Risdiplam May Be Superior for Certain SMA Type, According to Indirect Comparison

Researchers compiled data from studies of oral Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec), finding evidence that risdiplam may be a favorable alternative to nusinersen for type 1 SMA.

With a lack of head-to-head trials, researchers have performed indirect comparisons of 3 treatments for spinal muscular atrophy (SMA), concluding that one of the treatments may be superior for certain types of the disease.

The researchers compiled data from studies of oral SMN2 splicing modifier Evrysdi (risdiplam), intrathecal splicing modifier Spinraza (nusinersen), and the gene therapy Zolgensma (onasemnogene abeparvovec), from which they found evidence to suggest that risdiplam may be a favorable alternative to nusinersen for type 1 SMA.

Their findings were published online in Journal of Comparative Effectiveness Research.

SMA Type 1

The researchers relied on data from the phase 2/3 FIREFISH trial of risdiplam and the phase 3 randomized trial of nusinersen, which had similar baseline characteristics among their patients, although patients in FIREFISH had a lower average baseline motor function.

Across the 2 studies, risdiplam seemed to be associated with favorable event-free survival (EFS) (HR, 0.20) and overall survival (HR, 0.26) compared with nusinersen. Although analyses showed no differences between being able to sit with and without support and standing milestones, the data did suggest that risdiplam may improve some motor milestones compared with nusinersen but that nusinersen may have improved results for rolling.

Despite longer follow-up with risdiplam (approximately 15 vs 9 months), the odds of reported serious adverse events (SAEs) were lower with the treatment than with nusinersen, which the researchers say could be attributed to superior efficacy rather than safety because the types of SAEs were comparable across the 2 studies.

The researchers were unable to perform unadjusted and matching-adjusted indirect comparisons between risdiplam and onasemnogene abeparvovec because of limited overlap in baseline prognostic factors in the FIREFISH trial and phase 3 STR1VE-US trial of the gene therapy.

SMA Types 2 and 3

In later-onset SMA, the researchers attempted to compare data from the second part of the phase 2/3 randomized SUNFISH study of risdiplam and the phase 3 randomized CHERISH study of nusinersen; they found that comparisons were limited due to significant differences in enrollment criteria.

SUNFISH enrolled a wider range of ages compared with CHERISH (2-25 years vs 2-9 years) and many patients with very low baseline motor function scores while CHERISH excluded certain patients permitted in SUNFISH, including patients with severe scoliosis. To mitigate these differences, the researchers focused on a small subset of patients from the SUNFISH study, which led to only a small subset of patients available for comparison.

“Upon matching, the control arms of SUNFISH and CHERISH showed similar responses with comparable improvements in RULM [Revised Upper Limb Module] scores over the same time span, indicating a good match of patients for this end point. Due to very wide [confidence intervals], analyses provided insufficient evidence to draw concrete conclusions on the relative efficacy in terms of RULM change from baseline and RULM response between risdiplam and nusinersen,” wrote the researchers.

Robust conclusions on the comparative efficacy and relative safety differences could also not be made.

To confirm their findings, the authors recommend additional studies in other patient populations, such as presymptomatic patients, adolescents, and adults.


Ribero VA, Daigl M, Martí Y, et al. How does risdiplam compare with other treatments for types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison. J Comp Eff Res. Published online January 18, 2022. doi:10.2217/cer-2021-0216