1820-P: ALP001E, a Novel Glucagon Receptor Antagonist, Improves Insulin Resistance, Glycemic Control, and Beta-Cell Function in Type 2 Diabetes

Introduction and Objective: Type 2 diabetes mellitus (T2DM) is characterized by islet dysfunction and insulin resistance (IR). Therapies that effectively reduce IR remain limited, and the etiology of IR is unclear. Hyperglucagonemia is a key feature of T2DM. ALP001E is a novel, orally available glucagon receptor antagonist. The objective was to evaluate the safety, tolerability, and effects of ALP001E in patients with T2DM. Methods: This Phase 1, double-blind, randomized, placebo-controlled study consisted of single ascending dose and multiple ascending dose (MAD) components. In the MAD cohorts, 20 patients with T2DM receiving stable metformin were randomized to receive placebo or ALP001E at doses of 20 mg, 40 mg, or 80 mg administered twice daily for 14 days. The primary endpoints were safety and tolerability. Secondary and exploratory endpoints included pharmacodynamic effects on glycemic parameters, fasting insulin, incremental area under the curve over 4 hours during oral glucose tolerance testing (OGTT), homeostatic model assessment for β-cell function (HOMA2-B), and HOMA2-IR. Results: All 20 participants completed the study. The most frequently reported treatment-emergent adverse events (TEAEs) were medical device site reactions. All TEAEs were mild with no significant differences in incidence rates between the ALP001E and placebo groups. After 14 days of treatment, ALP001E resulted in significant reductions in fasting plasma glucose and HbA1c compared with placebo. Reductions in postprandial plasma glucose and glucose excursion during OGTT were also observed. Significant increases in HOMA2-B and significant decreases in HOMA2-IR were observed with ALP001E compared with placebo (mean percentage change in HOMA2-IR: −39.175% vs −6.825%, P < 0.05). Conclusion: ALP001E was safe and well tolerated. These findings demonstrate favorable pharmacodynamic effects on glycemic parameters and insulin resistance, supporting further clinical development of ALP001E as a potential therapeutic approach for T2DM. Disclosure C. Chung: Board Member; Current; Alphala CO., LTD., Alphala Group, INC.