Idebenone Under Review for Leber Hereditary Optic Neuropathy

The Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for idebenone for the treatment of Leber hereditary optic neuropathy (LHON).

Leber hereditary optic neuropathy (LHON) is a genetic mitochondrial disorder that damages retinal ganglion cells, resulting in rapid vision loss. Idebenone is expected to restore mitochondrial function and reactivate retinal ganglion cell function.

The NDA acceptance was based on data from the phase 3 RHODOS trial (ClinicalTrials.gov Identifier: NCT00747487), as well as from the open-label phase 4 LEROS study (ClinicalTrials.gov Identifier: NCT02774005). 

The RHODOS trial compared the efficacy of idebenone vs placebo in 85 participants aged 14 to 65 years carrying 1 of 3 primary mitochondrial DNA mutations (m.11778G>A, m.3460G>A, or m.14484T>C) and with disease duration of less than or equal to 5 years.

The primary endpoint was the best recovery of logMAR visual acuity, defined as the change from baseline to week 24 in the eye showing the most improvement or least deterioration, measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Findings showed the idebenone group had a logMAR of -0.136 with an improvement by about 6 letters on the ETDRS chart vs the placebo group which had a logMAR of -0.036 and an improvement of approximately 1 letter (P =.0862).

Results also showed statistically significant improvements in key secondary endpoints:

• Change in best visual acuity: idebenone: logMAR –0.037 (+1 letter); placebo: logMAR +0.123 (-6 letters); P =.0152.
• Change in visual acuity in the best eye: idebenone: logMAR –0.030 (+1 letter); placebo: logMAR +0.098 (-6 letters); P =.0126.

The LEROS study evaluated the efficacy and safety of long-term idebenone treatment in 199 patients with LHON. Study participants who were initiated on idebenone within less than or equal to 1 year of symptom onset were compared with a matched external natural history control group. 

The primary endpoint was the proportion of eyes achieving a clinically relevant benefit (CRB) at month 12. CRB included those with either a clinically relevant recovery (CRR) or clinically relevant stabilization of visual acuity from baseline.

Findings showed 42.3% of eyes in the idebenone arm achieved CRB compared with 20.7% in the natural history control arm (odds ratio [OR], 2.29; P =.002). 

In patients who started treatment more than 1 year after symptom onset (secondary analysis), 50.3% of eyes treated with idebenone achieved CRB vs 38.6% of those in the natural history cohort (OR, 1.93; P =.0087). Additionally, in a post-hoc responder analysis, the odds of achieving an overall benefit (CRR or no-clinical relevant worsening) in best-corrected visual acuity were 3.4 times higher in the idebenone arm vs the natural history arm. 

“LHON is a serious condition marked by rapid central vision loss, often beginning in one eye and quickly affecting the other, placing a profound and immediate burden on patients and their loved ones,” said Nancy J Newman, MD, LeoDelle Jolley Chair in Ophthalmology at Emory University School of Medicine. “If approved in the United States, idebenone would represent a meaningful advancement in treatment, offering hope to the LHON community.”

A Prescription Drug User Fee Act target date of February 28, 2026 has been set for the application.

This article originally appeared on MPR