314-OR: A Randomized Study of a GPR119 Agonist on Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes Mellitus (T1DM)

Introduction: Activation of GPR119 receptors (expressed on enteroendocrine and pancreatic islet cells) augments glucagon counter-regulatory responses to hypoglycemia in pre-clinical models. This response is studied using MBX-2982, a GPR119 agonist, in participants with T1D. Methods: This phase 2a double-blind, cross-over study randomized participants (age;20-60 years, T1D diagnosis ≥5 years) to treatment with 600 mg MBX-2982 or placebo for 14 days with two weeks washout between periods. The study endpoints included glucagon response, epinephrine response, and endogenous glucose production during a euglycemic/hypoglycemic clamp. Glucagon, GLP-1, and GIP in response to a mixed meal test and glycemic metrics from continuous glucose monitor (10 days) were also measured. Results: 18 participants (age 38.3±12 years, 50% females, 88.9% White, A1c 7.0±0.8%) were enrolled. Compared to placebo, MBX-2982 did not alter counter-regulatory responses to insulin-induced hypoglycemia. GLP-1 response to the MMT were higher following MBX-2982 administration. (Table) Conclusion: GPR119 activation with MBX-2982 did not improve glucagon counterregulatory responses to hypoglycemia in participants with T1D. The significant increases in fasting GLP-1 and responses during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L-cells. Disclosure A. Bilal: None. A. Casu: None. F. Yi: None. J.M. Mucinski: None. G. Mercouffer: None. D.E. Kelley: Consultant; Pramana Pharmaceuticals, Inc. R.E. Pratley: Other Relationship; Bayer AG, Dompé, Endogenex, Inc., Gasherbrum Bio, Inc., Hengrui (USA) Ltd., Intas Pharmaceuticals Ltd., Eli Lilly and Company, Merck Sharp AbbVie Inc., AstraZeneca. Other Relationship; Bayer HealthCare Pharmaceuticals, Inc., Biomea Fusion, Carmot Therapeutics, Inc., Corcept Therapeutics, Fractyl Health, Inc., Genprex. Consultant; Getz Pharma. Other Relationship; Lilly USA LLC, Sanofi. Consultant; Scholar Rock, Inc. Funding The Helmsley Charitable Trust, CymaBay Therapeutics.