MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, in Patients with Type 2 Diabetes—A Multiple-Ascending-Dose Study

Abstract

MEDI0382 is a GLP-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus (T2DM). This double-blind study (NCT02548585) evaluated MEDI0382 in T2DM patients with BMI 27-40 kg/m2. Subjects (n = 61) were randomized to once-daily subcutaneous MEDI0382 or placebo (PBO) at different dosing levels and uptitration schedules (100 μg [C1], 150 μg [C2], 200 μg [C3], and 300 μg (2 uptitration schedules, C4 and C5). Marked reduction in fasting and postprandial glucose was achieved with a ∼40% decrease in glucose AUC0-4h after mixed-meal testing across all cohorts (P ≤ 0.0102) (Figure 1A). Weight loss was observed at all dose levels and reached statistical significance (P = 0.024) at 300 μg (C4) (Figure 1B). Ambulatory systolic blood pressure decreased nonsignificantly from baseline in the 300-μg cohort (C4, -4.9 vs. -6.5 mmHg; C5, -9.1 vs. -5.0 mmHg). Similar to other marketed GLP-1 analogs, MEDI0382 increased pulse rate vs. PBO (C4, 8.4 vs. -2.4 BPM, P = 0.0039; C5, 5.8 vs. 0.2 BPM, P = 0.0796). Treatment-related adverse events occurred more often with MEDI0382 vs. PBO (86% [36/42] vs. 47% [9/19]); most events were mild or moderate in severity. In conclusion, MEDI0382 administered for up to 22 days showed a marked reduction in both fasting and postprandial glucose with weight reduction and an acceptable tolerability profile. Disclosure D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M.W. Stumvoll: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. G. Klein: None. L. Tsai: Employee; Self; MedImmune. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.