The multinational, open-label clinical trial enrolled 26 infants from seven countries who had genetically confirmed SMA but no clinical symptoms at screening. Patients were aged 1 to 42 days at the first dose, and received daily oral risdiplam, an SMN2 pre-mRNA splicing modifier that increases functional SMN protein levels.
Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disorder caused by deficiency of survival of motor neuron (SMN) protein, most often due to SMN1 gene deletion or mutation. The number of SMN2 gene copies influences disease severity; untreated infants with two SMN2 copies usually develop type 1 SMA, never sit independently, and often require permanent ventilation within the first year.
The primary endpoint was sitting unsupported for at least 5 seconds at 12 months in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) of at least 1.5 mV.
Four of the five infants in this subgroup achieved this milestone. At 12 months, 21 of 26 infants could sit unsupported for 30 seconds, 14 could stand alone, and 11 could walk alone.
At 24 months, all 23 infants who remained in the study were alive without permanent ventilation or feeding support. Three infants were withdrawn by caregivers after the 12-month visit. Infants with three or more SMN2 copies generally achieved sitting, standing, and walking within World Health Organization developmental windows. Median SMN protein levels and CMAP increased over time.
Adverse events occurred in 25 infants. Over 24 months, nine treatment-related adverse events were reported in seven infants, none of which were serious. Common events included teething, gastroenteritis, COVID-19 infection, and diarrhea. Four infants experienced serious adverse events, all of which were resolved and deemed unrelated to treatment. Retinal findings in three infants were either preexisting or unconfirmed.
“This study showed that infants in whom type 1 SMA was predicted to develop who were treated presymptomatically with risdiplam within the first 6 weeks after birth survived without assisted ventilation and achieved motor milestones over a period of 24 months,” wrote senior study investigator Richard S. Finkel, MD, of the Center for Experimental Neurotherapeutics at St. Jude Children’s Research Hospital, and colleagues.
Limitations included the open-label design without a control group, small sample size, and follow-up limited to 24 months. Some infants switched to alternative SMA therapies during the study, and milestone achievement may have been missed between scheduled visits.
These findings suggest that presymptomatic risdiplam initiation supports survival and motor milestone attainment in SMA, though larger, controlled studies with longer follow-up are needed to confirm efficacy and safety.
Full disclosures can be found in the published study.
