Transforming Spinal Muscular Atrophy: From Pivotal Trials to Real-World Evidence and Future Therapeutic Frontiers in Types 1 and 2

Abstract

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disorder and a leading genetic cause of infant mortality. The past decade has witnessed a paradigm shift in SMA management with the advent of disease-modifying drugs (DMDs). This narrative review aims to (i) summarize pivotal randomized controlled trials (RCTs) that led to the approval of DMDs for SMA Types 1 and 2; (ii) synthesize real-world evidence on their safety and effectiveness; and (iii) explore emerging therapeutic frontiers, including gene modifiers, predictive biomarkers, prenatal interventions, and combination strategies. Pivotal RCTs and real-world studies demonstrate that onasemnogene abeparvovec (a single-dose gene therapy), nusinersen (an intrathecal antisense oligonucleotide), and risdiplam (an oral SMN2 splicing modifier) each significantly improve survival and motor function milestones compared to natural history in Type 1 and Type 2 SMA, with the majority of treated patients achieving independent sitting and prolonged ventilator-free survival, while safety profiles are generally manageable and distinct for each therapy. Similar outcomes have been demonstrated for presymptomatic patients with SMA. The introduction of DMDs has transformed the prognosis of SMA, particularly for early-onset forms, with robust evidence supporting their efficacy and safety. Continued real-world monitoring and exploration of adjunctive therapies are essential to optimize outcomes across the SMA setting and address unmet needs in non-responders and older patients.

Keywords: SMA; disease-modifying drugs; nusinersen; onasemnogene abeparvovec; real-world evidence; risdiplam; spinal muscular atrophy.

Figure 1

Mechanisms of action of approved SMA treatments.