Safety/tolerability, efficacy and pharmacokinetics of 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher: A phase I, randomized, double-blind, placebo-controlled study.

AIM: To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher. MATERIALS AND METHODS: This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight. RESULTS: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m2 , respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were -1.13% (0.64%) and -0.17% (0.65%); and mean percentage changes in body weight were -6.93% (3.44%) and -1.23% (1.20%). CONCLUSIONS: Cotadutide was well tolerated at doses up to 600 µg; efficacy versus placebo for weight loss and glycaemic control was shown.

Pharmacokinetics, safety, tolerability and efficacy of cotadutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, in phase 1 and 2 trials in overweight or obese participants of Asian descent with or without type 2 diabetes.

AIM: To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). MATERIALS AND METHODS: In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 µg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 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 versus 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.