Pharmacokinetics, safety, tolerability, and efficacy of cotadutide, a GLP-1 and glucagon receptor dual agonist, in phase 1/2 trials in overweight or obese participants of Asian descent with or without T2D

Aims Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for non-alcoholic steatohepatitis and chronic kidney disease with type 2 diabetes (T2D). Phase 1 (NCT03385369) and phase 2a (NCT03645421) trials evaluated cotadutide in overweight Asian participants without and with T2D. Materials and methods In the Phase 1 randomized, blinded, single-ascending dose study, 24 Japanese and 8 Chinese healthy adults (BMI 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 μg, respectively) or placebo. Primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced up-titration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0-10.5%) received cotadutide (100, 200, 300 μg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h , and body weight. Results Significant reductions from baseline to Day 48 were observed with cotadutide for glucose AUC0-4h (33.6-42.1% reduction vs +2.5% with placebo; 95% CIs: 100 μg -45.7, -33.7; 200 μg -35.6, -23.7; 300 μg -45.0, -30.8; placebo 3.4, 8.3) and body weight (1.3-2.5% decrease vs +0.8% with placebo; 95% CIs: 100 μg -3.4, -0.8; 200 μg -4.7, -2.0; 300 μg -4.6, -2.1; placebo -2.1, 0.4). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide vs placebo is consistent with GLP-1 monoagonists. Conclusions Once-daily cotadutide was effective and well tolerated up to 300 μg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted. This article is protected by copyright. All rights reserved.