Regulatory Decision Summary for Evrysdi

This Supplement to a New Drug Submission (SNDS ) was filed for Evrysdi (risdiplam) to support the introduction of a new 5 milligram (mg) film-coated tablet dosage form and to add safety information from a 2-year carcinogenicity rat study and from a human cardiac QT prolongation study.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Upon review of the submitted data package, Health Canada authorized a new 5 mg film-coated dosage form of Evrysdi.

As part of this most recent submission, Hoffmann-La Roche Limited submitted a 2-year carcinogenicity study in rats as a post-market commitment following the initial New Drug Submission. The study was appropriately designed and conducted, with the high dose of 3 milligram per kilogram per day (mg/kg/day) yielding exposures of approximately 2 to 8-fold the estimated therapeutic dose range of exposure at the maximum recommended human dose of 5 mg per day. At the low and mid doses of 0.3 and 1 mg/kg/day there was no evidence for tumorigenic potential of risdiplam. The high dose was associated with low survival in males, and both males and females showed risdiplam-related tumors (squamous cell carcinoma). These were present in the preputial gland of male rats and, in a few females, in the clitoral gland. No equivalent organs to the preputial and clitoral glands exist in humans. Therefore, it is not expected that these findings have relevance for human risk.

To support the introduction of the new 5 mg film-coated tablet dosage form, data on the drug-drug interaction of the antacid omeprazole and risdiplam was also presented in this submission. The results of the statistical analysis showed that there was no effect of omeprazole on the evaluated pharmacokinetics parameters of the Evrysdi/F21 5 mg tablet in the fasted state. The F21 tablet was chosen as the to be marketed tablet composition.

The safety of the tablet formulation was also assessed. Overall, administration of the 5 mg tablet was well tolerated by healthy adult subjects. A moderate treatment-emergent adverse event of rash maculo-papular was the cause of discontinuation for one subject. Rash is described in the Product Monograph for Evrysdi as a common adverse event. There were no remarkable findings in the assessments for clinical laboratory, vital signs, and electrocardiograms.

To investigate the effect of Evrysdi on the QT interval, a double-blind, placebo and positive controlled crossover QT study was submitted. Evrysdi at a 45 mg dose had no clinically relevant effect on heart rate, cardiac conduction (the PR and QRS intervals), or cardiac repolarization. A corrected QT (QTc) effect exceeding 10 milliseconds can be excluded at plasma concentrations of Evrysdi up to 188 nanograms per millilitre.

The chemistry and manufacturing information submitted for Evrysdi has demonstrated that the formulation and process used for the bioequivalence lots were representative of the commercial lots. The comparative bioavailability data between the proposed tablet form and the marketed powder for oral solution were reviewed and found to meet the bioavailability requirements. Furthermore, a food effect study was also provided and confirmed that there is no food effect with either the powder for oral solution or the tablet formulations.

The final labelling, package inserts and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile remains favourable for Evrysdi 5 mg film coated tablet for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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