Nusinersen effectiveness and safety in children with type II/III 5q-spinal muscular atrophy: Second interim analysis from a Chinese disease registry

To the Editor: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the SMN1 (survival of motor neuron 1) gene, with an estimated global birth prevalence of approximately 1 in 10,000 live births. SMA leads to progressive motor function deterioration and reduced lifespan due to its degenerative nature and the historical absence of curative treatment. Disease-modifying therapies (DMTs) targeting the underlying molecular mechanisms have transformed SMA management. Among these, nusinersen—an intrathecally administered antisense oligonucleotide—has demonstrated significant improvements in motor function and survival in the clinical trials. In China, however, evidence regarding the real-world effectiveness and safety of nusinersen in children with SMA remains limited, primarily due to small sample sizes and short follow-up durations in previous studies. To address this, a multicenter, SMA-specific longitudinal registry with a planned 5-year follow-up was established in 2021.1 Preliminary results from this registry indicated improvements or stabilization in motor function among children receiving nusinersen. This follow-up analysis utilizes data from the registry to further evaluate the effectiveness and safety of nusinersen in individuals with type II/III SMA followed for up to 22 months. The registry collects longitudinal data on children with genetically confirmed 5q-SMA from 25 participating centers across China, with both retrospective and prospective enrollment beginning in November 2021. For individuals who received DMT prior to recruitment initiation, available data between DMT initiation and enrollment was collected retrospectively, and data after enrollment was prospectively gathered; if not, the registry only collected data after enrollment prospectively. The dates of DMT initiation were not earlier than April 28th, 2019, which was the approval date of nusinersen, the first DMT drug in China Supplementary Figure 1, https://links.lww.com/CM9/C800. Baseline assessments were conducted within 30 days before DMT initiation. Follow-up evaluations were scheduled according to routine clinical visits at approximately 6, 14, and 22 months post-nusinersen initiation. The study was approved by the Ethical Committees of the Children’s Hospital of Fudan University (No. 2021 307-03) and all other participating sites Supplementary Materials, https://links.lww.com/CM9/C800, and was registered at ClinicalTrials.gov (NCT05042921). Eligible participants met the following criteria: (1) Had the ability to understand the study’s purpose and risks, provide informed consent, and authorize the use of confidential health information in accordance with national and local privacy regulations—or, for minors, consent provided by a legally authorized representative (e.g., parent or legal guardian); (2) genetically confirmed 5q-SMA; and (3) age 5 years Supplementary Table 3, https://links.lww.com/CM9/C800. Additionally, 23 individuals with type II SMA acquired walking ability following nusinersen treatment. Safety analysis was conducted in a subset of 131 individuals who received initiated nusinersen at or after registry enrollment. Two individuals experienced nusinersen-related adverse events (aseptic meningitis and myalgia), both mild in severity, and no deaths occurred. This study evaluated the effectiveness and safety of nusinersen using longitudinal data from individuals with type II/Ⅲ 5q-SMA who received nusinersen as the first DMT. Most participants demonstrated improvement or stability in motor function scores. The treatment response flow diagram indicated the potential for continuous improvement in motor function with long-term nusinersen therapy. Individuals who initiated nusinersen at younger ages generally achieved more favorable treatment outcomes. Consistent with findings from the first interim analysis,1 these 22-month, real-world data provided robust evidence supporting the long-term effectiveness and safety of nusinersen. Our findings were generally consistent with previous reports, demonstrating that motor function measure scores increased incrementally over time following treatment. This positive change in motor function was further supported by the observed improvement or stabilization in most individuals.2 The magnitude of treatment response differed between individuals with type II and III SMA, with greater improvement observed in those with type II SMA. This difference may be attributed to the younger mean baseline age of the type II cohort, as prior studies have indicated that younger individuals tend to exhibit better treatment responses.3 The overlap between treatment initiation and the period of normal motor development in younger individuals may also contribute to the more pronounced functional gains observed in the type II group. Additionally, the disparity may reflect differences in the therapeutic window, as individuals with type III SMA typically experience longer disease durations accompanied by chronic SMN protein deficiency, leading to irreversible motor neuron loss and reduced treatment efficacy. The treatment response flow diagram indicated that many individuals experienced continuous improvement in motor function during the first 14 months of treatment, with potential for further gains beyond this period. These findings suggest that individuals who start treatment later or exhibit a weaker initial response can still achieve meaningful improvements with continued treatment, underscoring the sustained benefits of long-term nusinersen treatment and the importance of longitudinal real-world data in evaluating its effectiveness. Age subgroup analyses revealed greater improvements in younger individuals. In particular, increases in motor function measure scores among children under 5 years—even those who were treatment-naïve—suggest that nusinersen may confer amplified benefits on motor function in this age group. In contrast, without treatment, patients with later-onset SMA typically experience rapid or substantial declines in motor function after approximately 5 years of age.4 The observed improvements in our study—including gradual increases in motor function measure scores and the magnitude of score changes preceding clinically meaningful thresholds in both younger (≤5 years) and older (>5 years)—likely reflect the therapeutic impact of nusinersen treatment. Notably, many individuals with type II SMA achieved varying degrees of walking function following treatment. Although our study documented 23 individuals reaching this milestone, this number may underestimate the true extent of benefit due to incomplete data, and the actual number of patients who gained walking function may be larger. Findings from this analysis underscore the long-term therapeutic value of nusinersen for SMA and provide evidence supporting its continuous inclusion in national reimbursement programs. Early and rapid diagnosis, followed by prompt initiation of therapy, is critical, as younger individuals derive the greatest benefit from treatment. In this context, prenatal and newborn screening should be considered, particularly for individuals with a family history of SMA, to enable the timely identification of at-risk patients. Additionally, efforts to increase awareness of SMA among both healthcare providers and the general public are essential to ensure that diagnosis and treatment initiation occur promptly following symptom onset. In conclusion, nusinersen treatment demonstrated beneficial effects in children with type II/III SMA and was generally well tolerated. Although positive outcomes have been observed across all age groups, the treatment effect is more pronounced in younger children. Future research should focus on long-term follow-up to establish sustained effectiveness, develop standardized outcome measures applicable across SMA subgroups, and explore additional clinically meaningful outcomes, including patient-reported outcomes and respiratory function. Conflicts of interest None.