Objective: To determine the efficacy and safety of risdiplam, a centrally and peripherally distributed oral SMN2 pre-mRNA splicing modifier, in infants with Type 1 spinal muscular atrophy (SMA) treated for 12 months during the confirmatory Part 2 of the FIREFISH study (NCT02913482). Design/Methods: FIREFISH is an ongoing, multicenter, open-label study of risdiplam in infants aged 1–7 months at enrollment with Type 1 SMA and two copies of the SMN2 gene. Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels (plus exploratory efficacy outcomes). The primary objective of confirmatory Part 2 (n=41) is to investigate the efficacy of risdiplam at the dose selected in Part 1. The primary efficacy endpoint is the proportion of infants sitting without support for 5 seconds after 12 months on treatment, as assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, 3rd edition. Secondary outcomes include the achievement of motor milestones and respiratory endpoints such as time to permanent ventilation and percentage of infants who achieve a reduction of ≥30° in phase angle from baseline at Month 12 (as measured by respiratory plethysmography). Results: The primary endpoint of FIREFISH Part 2 at 12 months was met (data-cut: 14th November 2019). We will report efficacy and safety data, including respiratory outcomes, from the confirmatory Part 2 of the FIREFISH study in participants who have received risdiplam treatment for a minimum of 12 months. Conclusions: FIREFISH Part 2 will provide important data on the efficacy and safety of risdiplam in infants with Type 1 SMA.
