FIREFISH Part 1: Survival, Ventilation and Swallowing Ability in Infants with Type 1 SMA Receiving Risdiplam (RG7916) (S25.008)

Objective: To determine the event-free survival rates (defined as alive and no need for permanent ventilation) and swallowing ability in infants with Type 1 spinal muscular atrophy (SMA) receiving risdiplam in the FIREFISH Part 1 dose-finding study. Background: Type 1 SMA is a debilitating neuromuscular disease, in which untreated infants require nutritional assistance, permanent ventilation, and typically die before 2 years of age. SMA is caused by reduced levels of the survival of motor neuron (SMN) protein from deletions and/or mutations in the SMN1 gene. A second SMN 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. Design/Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label, operationally seamless study of risdiplam in infants aged 1–7 months at enrollment with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data cut-off September 7th 2018), survival rate was 90.5% (19/21), and no surviving infant has required tracheostomy, reached permanent ventilation or lost the ability to swallow. Updated data on event-free survival rates and swallowing ability will be presented based on 1-year data from the trial. Conclusions: In the FIREFISH Part 1 dose-finding study, event-free survival rates were improved in infants with Type 1 SMA receiving risdiplam compared with infants of the same age in natural history studies. Disclosure: 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. Baranello has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics and Sarepta Therapeutics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Deconinck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen and Sarepta Therapeutics. 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. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Santhera, PTC Therapeutics, Sarepta and Biogen. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Masson has nothing to disclose. 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. Cleary has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche. Dr. El-Khairi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Products Limited. Dr. El-Khairi holds stock and/or stock options in Roche Holding AG. Dr. Seabrook has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Hoffmann-La Roche. Dr. Seabrook holds stock and/or stock options in Hoffmann-La Roche which sponsored research in which Dr. Seabrook was involved as an investigator. Dr. Seabrook has received research support from Hoffmann-La Roche. Dr. Czech has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann–LaRoche. 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. Nguyen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Gelblin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Gelblin holds stock and/or stock options in F. Hoffmann-La Roche which sponsored research in which Dr. Gelblin was involved as an investigator. Dr. Gelblin has received research support from 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.