Drugs for Adults With Spinal Muscular Atrophy: A Focused Review and Critical Appraisal of Recent Evidence (2021 to 2025) on Nusinersen and Risdiplam

What Is the Issue? Spinal muscular atrophy (SMA) is a rare genetic condition that affects muscle strength and movement in both children and adults. Two treatments, nusinersen (Spinraza) and risdiplam (Evrysdi), are publicly reimbursed in Canada, primarily for use in children. The Canadian Drug Expert Committee (CDEC) reimbursement recommendations for both drugs highlighted serious limitations in the evidence for the effectiveness and safety of these treatments in adults with SMA. In particular, the evidence is limited by the lack of high-quality, comparative data, making it difficult to determine whether observed effects are due to the drugs or to other factors, and whether these effects are clinically meaningful in adults. As a result, reimbursement recommendations issued by CDEC do not support treatment initiation of nusinersen in patients older than aged 18 years or initiation of risdiplam in patients aged older than 25 years. What Did We Do? We searched for recently published, peer-reviewed studies using clinical trial and comparative observational study designs to answer these questions: What is the quality of comparative evidence on the effectiveness and safety of nusinersen and risdiplam in adults with SMA? What is the quality of comparative evidence on the effectiveness and safety of nusinersen and risdiplam in adults with SMA who were previously treated with gene therapy (onasemnogene abeparvovec)? Is it feasible and useful to conduct a new, comprehensive review to inform future reimbursement decisions for these treatments? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant clinical trials and comparative observational studies published since the initial search dates of the previous CADTH reimbursement reviews for nusinersen and risdiplam. We focused on studies that directly compared these treatments with each other, with other therapies, or with standard care in adults with SMA to address concerns raised about the previously reviewed evidence. What Did We Find? Only 1 new comparative study (Vázquez-Costa et al.) was found for nusinersen in adults with SMA. This study compared adults treated with nusinersen with those who received no treatment over a follow-up period of up to 30 months. No eligible comparative studies were found for risdiplam in adults aged older than 25 years with SMA. No published studies were identified for nusinersen or risdiplam in adults with SMA who were previously treated with gene therapy (onasemnogene abeparvovec). The Vázquez-Costa et al. study had significant limitations, including a high risk of bias due to differences in patient characteristics between the treated and untreated groups (e.g., ability to sit or to walk at start of treatment), missing data, inconsistent findings within and across motor function outcomes, use of unvalidated thresholds to define clinically meaningful treatment effects, and incomplete outcome reporting. These limitations make it difficult to draw reliable conclusions about the benefits or harms of nusinersen in adults with SMA. Many additional real-world studies were identified; however, they were noncomparative or did not focus specifically on adults with SMA, included small numbers of adults, and had similar methodological limitations to previously reviewed studies. None provided robust evidence to answer the research questions or to address the methodological limitations and uncertainties of the studies included in previous reviews. What Does This Mean? Comparative evidence is required to establish the relative benefits and harms of a therapy versus existing standards of care and to draw meaningful conclusions about their outcomes to inform policy decision-making. The current evidence base for nusinersen and risdiplam in adults with SMA remains very limited and of low quality, which makes it difficult to determine if the drugs achieved their outcomes. There is still no strong comparative evidence to support reimbursement of these treatments for adults with SMA, and due to serious limitations in the available real-world studies, it remains unclear whether either nusinersen or risdiplam have clinically meaningful benefit in adults. Given the limitations of the available evidence — including the lack of robust comparative studies; methodological weaknesses in existing data; and the absence of consistent, clinically meaningful outcomes — conducting a de novo systematic review at this time is not feasible and is unlikely to yield clearer conclusions. As such, we do not anticipate that such a review would provide sufficient new information to support a reassessment of current reimbursement criteria for nusinersen and risdiplam in adults with SMA.

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