Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy in the LEROS study: Analysing change in visual acuity according to causative mutation and disease phase

Abstract

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in severe vision loss. The causative mitochondrial DNA (mtDNA) mutation impacts disease progression and prognosis. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort. Here, we compare VA change from baseline to Month 24 according to primary mtDNA mutation and disease stage.Methods: Eyes of patients with LHON and either a m.G11778A, m.T14484C or m.G3460A, mtDNA mutation were stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients were compared to retrospective data from the NH cohort (N = 372), matched by time since symptom onset at baseline. We compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in IDE versus NH eyes (a negative value favours IDE).Results: In treated subacute/dynamic m.G11778A eyes (n = 60 IDE), delta VA was −0.32 logMAR (p = 0.002) versus the NH cohort (n = 47). In chronic m.G11778A eyes, delta VA was −0.11 logMAR (n = 82 IDE vs n = 51 NH; p = 0.043). In subacute/dynamic m.T14484C eyes, delta VA was +0.20 logMAR (n = 35 IDE vs n = 10 NH; p = 0.285). In chronic m.T14484C eyes, delta VA was −0.52 logMAR (n = 11 IDE vs n = 18 NH; p < 0.001). In subacute/dynamic m.G3460A eyes, delta VA was +0.53 logMAR (n = 26 IDE vs n = 18 NH; p = 0.001). In chronic m.G3460A eyes, delta VA was −0.13 logMAR (n = 23 IDE vs n = 24 NH; p = 0.162).Conclusions: Idebenone improved VA in a large proportion of eyes; this benefit manifested to varying degrees depending on disease stage and mtDNA mutation. m.G11778A eyes saw a consistent benefit regardless of disease stage. m.T14484C and m.G3460A results should be interpreted with caution in some cases due to the relatively low number of eyes; further study is warranted.