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Controlled Clinical Trial
. 2024 Mar 19;5(3):101437.
doi: 10.1016/j.xcrm.2024.101437. Epub 2024 Feb 29.

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Patrick Yu-Wai-Man  1 , Valerio Carelli  2 , Nancy J Newman  3 , Magda Joana Silva  4 , Aki Linden  5 , Gregory Van Stavern  6 , Jacek P Szaflik  7 , Rudrani Banik  8 , Wojciech Lubiński  9 , Berthold Pemp  10 , Yaping Joyce Liao  11 , Prem S Subramanian  12 , Marta Misiuk-Hojło  13 , Steven Newman  14 , Lorena Castillo  15 , Jarosław Kocięcki  16 , Marc H Levin  17 , Francisco Jose Muñoz-Negrete  18 , Ali Yagan  19 , Sylvia Cherninkova  20 , David Katz  21 , Audrey Meunier  22 , Marcela Votruba  23 , Magdalena Korwin  7 , Jacek Dziedziak  24 , Neringa Jurkutė  25 , Joshua P Harvey  26 , Chiara La Morgia  27 , Claudia Priglinger  28 , Xavier Llòria  29 , Livia Tomasso  29 , Thomas Klopstock  30 ; LEROS Study Group
Affiliations
Controlled Clinical Trial

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Patrick Yu-Wai-Man et al. Cell Rep Med. .

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Keywords: LHON; Leber hereditary optic neuropathy; idebenone; mitochondrial disease; mtDNA; neuro-ophthalmology; optic atrophy; optic neuropathy; retinal ganglion cells.

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Conflict of interest statement

Declaration of interests P.Y.-W.-M., V.C., N.J.N., B.P., L.C., and T.K. received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics. P.Y.-W.-M. is also a consultant for Neurophth and Stoke Therapeutics. N.J.N. is also a consultant for Santhera Pharmaceutical, Chiesi, GenSight Biologics, Stoke Therapeutics, Avidity Biosciences, and Neurophoenix SAS, and has been a speaker and contributing writer for educational activities under the auspices of WebMD and First Class. P.S.S. is a consultant to GenSight Biologics and received research support from GenSight Biologics and Santhera Pharmaceuticals. M.H.L. received personal compensation from Santhera Pharmaceuticals. C.L.M. has acted as a consultant for Chiesi Farmaceutici, Regulatory PharmaNet, and Thenewway srl, and has also received speaker honoraria and/or financial support for meetings from these companies, as well as from First Class srl and Biologix. C.L.M. has also acted as a principal or study investigator for clinical trials sponsored by GenSight Biologics, Santhera Pharmaceuticals, Stoke Therapeutics, and Reneo Pharmaceuticals. C.P. received personal compensation from Novartis and has acted as an investigator in clinical trials for Santhera Pharmaceuticals, GenSight Biologics, and Iveric Bio. X.L. and L.T. are employees of Chiesi Farmaceutici S.p.A.

Figures

None
Graphical abstract
Figure 1
Figure 1
Responder analyses Responder analyses in (A) subacute/dynamic eyes and (B) chronic eyes, overall and by mutation (mITT vs. matched NH). For CRS analyses, only eyes with a baseline VA <1.0 logMAR were included. Only eyes with a baseline VA ≤1.68 logMAR (on-chart VA) were included in analyses of CRW. Brackets indicate p values. See also Figures S3 and S4 and Tables S5–S7. N.E., not estimable.
Figure 2
Figure 2
Cumulative frequency of change in VA from baseline to 24 months by disease phase and mutation status (mITT vs. matched NH) The dotted lines at −0.2 logMAR and +0.2 logMAR indicate the thresholds for improvement and worsening, respectively, by at least 10 letters on the ETDRS chart. BL, baseline; cum, cumulative.
Figure 3
Figure 3
Kaplan-Meier (K-M) analysis Kaplan-Meier analysis of initial CRR from baseline up to month 24 as a function of treatment duration in (A) subacute/dynamic and (B) chronic eyes (ITT). CRR is presented as the Kaplan-Meier estimate.
Figure 4
Figure 4
Change in VA (LS-mean VA) from baseline to 12 and 24 months (mITT vs. matched NH) Difference in change of LS-mean VA from baseline to visit time point between treated eyes and matched eyes in the NH group (delta VA) were calculated using analysis of covariance (ANCOVA) with fixed factors of treatment, gender, mutation, and VA at baseline as a covariate. Error bars indicate 95% confidence limits. ns p > 0.05; ∗p ≤ 0.05; ∗∗p ≤ 0.01; ∗∗∗p ≤ 0.001. See also Figure S5 and Table S8. ns, nonsignificant.
See this image and copyright information in PMC

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