AbstractPurpose: In LEROS, visual acuity (VA) outcomes in idebenone‐treated patients with LHON were compared to an external, matched, natural history (NH) cohort. Here, we report results from a cumulative frequency analysis to understand the impact of idebenone on carriers of each of the primary mitochondrial DNA (mtDNA) mutations.Methods: Patients with LHON and a confirmed primary mtDNA mutation (11 778, 14 484 or 3460) were enrolled and stratified by time since onset: acute (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients treated up to 24 months were compared to retrospective data from the NH cohort (372 patients), matched by time since onset. In a cumulative frequency analysis, VA change was assessed from baseline to month 24. A change of ≥0.2 logMAR was considered a clinically relevant recovery or worsening, depending on the direction of change.Results: For carriers of the 11 778 mutation, VA outcomes were observed, in treated versus untreated eyes, as follows: recovery: 38.3% (23/60) vs. 14.9% (7/47) [acute], 24.4% (20/82) vs. 13.7% (7/51) [chronic]; worsening: 24.4% (10/41) vs. 66.7% (20/30) [acute], 4.4% (2/45) vs. 31.6% (6/19) [chronic]. For 14 484 carriers VA outcomes were as follows: recovery: 74.3% (26/35) vs. 70.0% (7/10) [acute], 90.9% (10/11) vs. 16.7% (3/18) [chronic]; worsening: 2.9% (1/35) vs. 22.2% (2/9) [acute], 0.0% (0/8) vs. 16.7% (3/18) [chronic]. For 3460 carriers, outcomes were as follows: recovery: 34.6% (9/26) vs. 61.1% (11/18) [acute], and 30.4% (7/23) vs. 20.8% (5/24) [chronic]; worsening: 76.5% (13/17) vs. 30.0% (3/10) [acute], and 0.0% (0/15) vs. 13.0% (3/23) [chronic].Conclusions: Idebenone can improve the ratio of positive to negative VA outcomes in a large proportion of patients with LHON, although these benefits seem to manifest to varying degrees dependent on disease stage and/or causative mtDNA mutation. Carriers of the most prevalent mutation, 11 778, saw a consistent treatment benefit regardless of disease stage.
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