To determine the efficacy and safety of risdiplam in infants with Type 1 spinal muscular atrophy (SMA) after 24 months of treatment.

SMA is a severe, progressive neuromuscular disease caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein. Risdiplam is a centrally and peripherally distributed oral SMN2 pre-mRNA splicing modifier that increases the levels of functional SMN protein. Risdiplam (EVRYSDI™) has been approved by the FDA for the treatment of patients with SMA, aged 2 months and older.

FIREFISH (NCT02913482) is a multicenter, open-label, two-part study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria 1–7 months at enrollment). Part 1 (N=21) assesses the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (N=41) assesses the efficacy and safety of the Part 1-selected dose of risdiplam.

The primary endpoint of Part 2 at 12 months was met (data-cut: 14th November 2019); 29% (P<0.0001, performance criterion=5%) of infants were able to sit without support for ≥5 seconds, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition. This milestone was never achieved in natural history cohorts. After 12 months, risdiplam treatment also resulted in a significantly higher percentage of infants surviving, demonstrating improvements in motor function and achieving motor milestones compared with natural history cohorts. No treatment-related safety findings leading to withdrawal were reported in Part 2.

For the first time, we will present efficacy and safety data from infants in Part 2 who have received risdiplam treatment for 24 months.