Introduction and Objective: Dapiglutide is a first-in-class GLP-1R/GLP-2R agonist in development for weight management designed to address low-grade inflammation and obesity-associated co-morbidities. Safety, tolerability, pharmacokinetics and pharmacodynamics of once-weekly s.c. dapiglutide were investigated in a phase 1b trial.Methods: In a double-blind, placebo-controlled trial, 54 healthy participants with BMI 27-39.9 kg/m2 (85% male, median age: 46 yrs, BMI: 30.0 kg/m2, body weight: 95.1 kg) were randomized (14:4) within 3 dose cohorts. Dose escalation every 2nd week was used to reach target doses of 7.5 mg, 10 mg and 13 mg during a 13-week treatment period. No lifestyle interventions were included in the trial.Results: Dapiglutide appeared safe with no related serious or severe adverse events (AEs). The most frequent AEs reported were gastrointestinal (GI) disorders and metabolism and nutrition disorders (mainly decreased appetite). Most AEs were mild. Two dapiglutide treated participants discontinued due to AEs (GI AEs). The pharmacokinetics showed dose proportionality and a mean half-life of 112-119 hours across the 3 dose cohorts. Low titers of ADA were detected at follow-up in 14.3% of the participants dosed with dapiglutide with no apparent impact on pharmacokinetics, efficacy or safety. After 13 weeks (of which 9, 7 and 5 weeks were on target doses), the placebo-corrected estimated mean decrease in body weight (efficacy estimand) was 6.7%, 8.3% and 7.1% for the dose cohorts of 7.5 mg, 10 mg and 13 mg, respectively. The mean body weight gain on placebo was 2.1%.Conclusion: Dapiglutide treatment of up to 13 mg appeared safe and well-tolerated with an AE profile similar to other incretin-based therapies. The placebo-adjusted reductions in body weight were up to a mean of 8.3% with dapiglutide after 13 weekly doses. The half-life of dapiglutide is suitable for once-weekly dosing. Doses up to 26 mg are currently being evaluated.
S. Maarbjerg: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. R. Zachariae: Employee; Zealand Pharma A/S. U. Hövelmann: None. N.J. Johansen: Employee; Zealand Pharma A/S. J.U.E. Lundahl: Employee; Zealand Pharma A/S. L.F. Larsen: Employee; Zealand Pharma A/S. N.S. Sørensen: Employee; Zealand Pharma A/S. E. Frary: Employee; Zealand Pharma A/S. T. Heise: Research Support; ADOCIA, Afon Technology, AstraZeneca, Altimmune Inc, Biocon, BIOTON, Civica Foundation, Eli Lilly and Company, Zealand Pharma A/S, Betagenon, Cass Pharmaceuticals, Novo Nordisk A/S, Corteria, Zealand Pharma A/S, Cytoki, Enyo Pharma, Gan & Lee Pharmaceuticals, Genova, Nanexa, Neodyne, SamChunDang Pharma. Co., Spiden, Sun Pharmaceutical Industries Ltd. Speaker’s Bureau; Eli Lilly and Company, Novo Nordisk A/S. Consultant; Gan & Lee Pharmaceuticals.
Zealand Pharma A/S
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