Indirect treatment comparisons of nusinersen versus onasemnogene abeparvovec-brve in treatment-naïve and -experienced spinal muscular atrophy patients

AIMS: Nusinersen 12 mg was the first regulator-approved disease-modifying therapy (DMT) for spinal muscular atrophy (SMA); intrathecal onasemnogene abeparvovec-brve (OAV101 IT) and nusinersen 50/28 mg have gained recent approval. In absence of head-to-head evidence, this research assessed the comparative efficacy of these treatments in DMT-naïve and DMT-experienced SMA patients using indirect treatment comparisons (ITCs). MATERIALS AND METHODS: An ITC feasibility assessment was conducted. Individual patient data (IPD) from CHERISH (NCT02292537) and DEVOTE Part B (NCT04089566) clinical trials assessing nusinersen in DMT-naïve, later-onset participants were trimmed to align with STEER (NCT05089656). DMT-experienced IPD from DEVOTE Part C (NCT04089566) were trimmed to align with STRENGTH (NCT05386680). Matching adjusted indirect comparisons (MAIC) were conducted to assess motor function improvement using the Hammersmith Functional Motor Scale-Expanded (HFMSE) and Revised Upper Limb Module (RULM). RESULTS: The anchored MAIC in DMT-naïve participants numerically favored nusinersen 12 mg compared with OAV101 IT in change from baseline (CFB) in HFMSE (mean difference [MD]: 1.86; 95% confidence intervals [CIs]: -1.08, 4.80; starting sample [N]/effective sample size [ESS]: 97/58), and RULM (MD: 1.52; CIs: -0.57, 3.61; N/ESS: 97/58) in participants aged 2 to <5 years. The unanchored MAIC in DMT-experienced participants numerically favored nusinersen 50/28 mg compared with OAV101 IT in CFB in HFMSE (MD: 1.02; CIs: -1.31, 3.34; N/ESS: 10/3), and RULM (MD: 1.41; CIs: -3.64, 6.46; N/ESS: 10/5) in participants aged <18 years. Trends were consistent across weighting scenarios. After applying participant weights, the ITC of DEVOTE Part B and STEER was deemed infeasible. LIMITATIONS: As is common in rare diseases, small sample sizes from available trial data may have limited the precision of the estimates despite consistent numerical trends. CONCLUSIONS: Nusinersen resulted in numerical functional gains compared with OAV101 IT in both DMT-naïve and DMT-experienced patients. Further studies should be undertaken to validate any between-treatment difference.