Long‐term efficacy and safety of idebenone in patients with Leber's hereditary optic neuropathy (LHON) in the subacute/dynamic phase: Results from the prospective, natural history‐controlled LEROS study

Abstract

AbstractPurpose: Idebenone is approved in Europe for the treatment of LHON – a rare mitochondrial disorder resulting in severe, bilateral vision loss. Controlled data beyond a 6‐month treatment duration is lacking. Here, we report primary results from LEROS, a Phase 4, externally controlled interventional study in patients with subacute/dynamic LHON treated with idebenone for up to 24 months.Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 year). Visual acuity (VA) outcomes from 181 patients, treated for up to 24 months were compared to retrospective data from an external natural history (NH) cohort (N = 372) matched by time since onset. Outcome measures, from baseline, were clinically relevant recovery (CRR): improvement from ‘off‐chart’ VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already ‘on‐chart’; clinically relevant stabilization (CRS): maintenance of VA < 1.0 logMAR; and clinically relevant benefit (CRB): reaching a CRR, a CRS, or both.Results: The primary endpoint – the proportion of subacute/dynamic eyes with a CRB from baseline following 12 months of treatment, versus matched NH eyes – was met (42.3% [60/142] vs. 20.7% [40/193] [p = 0.0020]); this difference was maintained after 24 months (52.9% [64/121] vs. 36.0% [27/75] [p = 0.0297]). The difference in the CRB rate was largely driven by CRS, occurring in 64.5% (20/31) of eligible (<1.0 logMAR at baseline) treated eyes versus 22.5% (9/40) of eyes in the NH cohort at 12 months (p = 0.0005). The proportion of off‐chart patients (best VA) continuously decreased after the likely nadir at 6 months. By 24 months, a larger proportion of patients had moved into the non‐legally blind category than at BL (42.9% vs. 33.9%).Conclusions: LEROS corroborates previous idebenone efficacy results, demonstrating that long‐term treatment is well tolerated and results in prolonged clinical benefit in patients with LHON in the subacute/dynamic phase.