Safety, Efficacy and Pharmacokinetics of Repeat Subcutaneous Dosing of Avexitide (Exendin 9-39) for Treatment of Post-Bariatric Hypoglycemia.

AIMS: To evaluate the safety, efficacy, and pharmacokinetics of repeat dosing of two formulations of subcutaneous (SC) avexitide (exendin 9-39) in patients with post-bariatric hypoglycemia (PBH). METHODS: In this Phase 2, multiple-ascending-dose study conducted at Stanford University, 19 women with PBH underwent a baseline oral glucose tolerance test (OGTT) with metabolic and symptomatic assessments. Fourteen participants were then sequentially assigned to receive 1 of 4 ascending dose levels of twice daily (BID) lyophilized (Lyo) avexitide by SC injection for 3 days. On the basis of safety, efficacy and tolerability, 5 additional participants then received a novel liquid formulation (Liq) of avexitide by SC injection at a fixed dose of 30 mg BID for 3 days. All 19 subjects underwent a repeat OGTT on Day 3 of dosing to quantify metabolic, symptomatic, and pharmacokinetic responses. RESULTS: Treatment with Lyo avexitide reduced the magnitude of symptomatic hyperinsulinemic hypoglycemia at all dose levels, with dose-dependent improvements in glucose nadir, insulin peak and symptom score; doses >/=20 mg BID did not require glycemic rescue (administered at glucose <50 mg/dL). Participants receiving Liq avexitide 30 mg BID did not require any glycemic rescue, and on average achieved a 47% increase in glucose nadir, 67% reduction in peak insulin, and 47% reduction in overall symptom score. Equivalent doses of Liq vs Lyo avexitide yielded higher and more sustained plasma concentrations. Both formulations were well tolerated. CONCLUSIONS: In patients with PBH, BID administration of SC avexitide effectively raised the glucose nadir and prevented severe hypoglycemia requiring rescue intervention. Avexitide may represent a viable therapy for PBH.