Treatment of Leber's hereditary optic neuropathy (LHON): Results using a novel quinone, EPI-743

Abstract

Purpose: LHON is a maternally inherited disease, associated with mitochondrial DNA (mtDNA) point mutations and characterized by sudden and profound bilateral loss of central vision and blindness, for which there is no effective treatment. The purpose of this study is to describe the results of treating LHON with a novel experimental drug, EPI-743, in 12 consecutively enrolled patients who were actively losing vision.

Methods: Twelve affected patients were treated under an FDA emergency use protocol; eight patients had the 11778 mutation, three patients had the 14484 mutation and one patient had the 3460 mutation. Eleven of the 12 patients were male; mean patient age was 22.5 years (range 8 to 52). Follow-up varied from 12 to 36 months with a mean of 22 months. Time between visual loss and treatment varied from 0 to 8m with a mean of 2.5m. Clinical measurements of efficacy were visual acuity (VA) (improvement if 2 or more lines of change), visual fields (VF) (improvement if >7dB of changes in mean deviation), OCT, and color vision (CV) (improvement if > 2 plates in Ishihara plates). Measurements of safety included renal and liver function tests, coagulation measurements and EKG. Twenty-three eyes of 12 patients were included (one patient had retinal detachment in one eye).

Results: VA: seven eyes improved (31%) two to 20/20 level (from 20/400 and 20/50), one to 20/30 (from 20/200) and one to 20/50 (from 20/400); ten (43%) were unchanged and six (26%) were worse when compared to initial VA. VF: five eyes improved (21%), ten (43%) were unchanged and eight (36%) were worse than initial VF. CV: three eyes improved (13%) (2/8 to 8/8, 2/8 to 7/8 and 5/8 to 8/8), thirteen were unchanged (57%) and seven were worse (30%). OCT: All but one patient presented with progressive loss of fibers over time (25 to 50% of the normal values). Safety: two patients (16%) presented abnormal liver function tests related to alcohol consumption. One patient (8%) had an adverse side effect of dizziness, which was shown to be related to a dental anesthesia.

Conclusions: EPI-743 treatment improved or stabilized visual function in 70% of treated eyes. There were no significant drug related adverse events or clinical laboratory abnormalities. EPI-743 may demonstrate the potential to be a safe and effective treatment for LHON. Prospective trials to better characterize the EPI-743 treatment effect in LHON are planned.

Keywords: 613 neuro-ophthalmology: optic nerve • 758 visual fields • 471 color vision