Use of Idebenone for the Treatment of Leber’s Hereditary Optic Neuropathy: Review of the Evidence

Abstract

Leber’s hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP) production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA]) did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes) showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.