236-OR: Volagidemab, a Human Glucagon Receptor Antagonist, Improves Glycemic Control in Subjects with Type 1 Diabetes (T1D): A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Abnormal regulation of glucagon secretion contributes to impaired glycemic control in patients with T1D. We conducted two 12-week, double-blind, randomized, placebo-controlled trials to evaluate the efficacy of blocking glucagon action with the glucagon receptor antagonist antibody, volagidemab (VOLA), on glycemic control in patients with T1D. In both trials, participants were randomized in a 1:1:1 fashion to weekly subcutaneous injection with placebo (PBO), VOLA 35 mg, or VOLA 70 mg. Participants in Trial 1 (n=75) were unblinded and participants in Trial 2 (n=78) were blinded to the data from the study-provided continuous glucose monitoring (CGM). All participants could monitor glucose values by fingerstick or their own CGM, if these modalities were part of their usual care before the study. In Trial 1, baseline A1C was 7.5% and decreased by 0.39% (PBO), 0.64% (35 mg, p=0.029), and 0.69% (70 mg, p=0.008) at week 12. An A1C target of ≤ 7.0% was achieved in 43% (PBO), 70% (VOLA 35 mg), and 71% (VOLA 70 mg) of participants. Insulin total daily dose (TDD) decreased by 6.3% (PBO), 12.9% (VOLA 35 mg, NS) and 12.2% (VOLA 70 mg, NS) at week 12. In Trial 2, baseline A1C was 7.9% and decreased by 0.03% (PBO), 0.63% (VOLA 35 mg, p=0.001) and 0.66% (VOLA 70 mg, p=0.001). An A1C target of ≤7.0% was achieved in 17% (PBO), 50% (VOLA 35 mg), and 38% (VOLA 70 mg) of participants. Insulin TDD decreased by 3.5% (PBO), 15.1% (VOLA 35 mg, NS), and 10.2% (VOLA 70 mg, NS). A majority of adverse events were Grade 2 or lower in severity. Intermittent Increases in BP and ALT were observed in VOLA vs. placebo participants during the dosing period and returned to BL after treatment discontinuation. These data demonstrate that treatment with VOLA 35 mg or 70 mg once weekly as an adjunct to insulin is safe, well-tolerated, and decreases A1C with a trend toward decreased insulin dosing in people with T1D. Disclosure J. Pettus: Advisory Panel; Self; Novo Nordisk, Sanofi, Consultant; Self; Diasome Pharmaceuticals, Inc., Insulet Corporation, Lilly Diabetes, MannKind Corporation, Tandem Diabetes Care. B. W. Bode: Advisory Panel; Self; Eli Lilly and Company, Consultant; Self; Bigfoot Biomedical, Inc., Companion Medical, Lexicon Pharmaceuticals, Inc., Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Abvance Therapeutics, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Dompe, Eli Lilly and Company, Eyenuk, Inc., Insulet Corporation, Jaeb Center for Health Research, Medtronic, Nova Biomedical, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanofi, Senseonics, Viacyte, Inc., vTv Therapeutics, Xeris Pharmaceuticals, Inc., Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk, Sanofi, Stock/Shareholder; Self; AgaMatrix, Aseko, Inc., Glytec, LLC. E. D. Bautista: Consultant; Self; REMD Biotherapeutics. H. Yan: Board Member; Self; REMD Biotherapeutics, Other Relationship; Spouse/Partner; REMD Biotherapeutics. D. Thai: Employee; Self; REMD Biotherapeutics. S. K. Garg: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Medtronic. S. Klein: Advisory Panel; Self; Altimmune, Merck & Co., Inc., Novo Nordisk Inc., ProSciento, Research Support; Self; Janssen Research & Development, LLC. S. C. Boeder: Consultant; Self; Cecelia Health, Research Support; Self; Dexcom, Inc. M. P. Christiansen: Research Support; Self; Abbott Diabetes, Biolinq, Dexcom, Inc., Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Viacyte, Inc. D. S. Denham: None. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. H. K. Akturk: Consultant; Self; American Diabetes Association, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, IM Therapeutics, MannKind Corporation, REMD Biotherapeutics, Senseonics, Speaker’s Bureau; Self; American Diabetes Association. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo No