The treatment of spinal muscular atrophy (SMA) is undergoing a period of important advances: in the last few years innovative treatments have emerged and are being evaluated by regulators, payers, and Health Technology Assessment bodies across the globe. None of the novel treatments were directly compared through head-to-head trials. The objective of this study is to perform indirect treatment comparisons (ITCs) to evaluate relative efficacy of risdiplam against novel therapies (nusinersen and AVXS-101) and best supportive care (BSC). Methods: Comparator studies that formed the evidence base were identified through a systematic literature review, data was extracted and/or digitized. Baseline prognostic and predictive factors (age, duration/onset of symptoms, baseline CHOP intend score) were compared. As appropriate, unadjusted and matching-adjusted indirect comparison (MAIC) estimates of relative efficacy were calculated. Confidence intervals were estimated using bootstrap resampling methods. Results: Comparative efficacy relative to BSC and nusinersen was evaluated against the ENDEAR study. FIREFISH and ENDEAR populations were found to be comparable in terms of prognostic and predictive factors. The matching-adjusted indirect treatment comparison suggests that risdiplam may significantly reduce the number of deaths and permanent ventilations as compared to BSC and nusinersen. The hazard ratios for Event-Free Survival were respectively 0.11 (95%CI:0.00;0.35) and 0.23 (95%CI:0.00;0.68). Unadjusted ITC analyses yielded similar results. Comparative efficacy relative to AVXS-101 was evaluated against the CL-101 trial. The FIREFISH and CL-101 populations differed in terms of prognostic and predictive factors. Due to the lack of overlap in population characteristics it was not possible to perform matchingadjusted analyses. Conclusions: Preliminary results based on the Part 1 results of the FIREFISH study suggest that treatment of infantile onset SMA with risdiplam may yield better results than nusinersen. An unbiased estimate of relative efficacy of risdiplam against AVXS-101 would require a comparison of treatments in similar patient populations.

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