Regulatory Decision Summary for Rybelsus

This Supplement to a New Drug Submission was filed for Rybelsus (semaglutide) for new formulation for Rybelsus with the new strengths 1.5, 4 and 9 mg as an alternative to the currently approved formulation with the strengths of 3, 7, and 14 mg.

After evaluation of the submitted data package, Health Canada authorized Rybelsus oral semaglutide formulation D at strengths of 1.5 mg, 4 mg, and 9 mg for the same indication and dose regimen as the currently authorized oral semaglutide formulation with strengths of 3 mg, 9, mg, and 14 mg.

Authorization was primarily based on one bioequivalence study using the proposed formulation D versus (vs) the currently approved formulation of oral semaglutide in healthy subjects (Study 4799). Additional data from clinical studies of 4427 and 4486 in healthy subjects were also provided as supporting information.

Study 4799 is an interventional, multi-centre, randomised, 3-group, 4-period, full replicate crossover, open-label study comparing oral semaglutide D (new formulation) to the currently approved oral semaglutide formulation at steady-state. Healthy subjects received once daily doses at the three dose levels - Group 1: 9 mg vs 14 mg (n = 169), Group 2: 4 mg vs 7 mg (n = 113), Group 3: 1.5 mg vs 3 mg (n = 111). The primary endpoints were semaglutide exposure at steady-state (AUC_{0-24 h, ss}, and Cmax_{0-24 h, ss}) based on concentration data obtained from 24-h PK sampling post-last dose at the end of each 4 steady-state period. Bioequivalence was assessed in accordance with the pre-specified criteria and in compliance with the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidelines. Results of the estimated treatment ratio of AUC_{0-24 h, ss}, and Cmax_{0-24 h, ss} at steady-state met bioequivalence criteria (i.e. 90% confidence interval [CI] within 80 - 125%) at all three dose levels of oral semaglutide D (new formulation) versus the currently approved oral semaglutide formulation (1.5 mg vs 3 mg, 4 mg vs 7 mg and 9 mg vs 14 mg).

Safety data of oral semaglutide D, collected from both pivotal Study 4799 and the two supportive studies (4427 and 4486), were found to be consistent with the established safety profile of the currently approved oral semaglutide formulation. No new safety concerns related to treatment with oral semaglutide D or oral semaglutide were identified.

The recommended dose regimen of the new oral formulation D at the strengths of 1.5 mg, 4 mg, and 9 mg of Rybelsus is the same as the currently authorized oral formulation at 3 mg, 7 mg, and 14 mg, respectively.

Overall, the benefit-harm-uncertainty profile was favourable for Rybelsus at the strengths of 1.5 mg, 4 mg, and 9 mg for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

An updated Risk Management Plan (RMP) for Rybelsus was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Rybelsus has demonstrated that the drug substances and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered acceptable.

For further details about Rybelsus, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.