Early Motor Milestones Achieved in SMA Patients with Risdiplam in Phase II Trial

Recent findings from an open-label Phase II clinical trial have highlighted the promising potential of risdiplam, a pre-messenger RNA splicing modifier, in treating presymptomatic spinal muscular atrophy (SMA). This research, conducted by a team led by Richard S. Finkel, has been published in the New England Journal of Medicine and showcases significant early motor milestones in infants receiving the treatment.

SMA is a genetic neuromuscular disorder that leads to the degeneration of motor neurons in the spinal cord and brainstem. The condition primarily affects proximal limb, respiratory, and pharyngeal skeletal muscles. It occurs in approximately one in every 10,000 births and remains one of the leading hereditary causes of infant mortality outside of developed nations. Without treatment, a significant proportion of those affected by type 1 SMA, the most severe form, do not survive past the age of two, as they fail to achieve critical motor milestones.

The Phase II trial enrolled 26 infants diagnosed with SMA, categorized by their SMN2 gene copy number, with the aim of evaluating the effects of presymptomatic treatment with daily doses of risdiplam. The trial monitored the infants' ability to sit unsupported at 12 and 24 months, alongside assessments of motor functions and survival rates. Notably, the results indicated that 96% of infants could sit unsupported for five seconds by the end of the first year, and 81% could walk independently by 24 months.

Throughout the study, only six out of the 26 participants exhibited clinical symptoms of SMA, with the majority of these cases involving infants who had two copies of the SMN2 gene. The research identified that those with the lowest baseline muscle action potential measurements were more likely to develop clinical symptoms. Importantly, the trial demonstrated that early intervention with risdiplam could potentially halt the progression of irreversible neurodegeneration and support normal motor neuron and muscle development.

Risdiplam is distinct among SMA treatments due to its ability to cross the blood-brain barrier and its broad biodistribution across tissues. It stands alongside two other approved therapies for SMA: nusinersen, which employs an intrathecal delivery method, and onasemnogene abeparvovec, a gene therapy approach. These treatments have shown enhanced efficacy when initiated before the onset of symptoms, leading to the implementation of neonatal screening programs in many regions to expedite treatment.

As the first successful gene-specific RNA-processing medication, risdiplam illustrates the potential of small-molecule drugs to effectively target mRNA. Ongoing research aims to explore the long-term outcomes of these treatments, including the impact of sequential or combined therapies for infants diagnosed with SMA.