A comprehensive analysis of 343 patients with spinal muscular atrophy (SMA) treated with onasemnogene abeparvovec (OA), marketed as Zolgensma, reinforces the critical importance of early intervention to maximize motor function outcomes. The study, which included a significant subgroup of 79 clinically pre-symptomatic children, demonstrated that treatment before six weeks of age is the strongest predictor of motor milestone achievement.
The research, which leveraged data from academic registries in German-speaking countries, stratified the patient cohort by age at gene therapy (GAT) and found a robust effect of gene addition therapy in children up to 24 months. While motor outcomes stabilized in older children, they did not significantly improve across all measures. Notably, children treated before symptom onset achieved independent sitting at a median age of 10 months, and standing and walking at a median age of 15 months. In contrast, symptomatic children at the time of treatment achieved sitting at a median age of 18.5 months but were unable to stand or walk within the study's observation period.
Impact of SMN2 Copy Number and Prior Therapies
The study also identified SMN2 copy number as a significant factor influencing motor outcomes, with patients having three copies showing better results compared to those with two. This suggests that the patient’s own production of fully functional SMN protein complements the effect of OA. Interestingly, previous treatment with SMN2 splicing modifiers led to higher baseline motor scores but did not significantly change disease trajectories after OA administration.
Respiratory and Bulbar Function
In addition to motor development, the research indicated that lower age at treatment and higher SMN2 copy number positively influence respiratory and swallowing outcomes. The need for ventilatory or nutritional support remained stable after OA treatment, with some children being weaned off either non-invasive ventilation or tube feeding. These findings align with other real-world observations regarding bulbar and respiratory function in SMA patients treated with gene therapy.
Safety Profile and Adverse Events
OA was generally well-tolerated in the cohort, with no new safety alerts beyond those already included in the Summary of Product Characteristics. While six deaths occurred during the observation period, they were deemed unrelated to OA. Serious side effects included severe hepatopathy (n = 17) and thrombotic microangiopathy (n = 1), which were managed with immunosuppressive regimens. The study highlighted an increased risk of hepatopathy with age, particularly in children older than eight months, reinforcing the need for vigilant monitoring.
Implications for Newborn Screening and Treatment Strategies
The inclusion of SMA in newborn screening programs in Austria and Germany since 2021 has provided a unique opportunity to treat children pre-symptomatically. However, the study emphasizes that even with early treatment initiation, motor development may be less favorable in patients who have already developed SMA symptoms. The therapeutic window between newborn screening, genetic confirmation, and treatment initiation should be streamlined to avoid delays.
Future Directions
The researchers recommend refining the assessment and severity grading of safety events in future real-world observations to improve comparability across different treatment centers. They also suggest using standardized terminologies like the Common Terminology Criteria for Adverse Events (CTCAE) for adverse drug reactions and adverse events of special interest. As there will be no head-to-head studies comparing the three currently approved SMA treatments, larger registry studies will help guide treatment choices for individual patients. Predictive models incorporating SMN2 copy number and baseline clinical status should be extended to offer valid counseling for this patient population.
