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.

Olesoxime (TRO19622) was identified as a potential treatment of SMA based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with spinal muscular atrophy (SMA). 165 type 2 or non-ambulant type 3 SMA patients, aged 3–25 years old were enrolled from 22 sites in 7 European countries beginning in November 2010. Patients were randomized to olesoxime, 10 mg/kg, administered as a liquid oral formulation or matching placebo in a 2:1 ratio and treatment duration was for 104 weeks. The last patient completed the study in October 2013. The primary outcome measure was the change in motor function using the MFM scale. The secondary outcome measures included the HFMS for SMA, electromyography, pulmonary function, and patient-reported outcomes as well as safety. Patients in the placebo arm of the study experienced a loss of motor function at a similar rate to that previously reported (Vuillerot et al. 2013). This loss of function, assessed as the primary endpoint, was prevented for two years in olesoxime-treated patients, with fewer disease-related adverse events. Other secondary endpoints were consistent with these effects. Results from this pivotal double blind placebo-controlled clinical trial provide clinical proof of concept of olesoxime’s neuroprotective effect that is sustained over two years. This combined with fewer adverse events caused by the disease itself will be submitted for the registration of olesoxime as the first neuroprotection treatment for SMA. Olesoxime (TRO19622) was identified as a potential treatment of SMA based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with spinal muscular atrophy (SMA). 165 type 2 or non-ambulant type 3 SMA patients, aged 3–25 years old were enrolled from 22 sites in 7 European countries beginning in November 2010. Patients were randomized to olesoxime, 10 mg/kg, administered as a liquid oral formulation or matching placebo in a 2:1 ratio and treatment duration was for 104 weeks. The last patient completed the study in October 2013. The primary outcome measure was the change in motor function using the MFM scale. The secondary outcome measures included the HFMS for SMA, electromyography, pulmonary function, and patient-reported outcomes as well as safety. Patients in the placebo arm of the study experienced a loss of motor function at a similar rate to that previously reported (Vuillerot et al. 2013). This loss of function, assessed as the primary endpoint, was prevented for two years in olesoxime-treated patients, with fewer disease-related adverse events. Other secondary endpoints were consistent with these effects. Results from this pivotal double blind placebo-controlled clinical trial provide clinical proof of concept of olesoxime’s neuroprotective effect that is sustained over two years. This combined with fewer adverse events caused by the disease itself will be submitted for the registration of olesoxime as the first neuroprotection treatment for SMA.