Combination therapies in spinal muscular atrophy: a systematic review

The purpose of this study was to evaluate the safety, efficacy, and clinical application of combination therapies involving nusinersen, onasemnogene abeparvovec-xioi, and risdiplam in patients with spinal muscular atrophy (SMA), and to assess their potential advantages over monotherapy. This systematic review included studies up to May 2025 from PubMed, Scopus, Web of Science, and ClinicalTrials.gov. Studies involving dual- or triple-combination therapies, either as switching or add-on strategies, were identified and categorized. Data extraction included patient demographics, treatment regimens, motor function outcomes, and adverse events. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal tools. Out of 985 records, 19 studies and 6 ongoing clinical trials met inclusion criteria. A total of 29 individual patients receiving combination therapies (dual: n = 26, triple: n = 3) were analyzed. Switching therapies were the most common, particularly from nusinersen or risdiplam to onasemnogene abeparvovec-xioi. Combination regimens were generally well-tolerated with no consistent evidence of additive toxicity. However, long-term efficacy remains uncertain. Some patients demonstrated improved motor milestones and respiratory function, particularly with early intervention.

Combination therapies for SMA are emerging as a feasible and generally safe strategy, especially in patients with suboptimal response to monotherapy. While current evidence is encouraging, robust long-term trials are essential to determine their true efficacy, optimal sequencing, and broader impacts, including cost-effectiveness and systemic benefits.

•Three disease-modifying therapies are approved for SMA, but monotherapy may not halt disease progression in all patients.

•This systematic review evaluates existing evidence on combination therapies (add-on/switching) for SMA. •Combination therapies appear safe and well-tolerated in short-term studies. •Long-term efficacy and optimal sequencing of dual/triple regimens remain uncertain and warrant further research.