Background
Risdiplam and nusinersen are disease-modifying therapies approved for the treatment of SMA. Without treatment, children with severe Type 1 SMA fail to achieve major motor milestones and typically do not survive beyond 2 years of age. The efficacy of risdiplam and nusinersen have been established in Type 1 SMA in separate clinical trials. In the absence of head-to-head trials, indirect treatment comparisons adjusted for cross-trial differences can inform treatment decision-making.
Objectives
The objective of this study was to compare the efficacy and safety of the approved risdiplam dose (0.2 mg/kg daily in children aged 2 months to <2 years; 0.25 mg/kg daily in children ≥2 years and <20 kg in weight) versus the investigational higher-dose (HD) nusinersen regimen (50/28 mg) in children with Type 1 SMA treated in clinical trials. Results Patient-level risdiplam data were obtained from 58 children who received the pivotal dose in the FIREFISH clinical trial (Part 1 n=17, Part 2 n=41, NCT02913482) and published aggregate nusinersen data were obtained from 50 children in the DEVOTE clinical trial (Part B, infantile onset; NCT04089566). Unanchored matching-adjusted indirect comparisons were used to compare outcomes between risdiplam and HD nusinersen groups, adjusting for age at first dose, disease duration, and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score at baseline. Cox proportional‑hazards models were used to compare overall survival and event-free survival. After matching, relevant baseline characteristics were similar across groups. The effective sample size for risdiplam was 33.2, a reduction of ~43%. Compared with the HD nusinersen group, after 15 months of risdiplam treatment, the risdiplam group had a 75% reduction in the rate of death (95% confidence interval [CI] 11–93%) and a 76% reduction in the rate of death or permanent ventilation (95% CI 34–92%). While adjustments were made for known prognostic factors, as in any non-randomised comparison, results may be confounded by unobserved baseline differences between groups. Conclusions Risdiplam was associated with lower risk of death or permanent ventilation when compared with HD nusinersen in children with Type 1 SMA for up to 15 months of follow-up. This comparative analysis leverages data from two robust clinical trial sources. Additional data sources should be consulted to expand on these findings.