FIREFISH Part 1: 1-Year Results on Motor Function in Babies with Type 1 SMA (S25.003)

Objective: To determine the effect of risdiplam on motor function in babies with Type 1 spinal muscular atrophy (SMA) in the FIREFISH Part 1 dose-finding study.

Background: Type 1 SMA is a debilitating neuromuscular disease, in which untreated babies fail to achieve major motor milestones 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 of the SMN1 gene. A second SMN 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 to increase SMN protein levels.

Design/Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label, operationally seamless study of risdiplam in babies 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 (September 2018), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at 8 months (Day 245; median change of 16 points). From baseline to Day 245 the number of babies meeting the following HINE-2 motor milestones increased: full head control (6/14, 43%), horizontal or upward kicking (7/14, 50%), rolling to side or from prone to supine (4/14, 29%) and sitting with or without support (6/14, 43%). To date, no drug-related safety findings have led to withdrawal of any baby from the study and no significant ophthalmological findings have been observed. One-year motor milestone data will be presented from FIREFISH Part 1.

Conclusions: In the FIREFISH Part 1 dose-finding study, risdiplam improved motor function in babies with Type 1 SMA. FIREFISH Part 2 is ongoing worldwide.

Disclosure: 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. 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. 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.