Update from SUNFISH Part 1: Safety, Tolerability and PK/PD from the Dose-Finding Study, Including Exploratory Efficacy Data in Patients with Type 2 or 3 Spinal Muscular Atrophy (SMA) Treated with Risdiplam (RG7916) (S25.007)

Objective: To determine safety, tolerability and PK/PD in patients with Type 2 or 3 SMA who received risdiplam for the duration of the SUNFISH Part 1 dose-finding study, and exploratory efficacy data in patients treated for at least 1 year in Part 1. Background: SMA is caused by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2 , produces 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 towards the production of full-length SMN2 mRNA to increase SMN protein levels. Design/Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2 or 3 SMA. Part 1 (n=51) assesses safety, tolerability and PK/PD of different risdiplam dose levels. Pivotal Part 2 (n=180) is assessing the safety and efficacy of the risdiplam dose level that was selected based on results from Part 1. Results: SUNFISH Part 1 included patients of broad age ranges and clinical characteristics (functional level, scoliosis and contractures). To date, a sustained, >2-fold increase in median SMN protein versus baseline was seen after 1 year of risdiplam. Adverse events have been mostly mild, resolved despite ongoing treatment and reflect the underlying disease. No drug-related safety findings have led to withdrawal. Safety, tolerability and PK/PD will be presented from all patients in Part 1. Exploratory efficacy will be presented in patients treated for ≥1 year. Conclusions: To date, risdiplam has been shown to be well tolerated and leads to sustained increases in SMN protein. Despite not being designed and powered to detect efficacy, patients on risdiplam experienced improvement over 12 months on the Motor Function Measure versus natural history. Disclosure: Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc., Novartis, and Roche. Dr. Mercuri has received research support from Ionis Pharmaceuticals, Inc./Biogen and Roche clinical trials, Famiglie SMA Italy, Italian Telethon, and SMA Europe. Dr. Baranello has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics and Sarepta Therapeutics. Dr. Kirschner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Ionis Pharmaceuticals, Inc., Novartis, and Roche. Dr. Kirschner has received research support from Biogen, Roche, Santhera, and PTC Therapeutics. Dr. Servais has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Sarepta, Dynacure, Pfizer, Servier, Roche and Cytokinetics. Dr. Servais has received research support from Roche, Valerion, Dynacure, Biogen and Avexis. Dr. Goemans has nothing to disclose. Dr. Pera has nothing to disclose. Dr. Buchbjerg has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Yeung has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Products Ltd. Dr. Kletzl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Kletzl holds stock and/or stock options in F. Hoffmann-La Roche which sponsored research in which Dr. Kletzl was involved as an investigator. Dr. Kletzl holds stock and/or stock options in F. Hoffmann-La Roche. Dr. Kletzl has received research support from F. Hoffmann-La Roche. Dr. Gerber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Gerber has received royalty, license fees, or contractual rights payments from Hoffmann-La Roche. Dr. Gerber holds stock and/or stock options in F. Hoffmann-La Roche which sponsored research in which Dr. Gerber was involved as an investigator. Dr. Czech has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann–LaRoche. Dr. Cleary has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche. Dr. Gorni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Khwaja has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Hoffmann-La Roche. Dr. Khwaja holds stock and/or stock options in Hoffmann-La Roche which sponsored research in which Dr. Khwaja was involved as an investigator. Dr. Khwaja holds stock and/or stock options in Hoffmann-La Roche. Dr. Khwaja has received research support from Hoffmann-La Roche.