Regulatory Decision Summary for Evrysdi

This Supplement to a New Drug Submission for Evrysdi (risdiplam) was filed under the Priority Review Policy to expand the existing pediatric indication to include children below 2 months of age.

Evidence to support the population expansion to infants under 2 months of age was provided by the Phase II study, RAINBOWFISH.

RAINBOWFISH is an ongoing, open-label, single-arm, clinical study in 26 infants aged from birth to 6 weeks (at first dose), who have been genetically diagnosed with spinal muscular atrophy (SMA) but are not yet presenting with symptoms. The efficacy in pre-symptomatic SMA patients was evaluated at Month 12 of Evrysdi treatment, with Month 24 to come as additional secondary outcomes.

In RAINBOWFISH, the median age of patients at first dose was 25 days (range: 16 to 41 days). These patients had 2 copies of the SMN2 gene (9 patients); 3 copies (13 patients) or 4 or more copies (5 patients). The primary efficacy population (PE Pop) subset included 5 infants, all with 2 copies of SMN2 gene.

All patients completed efficacy assessments for the Month 12 visit, following which 3 patients withdrew (in order to take gene therapy), all before 16 months of treatment. The primary endpoint was the proportion of patients in the PE Pop, at Month 12, with the ability to sit without support for at least 5 seconds; a clinically and statistically meaningful proportion of patients achieved this milestone in the PE Pop (80% ; 4/5) and Intent to Treat (ITT) set (96.2%; 25/26).

No key secondary outcomes were designated from among various established motor, feeding and survival endpoints. Overall, the results were meaningfully different from historical controls: at 12 months, all patients were alive without permanent ventilation; all maintained their ability to feed orally; and all showed an increase in gross motor skills, such as standing (84%; 21/26), and walking (46%; 12/26). The final agreed-upon description in the Clinical Trial section of the Product Monograph (PM) included the primary outcome (PR pop, and ITT), as well as a brief line-listing of 3 secondaries; this text appropriately conveys, as in the PM of the other two disease-modifying SMA treatments, that the drug has significant impact but does not normalize patients, with uncertainties in extent and duration of efficacy.

The median exposure duration was 20 months. The safety profile was in line with that observed previously for infants in FIREFISH (an open-label efficacy, safety and tolerability study in infants aged 1 to 7 months with Type I SMA).

Pharmacokinetics (PK) data from the RAINBOWFISH sparse sampling were combined with the dataset used for the previous Population PK (Pop PK) model development. The updated reference Pop PK model supports a daily dose of 0.15 milligrams per kilogram (mg/kg) for pre-symptomatic infants, with an increase to 0.2 mg/kg at 2 months of age. However, on examination by Health Canada, the Pop PK model also indicates that the higher exposure seen previously in FIREFISH study was not simply an anomaly of limited data, that is, where symptomatic patients, started at ages 2-5 months on 0.2 mg/kg daily, showed a tendency towards overexposure for several months. Given recent mandatory newborn screening in Canada now, this means that essentially all infants with two SMN2 gene copies (and many with 3 or more copies) will be started pre-symptomatically as newborns on one of the disease modifying therapies, the existing Warning with respect to this potential overexposure to risdiplam is no longer needed, but information regarding this apparent robust characteristic of the PK profile is retained in the Product Monograph.

This submission also included the final study report for the JEWELFISH study, an open-label, 24-month tolerability Phase II study in SMA patients aged 6 months to 60 years, previously exposed to SMA treatment. Of 173 patients, 76 were previously treated with nusinersen (Spinraza) and 14 with AVXS-101 (Zolgensma). There was no safety signal seen in the additional two years of data since the original assessment conducted during the original application (New Drug Submission) for Evrysdi.

With the addition of the safety and efficacy data from RAINBOWFISH in pre-symptomatic infants, the expansion of the indication to include less than 2 months of age is supported. The benefit-harm-uncertainty profile for Evrysdi (risdiplam) remains positive when used under the conditions described 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.