Presymptomatic treatment of spinal muscular atrophy with risdiplam leads to improved functional outcomes

1. In this single-group trial, among infants predicted to develop type 1 spinal muscular atrophy (SMA) who were treated presymptomatically with risdiplam within the first six weeks after birth, most had the ability to sit up within 12 months, which would not be possible for most untreated infants.

2. These infants also survived without assisted ventilation and achieved appropriate motor milestones over a period of 24 months, which would not be attainable with supportive care alone.

Evidence Rating Level: 1 (Excellent)

Study Rundown: SMA is an autosomal recessive neuromuscular disease caused by a deficiency of the survival of motor neuron (SMN) protein due to mutations in the SMN1 gene, leading to progressive muscle weakness and, in severe cases, respiratory failure and death. The gene SMN2 also produces SMN protein, but is unable to compensate for the loss of SMN1 fully. Risdiplam is an oral SMN2 pre-mRNA splicing modifier that increases functional SMN protein levels and has been shown to be safe and effective in both children and adults with symptomatic SMA. Since enhanced treatment efficacy has been seen with earlier treatment with risdiplam, the present trial examined the efficacy and safety of risdiplam in infants up to six weeks of age with genetically diagnosed SMA but without strongly suggestive clinical signs of SMA. Most infants had the ability to sit up within 12 months, including seven of eight infants with two SMN2 copies; in contrast, without treatment, 79% of infants with two SMN2 copies would be unable to sit up within this timeframe. These infants also survived without assisted ventilation and achieved appropriate motor milestones over a period of 24 months, which would not be attainable with supportive care alone. With regards to safety, the majority of adverse events were not considered to be treatment-related and resolved over time. While larger comparative trials with longer follow-up periods are needed to further understand its relative safety and efficacy, these findings demonstrate that risdiplam may be a therapeutic option for the treatment of presymptomatic SMA.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This phase two, single-group study assessed the efficacy and safety of risdiplam in infants up to six weeks of age with genetically diagnosed SMA but without strongly suggestive clinical signs of SMA. Infants between one and 42 days of age with a genetic diagnosis of 5q-autosomal recessive SMA and no clinical signs or symptoms strongly suggestive of SMA at the time of screening were included. The primary efficacy outcome was the ability to sit without support for at least five seconds at month 12. Secondary efficacy outcomes included the development of clinically manifested SMA, the need for permanent ventilation, the achievement of motor milestones, swallowing and oral feeding, and changes in ulnar CMAP amplitude, all measured at month 24. A total of 26 infants were included in the study. At 12 months, 25 of 26 infants (96%) were able to sit unsupported, including four of five infants with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV (80%; 95% Confidence Interval [CI], 28 to 100), which was higher than the 5% performance criterion of the protocol. Additionally, 21 of 23 infants (91%) were able to stand and walk alone at 24 months, and all 23 infants maintained swallowing and oral feeding abilities and did not need any respiratory support. Over the 24-month period, median ulnar CMAP amplitude increased, and the median SMN protein level increased from 5.69 ng/mL at baseline to 7.24 ng/mL at month 24. With regards to safety, a total of nine treatment-related adverse events were reported, none of which were serious. In summary, among infants predicted to develop type 1 SMA who were treated presymptomatically with risdiplam within the first six weeks after birth, most had the ability to sit up within 12 months, including seven of eight infants with two SMN2 copies; in contrast, without treatment, 79% of infants with two SMN2 copies would develop type 1 SMA and be unable to sit up. These infants also survived without assisted ventilation and achieved appropriate motor milestones over a period of 24 months, which would not be attainable with supportive care alone.

Image: PD

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