Objective: To evaluate the long-term safety and clinical effects of EPI-743 in Friedreich’s Ataxia (FRDA).
Background: FRDA is an inherited ataxia caused by impairment of mitochondrial iron-sulfur-cluster protein assembly. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism.
Design/Methods: We conducted a multicenter trial that included a 6-month multiple dose placebo controlled phase, followed by an 18-month phase in which all subjects received treatment with EPI-743. The primary study objective was low contrast visual acuity as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS). The key secondary study endpoint was neurological function as assessed by the Friedreich’s Ataxia Rating Scale (FARS)-NEURO.
Results: A total of 63 subjects were enrolled in the trial; 61 completed the initial phase. EPI-743 was found to be safe and well tolerated, and demonstrated consistent pharmacology. During the placebo-controlled phase, there were no significant improvements in the primary or secondary endpoints using raw scores. However, significantly more patients taking low-dose EPI-743 had a 3-point or greater improvement (equivalent to one year of symptom progression in natural history cohorts) in the FARS NEURO than patients taking placebo (p = 0.047). Longitudinal modeling at 24 months revealed significantly improved disease progression in all drug groups when compared to natural history data. Using FA Clinical Outcome Measure data, the mean FARS increase (worsening) in untreated patients over 24 months is 4.8 points, compared to a mean decrease (improvement) in all patients taking EPI-743 of 1.8 points (2 tailed t-test with equal variance p = 0.00001).
Conclusions: EPI-743 was safe and well tolerated, and although it did not reach the primary endpoint following six months, long-term treatment resulted in significantly improved neurological outcome after 24 months compared to natural history data.
Available at: http://works.bepress.com/kelly_sullivan/195/