Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy according to age at symptom onset and disease phase: Results from the LEROS study

Abstract

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age influences disease progression and, potentially, treatment response. 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.Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare clinically relevant recovery (CRR) and clinically relevant worsening (CRW) from baseline to Month 24 in IDE eyes versus NH eyes, stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years).Results: In patients aged <18 years, VA outcomes were observed, in IDE versus NH eyes, as follows: CRR: subacute/dynamic 31.8% (7/22) vs 59.1% (13/22), p = 0.048; chronic 31.3% (5/16) vs 21.6% (8/37), p = 0.241; CRW: subacute/dynamic 26.3% (5/19) vs 21.4% (3/14), p = 0.558; chronic 8.3% (1/12) vs 19.2% (5/26), p = 0.078. In patients aged ≥18 years, the following VA outcomes were observed: CRR: subacute/dynamic 51.5% (51/99) vs 22.6% (12/53), p = 0.001; chronic 32.0% (32/100) vs 12.5% (7/56), p < 0.001; CRW: subacute/dynamic 25.7% (19/74) vs 62.9% (22/35), p < 0.001; chronic 1.8% (1/56) vs 20.6% (7/34), p = 0.003.Conclusions: Idebenone improved the ratio of positive to negative VA outcomes. Treatment benefit was particularly pronounced in patients ≥18 years at onset, with only non‐significant positive trends observed in chronic patients <18 years. Results in subacute/dynamic patients aged <18 years were limited by an unusually high recovery rate in the NH cohort, warranting further study.