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. 2025 Feb;16(2):269-287.
doi: 10.1007/s13300-024-01674-8. Epub 2024 Dec 21.

A Bioequivalence Study of Two Formulations of Oral Semaglutide in Healthy Participants

Mette Søndergaard Nielsen  1 , Lise Brøndsted  1 , Martin Kankam  2 , Gaetano Morelli  3 , David Nguyen  4 , Trine Vang Skjøth  1 , Usha Rani Patted  5 , Marloes van Hout  6
Affiliations

A Bioequivalence Study of Two Formulations of Oral Semaglutide in Healthy Participants

Mette Søndergaard Nielsen et al. Diabetes Ther. 2025 Feb.

Abstract

Introduction: 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).

Methods: 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 (AUC0-24h,SS) and maximum semaglutide plasma concentration at SS (Cmax, 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.

Results: 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.

Conclusions: The 2G oral semaglutide formulation was confirmed as bioequivalent to 1G oral semaglutide, with no new safety concerns identified.

Trial registration: ClinicalTrials.gov identifier, NCT05227196.

Keywords: Antidiabetic drug; Bioavailability; Bioequivalence; GLP-1 analogue; Glycaemic control; Incretin therapy; Semaglutide; Type 2 diabetes.

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Conflict of interest statement

Declarations. Conflict of interest: Mette Søndergaard Nielsen—Employee and shareholder of Novo Nordisk A/S. Lise Brøndsted—Employee and shareholder of Novo Nordisk A/S. Martin Kankam—One of the clinical investigators who participated in the conduct of the study, which was sponsored by Novo Nordisk; employee at Altasciences and has received clinical trial funding from Amgen, Biogen, Biohaven, Camino, DynPort, Eli Lilly, EncuraGen, NIH/DMID, Staidson and Vertex. Gaetano Morelli—Employee at Altasciences. David Nguyen—Employee at Altasciences. Trine Vang Skjøth—Employee and shareholder of Novo Nordisk A/S. Usha Rani Patted—Employee of Novo Nordisk India Private Ltd. Marloes van Hout—Employee and shareholder of Novo Nordisk A/S. Ethical approval: The study protocol was approved by appropriate health authorities according to local guidelines and by the Institutional Review Board/Independent Ethics Committee Institutional Review Board, listed in the Supplementary Appendix. The study was conducted in accordance with the Declaration of Helsinki and International Council for Harmonization (ICH) Good Clinical Practice guidelines. Participants provided written informed consent prior to commencement of any study-related activities.

Figures

Fig. 1
Fig. 1
Study design. aNot all visits are shown in the diagram. 1G first generation, 2A dose escalation visit (group 1: day 1), 2B dose escalation visit (group 1: day 8; group 2: day 1), 2G second generation, N planned number of participants (please refer to Results and Fig. 2 for the actual number of participants enrolled); PK pharmacokinetic
Fig. 2
Fig. 2
Participant disposition. FAS: all randomised participants who were exposed to at least one dose of study product and completed at least one period on 2G oral semaglutide and one period on 1G oral semaglutide. SAS: all randomised participants who were exposed to at least one dose of study product. 1G first generation, 2G second generation, FAS full analysis set, SAS safety analysis set, TEAE treatment-emergent adverse event
Fig. 3
Fig. 3
Semaglutide dosing interval profiles at steady-state in group 1 (a), group 2 (b) and group 3 (c). Geometric mean semaglutide plasma concentrations after 5 weeks of once-daily dosing of oral semaglutide at doses of 9 and 14 mg (a), 4 and 7 mg (b) and 1.5 and 3 mg (c) in healthy participants. Full analysis set: all randomised participants who were exposed to at least one dose of study product and completed at least one period on 2G oral semaglutide and one period on 1G oral semaglutide. 1G first generation, 2G second generation, LLOQ lower limit of quantification
See this image and copyright information in PMC

References

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