Preliminary Evidence for Pharmacodynamics Effects of RG7916 in JEWELFISH, a Study in Patients with Spinal Muscular Atrophy who Previously Participated in a Study with Another SMN2-Splicing Targeting Therapy (S46.003)

Objective: JEWELFISH (NCT03032172) is an exploratory, open-label study to establish the safety, tolerability and pharmacokinetics (PK) of RG7916 in patients who have previously participated in a study with a therapy targeting survival of motor neuron 2 ( SMN2 ) mRNA splicing. Background: Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease caused by loss-of-function of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2 , produces low levels of functional SMN protein due to alternative splicing of SMN2 pre-mRNA. RG7916 is an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier that increases SMN protein levels. Design/Methods: JEWELFISH is a multicenter, open-label, exploratory study evaluating the safety, tolerability and PK of daily oral RG7916 in patients with SMA Type 2 or 3, age 12–60 years, who previously participated in a study with therapies targeting SMN2 splicing. The pharmacodynamic (PD) effects on SMN2 mRNA and SMN protein are also assessed. Results: At the time of abstract submission, 8 patients had received RG7916 for up to 32 weeks. To date, RG7916 has been safe and well tolerated, with no drug-related safety findings leading to withdrawal in any SMA patient exposed to RG7916. Preliminary PD data following RG7916 treatment showed a rapid increase in the full-length SMN2 ( SMN2FL )/ SMNΔ7 mRNA ratio after treatment onset, and an up to 4-fold increase from baseline over 4 weeks. This SMN2FL / SMNΔ7 mRNA ratio increase resulted in an up to 4-fold SMN protein increase over 4 weeks. A JEWELFISH update including safety and available biomarker data will be presented. Conclusions: JEWELFISH is currently recruiting in sites across Europe and the US. Together with the ongoing SUNFISH (SMA Type 2 and 3) and FIREFISH (SMA Type 1) studies, JEWELFISH will provide valuable insights into the safety, tolerability, PK and PD of daily oral RG7916. Study Supported by: Sponsored by F. Hoffmann-La Roche Disclosure: Dr Chiriboga has nothing to disclose. Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen MA, Inc, Ionis Pharmaceuticals, Inc. & F. Hoffman La-Roche Ltd. Dr. Fischer has nothing to disclose. Dr. Kraus has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Alexander has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Armstrong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Kletzl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Kletzl holds stock and/or stock options in Roche. Dr. Kletzl has received research support from Roche. Dr. Gerber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Gerber holds stock and/or stock options in 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. Bergauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Gorni has nothing to disclose. Dr. Khwaja has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Khwaja holds stock and/or stock options in Roche, which sponsored research in which Dr. Khwaja was involved as an investigator. Dr. Khwaja has received research support from Roche.