Risdiplam in Spinal Muscle Atrophy Type 2 and Type 3

Patients with nonambulant type 2 or type 3 spinal muscular atrophy (SMA) from ages 2 to 25 years were included in this double-blind, manufacturer-sponsored trial of risdiplam, a survival motor neuron 2 (SMN2) pre-mRNA splicing modulator. One hundred twenty patients were randomized to daily oral risdiplam, and 60 to placebo. Participants had not received other SMN2-targeting therapies. Patients with contractures and scoliosis were included. The study was not powered to detect differences by SMN2 subtype or age, although subanalysis was performed. Most participants had 3 SMN2 copies. Only 22 participants were aged 18 to 25.

Stabilization or improvement in motor function at 12 months, based on the 32-item Motor Function Measure (MFM32; maximum score, 96), occurred in 70% of risdiplam recipients compared with 54% of placebo recipients. The mean change from baseline in MFM32 score, the primary endpoint, was 1.36 points in risdiplam-treated patients, versus a decline of 0.19 with placebo, a significant difference of 1.55. Younger patients had larger gains in MFM32 scores (3.14 for ages 2–5; 1.58 for ages 6–11; 1.04 for ages 12–17; no improvement ages 18–25). However, a higher proportion of 18- to 25-year-olds in the treatment group than in the placebo group stabilized or improved (MFM32 total score of ≥0 points). Adverse events reported more frequently in patients receiving risdiplam included pyrexia, diarrhea, rash, mouth and aphthous ulcers, urinary tract infections, arthralgias, and pneumonia.