P.377 - Olesoxime in patients with type 2 or non-ambulatory type 3 Spinal muscular atrophy: a placebo-controlled phase 2 trial including a long-term, open-label follow-up study

Growing evidence suggests mitochondrial dysfunction is a key disease mechanism and valid therapeutic target in spinal muscular atrophy (SMA). Olesoxime is an orally-administered, mitochondria-targeting compound that promotes survival and function of motor neurons, muscle and other cell types. This study assessed the efficacy, safety and tolerability of olesoxime in patients aged 3–25 years with Type 2 or non-ambulatory Type 3 SMA (NCT01302600). Participants were eligible for a follow-up, open-label study (OLEOS; NCT02628743) to assess the long-term safety and efficacy of olesoxime. Participants (n = 165) were randomized 2:1 to once-daily, oral olesoxime 10 mg/kg or placebo (full analysis set, n = 160). Baseline characteristics (olesoxime vs placebo): mean age (9.1 vs 11.2 years), Type 2 (71.8 vs 68.4%), Type 3 (28.2 vs 31.6%), mean MFM D1 + D2 score (39.6 vs 39.0). Motor function was maintained over the 2-year double-blind period with olesoxime, whilst the placebo group worsened (0.18-point improvement in MFM D1 + D2 vs 1.82-point decline; primary endpoint P = 0.068). Secondary endpoints further supported motor function maintenance with olesoxime. Olesoxime was well tolerated, with safety comparable to placebo. 79% of patients from the placebo-controlled Phase 2 enrolled in OLEOS. The OLEOS baseline visit occurred 2.4–3.4 years after study drug discontinuation in Phase 2, and the 2:1 ratio between olesoxime and placebo was maintained indicating no selection bias. Despite a substantial decline in MFM D1 + D2 (>2 points/year) since stopping study drug, the ~2-point MFM treatment difference between olesoxime and placebo was maintained, suggesting that there may be a potential delay of disability progression. Data following 12 months' open-label olesoxime treatment will be presented. These data suggest that olesoxime offers the potential to provide meaningful clinical benefit and may play a role in the future therapeutic management of SMA.