development of avexitide for chronic treatment of PBH. Complete study results from PREVENT will be reported.