A Bioequivalence Study of Two Formulations of Oral Semaglutide in Healthy Participants
Mette S. Nielsen, Lise Brøndsted, Martin Kankam, Gaetano Morelli, D. Le Nguyen, Trine Vang Skjøth, Usha Rani H. Patted, Marloes van Hout
Abstract
The glucagon-like peptide-1 (GLP-1) analogue semaglutide is approved as an oral formulation for the treatment of type 2 diabetes. This study aimed to confirm bioequivalence between a new, second-generation (2G) oral semaglutide formulation (1.5, 4 and 9 mg) and the initially approved first-generation (1G) formulation (3, 7 and 14 mg). This was a randomised, multicentre, open-label, full replicate crossover study to confirm bioequivalence between 2G and 1G oral semaglutide formulations at steady-state (SS) in healthy participants (NCT05227196). Participants were recruited to three groups. In each group, participants were randomised to one of two alternating sequences comparing once-daily oral semaglutide treatment of 9 and 14 mg (group 1), 4 and 7 mg (group 2) or 1.5 and 3 mg (group 3) at SS. Treatment duration was 20 weeks, comprising four 5-week steady-state periods on alternating formulations. Repeated 24-h blood sampling at the end of each steady-state period supported pharmacokinetic analysis. Co-primary endpoints were area under the semaglutide plasma concentration–time curve during a dosing interval at SS (AUC 0–24h,SS ) and maximum semaglutide plasma concentration at SS ( C max, 0–24h,SS ). Bioequivalence for co-primary endpoints was assessed using European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA) criteria. Safety was monitored. A total of 222, 201 and 123 participants were recruited into groups 1, 2 and 3, respectively. The prespecified EMA, FDA and PMDA bioequivalence criteria were met for 2G versus 1G oral semaglutide for all three dose levels (1.5 vs 3 mg, 4 vs 7 mg and 9 vs 14 mg). The safety profile of 2G oral semaglutide was consistent with 1G oral semaglutide. The 2G oral semaglutide formulation was confirmed as bioequivalent to 1G oral semaglutide, with no new safety concerns identified. ClinicalTrials.gov identifier, NCT05227196.