Idebenone Treatment for Leber Hereditary Optic Neuropathy: Time to Clinically Relevant Recovery in the LEROS Study - European Medical Journal

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Idebenone Treatment for Leber Hereditary Optic Neuropathy: Time to Clinically Relevant Recovery in the LEROS Study

2 Mins
Neurology
Authors:
*Chiara La Morgia,1,2 Thomas Klopstock,3 Patrick Yu-Wai-Man,4-8 Valerio Carelli,1,2 Xavier Llòria Llàcer,9 LEROS Study Group
  • 1. IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy
  • 2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
  • 3. Friedrich Baur Institute at the Department of Neurology, University Hospital of Ludwig-Maximilians-Universität München, Munich, Germany
  • 4. John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK
  • 5. MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, UK
  • 6. Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, UK
  • 7. Moorfields Eye Hospital NHS Foundation Trust, London, UK
  • 8. Institute of Ophthalmology, University College London, UK
  • 9. Chiesi Farmaceutici S.p.A, Parma, Italy
*Correspondence to [email protected]
Disclosure:

The LEROS study was funded by Santhera Pharmaceuticals. Medical writing support was provided by nspm ltd, Switzerland, and funded by Chiesi Farmaceutici. La Morgia has acted as a consultant for Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, and Thenewway srl; has received speaker honoraria for meetings from Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, Thenewway, First Class srl, and Biologix; has received financial support for meetings and/or travel from Chiesi Farmaceutici, Regulatory PharmaNet, GenSight Biologics, Thenewway, First Class, and Biologix; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals, GenSight Biologics, Stoke Therapeutics, Stealth Biotherapeutics, and Reneo Pharmaceuticals. Yu-Wai-Man has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, GenSight Biologics, Neurophth, and Stoke Therapeutics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial support for meetings and/or travel from Santhera Pharmaceuticals, Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Klopstock has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial support for meetings and/or travel from Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Carelli has received research support from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received speaker honoraria from Santhera Pharmaceuticals, Chiesi Farmaceutici, and GenSight Biologics; has received financial support for meetings and/or travel from Chiesi Farmaceutici, GenSight Biologics, and First Class; has participated in an Advisory Board for Chiesi Farmaceutici and GenSight Biologics; and has acted as a principal or study investigator for clinical trials sponsored by Santhera Pharmaceuticals and GenSight Biologics. Llòria Llàcer is an employee of Chiesi Farmaceutici.

Acknowledgements:

The authors would like to thank all patients and healthcare professionals participating in LEROS for their participation and contribution in collecting the data.

Citation:
EMJ Neurol. ;12[1]:60-63. https://doi.org/10.33590/emjneurol/NOWG1634.
Keywords:
Clinically relevant recovery, idebenone, Leber hereditary optic neuropathy (LHON), LEROS, mitochondrial optic neuropathy, neuro-ophthalmology.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

INTRODUCTION

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral central vision loss, primarily caused by one of three primary mitochondrial DNA (mtDNA) mutations (m.11778G>A, m.3460G>A, or m.14484T>C).1 Idebenone has shown a favourable safety and efficacy profile in the treatment of LHON.2,3 In LEROS, a Phase IV, open-label interventional study (NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment were compared to an external matched Natural History cohort.4 Here, the authors present the cumulative percentage of eyes with a clinically relevant recovery (CRR) from baseline (Kaplan Meier [KM] estimate) in idebenone-treated eyes by disease phase and primary mtDNA mutation, as a function of treatment duration.

MATERIALS AND METHODS

LEROS included patients with LHON aged ≥12 years and with a disease onset ≤5 years prior. Patients in the intention-to-treat cohort were treated with 900 mg/day idebenone and VA was measured over 24 months using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. CRR was defined as an improvement from ‘off-chart’ VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already ‘on-chart’. Eyes were stratified by time since symptom onset (subacute/dynamic [≤1 year] and chronic [>1 year]).

RESULTS

The intention-to-treat population included 196 patients with a median age of 31.9 years. The overall KM estimate of a CRR from baseline increased progressively with idebenone in subacute/dynamic eyes from 18.4% at Month 6 to 47.3% at Month 24. When assessing subacute/dynamic eyes, the KM estimate of a CRR increased progressively until the end of observation in those with a m.11778G>A mutation, from 13.0% at Month 6 to 37.7% at Month 24. The rate of CRR increased up to 12 months in eyes carrying a m.3460G>A mutation, from 14.4% at Month 6 to 33.4% at Month 12. The proportion of eyes with a m.14484T>C mutation and a CRR increased progressively from 30.7% at Month 6 to 80.0% at Month 24 (Figure 1A).5

The overall KM estimate of a CRR from baseline also increased in chronic eyes treated with idebenone, from 18.2% at Month 6 to 29.1% at Month 24. In the chronic phase, a progressive increase in CRR was observed in those with a m.11778G>A mutation, from 17.5% at Month 6 to 24.6% at Month 24. In eyes carrying a m.3460G>A mutation, the rate of CRR increased only up to 12 months from 13.2% at Month 6 to 26.0% at Month 12. In m.14484T>C eyes, an increase in CRR was observed up to Month 18, from 31.2% at Month 6 to 70.9% at Month 18 (Figure 1B).5

Figure 1: Kaplan-Meier estimate of a clinically relevant recovery from baseline in A) subacute/dynamic eyes and B) chronic eyes.
BL: baseline; CRR: clinically relevant recovery; KM: Kaplan-Meier.

CONCLUSION

Overall, extended duration of idebenone treatment led to an increased rate of CRR, in both subacute/dynamic and chronic eyes. The proportion of m.11778G>A eyes with CRR increased progressively until the end of observation, irrespective of disease phase. In m.3460G>A eyes, an increasing rate of CRR was only observed up to 12 months of treatment. The observed improvement was most pronounced for eyes with the m.14484T>C mutation. Conclusions for m.3460G>A and m.14484T>C eyes are limited by the number of at-risk eyes available for analysis.

References
Carelli V et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J. Neuroophthalmol. 2017;37(4)371-81 Klopstock T et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(9)2677-86. Catarino CB et al. Real-world clinical experience with idebenone in the treatment of Leber hereditary optic neuropathy. J Neuroophthalmol. 2020;40(3)558-65. Yu-Wai-Man P et al. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell Rep Med. 2024;5(3)101437. La Morgia C et al. Idebenone treatment for Leber hereditary optic neuropathy; time to clinically relevant recovery in the LEROS study. Eur J Neurol. 2024;31:e16337.

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