EPI-743 for Friedreichs Ataxia Patients with Point Mutations (P5.388)

Objective: To assess the effects of EPI-743 in patients with Friedreich’s Ataxia (FA) point mutations on neurologic function as measured by the Friedreich’s Ataxia Rating Scale (FARS). Background: FA is an autosomal recessive degenerative disorder characterized by ataxia, dysarthria, sensory loss, diabetes, and cardiomyopathy. FA patients with a point mutation (FA-PM) carry an expanded GAA repeat on one allele and a point mutation/deletion on the other allele; this is a rare variant. The natural history of FA includes progressively deteriorating neurologic function with FARS worsening 3.55 points in 12 months and 6.16 points in 24 months. EPI-743 is a therapeutic being developed for treatment of patients with mitochondrial diseases and disorders of oxidative stress. Methods: Three patients with genetically confirmed FA-PM (G130V) were administered EPI-743 400mg PO TID for 18 months in an open-label study. Assessments were completed quarterly. Relative mean changes in FARS total and subscale scores from baseline to 6 and 18 months of treatment were calculated as change([percnt]) = ((meanX - mean0) / mean0 × 100) where X represents the time point. Results: After 6 months of treatment, total FARS score improved an average of 9[percnt] (baseline mean total FARS=64, 6m mean total FARS=58). While all subscales improved, bulbar and upper limb coordination sub-scales were most improved (bulbar mean improvement of 80[percnt] [from 0.83 to 0.17] and upper limb coordination 53[percnt] [from 3.17 to 1.5]). Mean improvements persisted at 18 months from baseline (FARS total: 6[percnt], bulbar subscale: 20[percnt], upper limb coordination: 37[percnt]), although they attenuated. No serious adverse events, including hematologic or cardiac, were observed. Conclusions: EPI-743 was associated with clinically significant improvement in neurological function in patients with FA-PM over 18 months. These findings support further study of EPI-743 in patients with FA due to point mutations. Study Supported by: FARA Disclosure: Dr. Sullivan has nothing to disclose. Dr. Freeman has nothing to disclose. Dr. Shaw has nothing to disclose. Dr. Gooch has received personal compensation for activities with NeuralStem, Baxter Pharmaceuticas, and CSL Behring Consultant. Dr. Huang has nothing to disclose. Dr. Klein has received personal compensation for activities with Edison Pharmaceuticals as an employee. Dr. Miller has received personal compensation for activities with Edison Pharmaceuticals as an employee. Dr Zesiewicz has received research support from FARA.