Long-term efficacy of idebenone in patients with LHON according to age at onset and disease phase: Results from the LEROS study

Abstract

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 were compared to those of an external Natural History (NH) cohort. Here, we report the results of sub-analyses according to age at symptom onset and disease phase.

Methods : LEROS included patients with LHON aged ≥12 years and with a disease onset ≤5 years prior. Overall, 199 patients were enrolled, 181 of which formed the modified Intention-To-Treat (mITT) population. NH data were available from 372 patients. Patients were divided into 2 groups based on time since onset in the most recent eye: subacute/dynamic (≤1 year) and chronic (>1 year), and further stratified based on age at symptom onset: <18 years and ≥18 years. Data from the idebenone-treated group was compared to retrospective data from the NH cohort, matched by time since disease onset. Outcome measures (from baseline) were clinically relevant recovery (CRR) and clinically relevant worsening (CRW).

Results : In patients aged <18 years, VA outcomes at 24 months were observed, in treated versus untreated eyes, as follows: subacute/dynamic CRR: 31.8% (7/22) vs 59.1% (13/22), p = 0.0476; chronic CRR: 31.3% (5/16) vs 21.6% (8/37), p = 0.2406; subacute/dynamic CRW: 26.3% (5/19) vs 21.4% (3/14), p = 0.5579; chronic CRW: 8.3% (1/12) vs 19.2% (5/26), p = 0.0784. In patients aged ≥18 years, corresponding VA outcomes were observed as follows: subacute/dynamic CRR: 51.5% (51/99) vs 22.6% (12/53), p = 0.0013; chronic CRR: 32.0% (32/100) vs 12.5% (7/56), p = 0.0009; subacute/dynamic CRW: 25.7% (19/74) vs 62.9% (22/35), p = 0.0002; chronic CRW: 1.8% (1/56) vs 20.6% (7/34), p = 0.0033.

Conclusions : Idebenone improved the ratio of positive to negative VA outcomes. Treatment benefit was particularly pronounced in patients aged ≥18 years, with only non-significant positive trends observed in chronic eyes of patients aged <18 years. Results in subacute/dynamic eyes of patients aged <18 years were limited by an unusually high recovery rate in the NH cohort, warranting further study.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.