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Show Letters to the Editor Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy—Response to Dr. Finsterer's Letter W e are happy to respond to Dr. Finsterer's comments on our article “Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy,” published in J Neuroophthalmol 2020; 40:558-565 (1). Dr. Finsterer criticizes our study design and writes that a “double-blind, placebo-controlled trial would be more suitable.” This suggestion is both trivial and pointless. As is widely known, at least in the mitochondrial and the neuroophthalmological communities, and as referenced in the article, idebenone in LHON was already investigated in a randomized double-blind, placebocontrolled trial, published in 2011 (2). The results of this study, together with interim data from a subsequent Expanded Access Program, led to the conditional approval of idebenone for LHON by the European Medicines Agency in 2015. Expanded Access Programs are a widely accepted tool to bridge the gap between completion of a randomized double-blind, placebo-controlled trial and approval of the respective drug, in particular when there are no other treatments available. Obviously, such Expanded Access Programs are open-label, since placebo treatment is considered unethical in this situation. Per definition, Expanded Access Programs conform to unsolicited requests by treating physicians, and leave dosage and duration of therapy “entirely at the discretion of the treating physician.” This way, much needed Real-World Evidence is collected (cf. https://www.fda.gov/science-research/science-and-researchspecial-topics/real-world-evidence). Obviously, open-label studies cannot provide direct information regarding “true benefit from the drug” vs. “spontaneous recovery.” We discussed this limitation in our article and accordingly compared the recovery rates to published natural history data and to the recovery rate in the placebo group of our randomized trial (2). In his next point, Dr. Finsterer mixes up “disease duration” and “treatment duration.” As explained in the Abstract and the body of our article, patients were eligible for this Expanded Access Program when they had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Treatment duration was at the discretion of the treating physician (see above), and the wide range of treatment duration is prerequisite for the main analysis of this study, which shows that the cumulative percentage of total number of patients and eyes, respectively, with clinically relevant recovery (CRR) increases as a function of treatment duration. e96 A discussion on the controversial concept of “LHON plus” is beyond the scope of our article, and would not add anything regarding the efficacy of idebenone on visual acuity. In his last point, Dr. Finsterer refers to a recent publication on “Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency”. Although this publication is about an interesting mouse model to preclinically test treatments, it is not relevant for our article. As is commonly known, there is some degree of retinal ganglion cell degeneration in all clinically manifest LHON patients. Our study, however, concentrated on CRR and clinically relevant stabilization of visual acuity which is the most important outcome measure for LHON patients. In conclusion, our article adds Real-World Evidence to what we already know about the effect of idebenone in LHON. It needs to be read and understood in the context of the available literature. Claudia B. Catarino, MD, PhD, Bettina von Livonius, MD, Claudia Priglinger, MD, Klara Landau, MD, FEBO, Nancy J. Newman, MD, Marcela Votruba, BMBCh, FRCOphth, Günther Rudolph, MD, Thomas Klopstock, MD, FEAN Department of Neurology (CBC, TK), Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (TK), Munich, Germany; Department of Ophthalmology (BL, CP, GR), University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; Department of Ophthalmology (KL), University Hospital and University of Zurich, Zurich, Switzerland; Emory University School of Medicine (NJN), Atlanta, Georgia; and School of Optometry and Vision Sciences (MV), Cardiff University, Cardiff, United Kingdom. T. Klopstock has received research support, consultancy fees, speaker honoraria, and travel funds from GenSight Biologics, Santhera Pharmaceuticals and Chiesi. The remaining authors report no conflicts of interest. REFERENCES 1. Catarino CB, von Livonius B, Priglinger C, Banik R, Matloob S, Tamhankar MA, Castillo L, Friedburg C, Halfpenny CA, Lincoln JA, Ghislaine LT, Acaroglu G, Black GCM, Doncel C, Fraser CL, Jakubaszko J, Landau K, Langenegger SJ, MuñozNegrete FJ, Newman NJ, Poulton J, Scoppettuolo E, Subramanian P, Ahmed T, Vidal M, Vincent AL, Votruba M, Zarowski M, Adam Z, Lob F, Rudolph G, Mikazans O, Silva M, Llòria X, Metz G, Klopstock T. Real-world clinical experience with idebenone in the treatment of leber hereditary optic neuropathy. J Neuroophthalmol. 2020;40:558–565. 2. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. A randomized placebocontrolled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677–2686. Letters to the Editor: J Neuro-Ophthalmol 2023; 43: e93-96 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
