O.41Sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with type 2 or 3 spinal muscular atrophy

Spinal muscular atrophy (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. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces only low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing to increase SMN protein levels. Sunfish (NCT02908685) is an ongoing, multicenter, double-blind, placebo-controlled study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2 or 3 SMA. Sunfish part 1 (n=51) is a dose-finding study assessing the safety, tolerability and PK/PD of risdiplam; pivotal Part 2 (n=180) assesses the safety and efficacy of the risdiplam dose level that was selected based on results from Part 1. Sunfish part 1 included patients of broad age ranges and clinical characteristics (functional level, scoliosis and contractures). An interim analysis of Part 1 (data cut-off, 06 July 2018) showed a sustained, >2-fold increase in median SMN protein versus baseline after 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflective of the underlying disease. Despite not being designed to detect efficacy, risdiplam improved motor function measures over 12 months versus natural history. Safety, tolerability and PK/PD will be reported from all patients in Part 1 who have received treatment with risdiplam for a minimum of 18 months. Updated Part 1 exploratory efficacy data, including motor outcome measures, will also be presented for the first time. The clinical benefit of risdiplam is being assessed in Part 2, which is ongoing worldwide. The authors would like to thank all individuals enrolled in the risdiplam studies, their families and the site staff involved.