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

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.

Treatment of Leber’s hereditary optic neuropathy: An overview of recent developments

“…4 Idebenone is a short chain ubiquinone (CoenzymeQ 10 -CoQ 10 ) analogue, developed in Japan for the treatment of neurodegenerative conditions. 3 Idebenone is the active substance of Raxone, first medicinal product authorised to treat LHON, approved in the EU in September 2015 3 (Figure 1). In the EU a marketing authorisation is required for a product to be placed on the market.…”

“…In LHON, Raxone bypasses the affected complex I of the ETC, restores electron flux and ATP generation by mitigating the inactive but still viable RGCs. [3][4][5] Raxone can promote vision recovery in LHON patients depending on time passed since manifestation of symptoms and number of RGCs already affected at the time of first administration.…”

“…Patients aged between 14 and 66 and suffering from LHON for ⩽5 years were included in RHODOS and randomly assigned to receive either Raxone at a dose of 900 mg/day or placebo for a period of 24 weeks. 3,11 The main primary endpoint evaluated was the best recovery of VA (BCVA). BCVA was assessed using an ETDRS chart after 24 weeks from the eye with the best improvement in VA from baseline.…”

“…Patients aged between 14 and 66 and suffering from LHON for ⩽5 years were included in RHODOS and randomly assigned to receive either Raxone at a dose of 900 mg/day or placebo for a period of 24 weeks. 3,11…”

“…1,2 Point mutations m.11778G>A, m.3460G>A and m.14484T>C are the three most prevalent in LHON population, respectively encoding for subunits ND4, ND6 and ND1 of the mitochondrial complex I. 3 Due to the mutated genes, an increased production of reactive oxygen species (ROS) occurs leading to a decreased production of ATP and causing apoptosis of RGCs. 1 The point mutations m.11778G>A, m.3460G>A and m.14484T>C are also called primary mutations as they cause up to 95% of LHON cases.…”