AAN 2026 highlights idebenone and gene therapy data in Leber hereditary optic neuropathy

New findings presented at AAN 2026 add to the evolving treatment evidence for Leber hereditary optic neuropathy, with updates on idebenone and lenadogene nolparvovec gene therapy.

New data presented at the AAN 2026 Annual Meeting in Chicago provided further insight into treatment outcomes in Leber hereditary optic neuropathy (LHON), with updates spanning idebenone use in clinical and real-world settings, as well as emerging evidence for lenadogene nolparvovec gene therapy in patients with ND4-LHON.

LHON is a mitochondrial disease associated with progressive, bilateral central vision loss. Treatment options remain limited, with idebenone approved in Europe and lenadogene nolparvovec, an investigational intravitreal gene therapy, continuing to be evaluated for patients carrying the m.11778G>A ND4 variant.

LHON often presents first with acute or subacute visual loss, requiring prompt recognition, genetic confirmation, and timely referral or treatment discussion. With limited approved therapies and emerging gene therapy approaches, new data on visual recovery, durability, and long-term safety are highly relevant for neuro-ophthalmologists and ophthalmologists managing inherited optic neuropathies.

Don’t miss out on hearing about our latest peer-reviewed articles, expert opinions, conference news, podcasts and more.

Register Register

Idebenone benefits maintained using stricter visual acuity threshold

A re-analysis of the phase 4 LEROS (NCT02774005) study assessed idebenone outcomes using the stricter FDA-recommended threshold for clinically relevant visual acuity change, defined as ±0.3 logMAR rather than ±0.2 logMAR.¹ The analysis compared idebenone-treated eyes with matched natural history controls and stratified outcomes by disease phase and mitochondrial DNA mutation.

In patients in the subacute/dynamic phase, defined as within 1 year of disease onset, idebenone-treated eyes had a higher rate of clinically relevant benefit than matched natural history eyes (36.6% versus 20.7%; p=0.039) and a lower rate of clinically relevant worsening (23.1% versus 53.1%; p<0.001). Clinically relevant recovery was numerically higher with idebenone but did not reach statistical significance.

In the chronic phase, idebenone was associated with significantly higher rates of clinically relevant benefit and recovery, and significantly lower rates of worsening, compared with natural history controls. Clinically relevant recovery was reported in 26.6% of idebenone-treated eyes versus 16.3% of matched natural history eyes (p=0.016), while clinically relevant worsening occurred in 3.1% versus 12.4%, respectively (p=0.010).

Overall, the findings suggest that the previously observed treatment effect of idebenone in LEROS was broadly maintained when a stricter threshold for clinically relevant visual acuity change was applied, although outcomes continued to vary by disease phase and mitochondrial DNA mutation.

Real-world idebenone safety consistent with known profile

Additional data from PAROS (NCT02771379), a phase 4, non-interventional, post-authorization safety study conducted across 26 centers in four European countries, supported the long-term safety profile of idebenone in real-world clinical practice.²

The analysis focused on patients with LHON and a history of alcohol or tobacco use or abuse, or vitamin B12 deficiency. Among 224 idebenone-treated patients in the overall safety population, the median treatment duration was 22.4 months. Treatment-emergent adverse events were reported in 58.0% of the overall population, 59.0% of patients with alcohol or tobacco use or abuse, and 75.0% of those with vitamin B12 deficiency.

Drug-related treatment-emergent adverse events were reported at broadly similar rates across the overall population and subgroups, ranging from 22.3% to 25.6%, with none considered serious in the subpopulations assessed. Overall, 15.2% of patients discontinued idebenone because of a treatment-emergent adverse event, most commonly lack or loss of treatment effect.

The authors concluded that long-term idebenone treatment was generally well tolerated, with no unexpected safety findings in these real-world subgroups.

Gene therapy data show visual acuity gains in early access setting

Real-world data from early access programs in France, Italy, the UK, and the USA evaluated lenadogene nolparvovec in 63 patients with ND4-LHON.³ Most patients received bilateral intravitreal injections, and the mean disease duration at first injection was 11.4 months. Most patients were also treated with idebenone at or after gene therapy injection.

At 1 year, best-corrected visual acuity (BCVA) data were available for 53 patients. Mean change in BCVA from nadir to 1 year was -0.42 logMAR, equivalent to a gain of approximately 21 ETDRS letters. Clinically relevant recovery from nadir was reported in 42.9% of treated eyes within 12 months of disease onset and in 76.5% of treated eyes after 12 months of disease onset.

Safety findings were reported to be comparable with those observed in clinical trial studies of lenadogene nolparvovec. Intraocular inflammation occurred at similar rates in patients treated bilaterally and unilaterally.

Indirect comparison suggests higher recovery with lenadogene nolparvovec, but interpretation requires caution

A matched adjusted indirect comparison evaluated the relative treatment effects of lenadogene nolparvovec and idebenone using data from the LEROS study, early access program data, and the REFLECT study.⁴

In the LEROS versus REFLECT comparison, clinically relevant recovery at 24 months was significantly higher with lenadogene nolparvovec than with idebenone (60.4% versus 35.4%; OR 2.78; 95% CI 1.53–5.06; p=0.001). No statistically significant difference was observed for time to initial clinically relevant recovery or change from baseline BCVA at 24 months.

A second comparison using early access program data was limited by low overlap between populations, particularly differences in time from vision loss to treatment. In a post-hoc sensitivity analysis comparing early access program data with the RESCUE study, clinically relevant recovery was reported in 69.5% of patients receiving lenadogene nolparvovec versus 39.0% of those receiving idebenone.

Taken together, the AAN 2026 abstracts suggest continued support for idebenone as an established treatment option in LHON, including reassuring long-term safety data, while also highlighting growing evidence for lenadogene nolparvovec gene therapy in ND4-LHON. However, further interpretation of comparative efficacy should take into account differences in study design, patient populations, and treatment timing.

References

1. Subramanian P, Yu-Wai-Man P, Carelli V, et al. Treatment effect of idebenone in Leber hereditary optic neuropathy using an alternate threshold of clinically relevant visual acuity change. Presented at: AAN Annual Meeting 2026, Chicago, April 14-22, 2026.

2. Newman N, Vignal-Clermont C, La Morgia C, et al. Lenadogene nolparvovec gene therapy for Leber hereditary optic neuropathy in the real-life setting. Presented at: AAN Annual Meeting 2026, Chicago, April 14-22, 2026.

3. Biousse V, Yu-Wai-Man P, Newman N, et al. Efficacy of lenadogene nolparvovec gene therapy versus idebenone: A matched adjusted indirect comparison. Presented at: AAN Annual Meeting 2026, Chicago, April 14-22, 2026.

4. Newman N, Pemp B, Klopstock T, et al. Long-term safety of idebenone in patients with Leber hereditary optic neuropathy with alcohol or tobacco use/abuse or vitamin B12 deficiency: Results from the PAROS study. Presented at: AAN Annual Meeting 2026, Chicago, April 14-22, 2026.