Outcomes of Idebenone Therapy for Leber Hereditary Optic Neuropathy in a cohort of patients from Wales

Outcomes of Idebenone Therapy for Leber Hereditary Optic Neuropathy in a cohort of patients from Wales | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Outcomes of Idebenone Therapy for Leber Hereditary Optic Neuropathy in a cohort of patients from Wales Francis Sanders, Marcela Votruba This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6465259/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Sep, 2025 Read the published version in Eye → Version 1 posted 7 You are reading this latest preprint version Abstract Background Leber hereditary optic neuropathy (LHON) poses a significant burden to patients with with the majority not showing significant spontaneous improvement in their vision. The recent validation of idebenone as a therapy provides some avenue for benefit for patients with LHON in Wales, where it has been approved for use within the NHS. Methods From March 2021 all patients being seen in a tertiary referral clinic and diagnosed with LHON by targeted genetic testing were offered treatment with idebenone and commenced on idebenone as part of standard care. For such patients their clinical records were used to collect demographic and outcome data. Visual acuity was analysed for clinically relevant recovery (CRR) defined as improvement from “off-chart” to “on-chart” or “on-chart” improvement of at least 10 letters. Results A total of 12 (67% male) individuals were treated with idebenone 300mg TDS for LHON for a mean period of 30.2 (±9.9) months. Two patients were lost to follow up after initiation of therapy, and two patients ceased therapy after 30 and 35 months respectively. Mean visual acuity at initiation of therapy was 2.22 (±0.32) LogMAR, improving to a peak of 1.12 (±0.77) LogMAR at 27 months. This timepoint was coincident with the maximum CRR achieved with 86% demonstrating CRR. Conclusion The present cohort demonstrates evidence of CRR in a high proportion of patients reaching 27 months of treatment. Further follow up and a larger cohort of patients will provide further insight into the real-world efficacy of idebenone in LHON. Health sciences/Medical research/Outcomes research Health sciences/Health care/Therapeutics/Drug therapy/Chemotherapy Figures Figure 1 Figure 2 Figure 3 Summary Box What was known before Leber hereditary optic neuropathy is a debilitating condition resulting in severe visual disability with emerging new therapies Prior clinical trials have demonstrated the efficacy of idebenone in treating patients with Leber hereditary optic neuropathy and providing some meaningful improvement in visual function What this study adds Real world outcomes from treatment with oral idebenone in a cohort of patients with a diverse background shows clinically relevant recovery of visual acuity in a majority of patients reaching 27 months of therapy The presented study provides evidence for an extended course of therapy with idebenone, potentially to continue beyond 3 years given the recovery in visual acuity did not present in some individuals until the 27 month time point Introduction Leber hereditary optic neuropathy (LHON) is a rare disease but one of the most commonly described hereditary optic neuropathies with a prevalence of 1 in 31,000 to 1 in 68,000 ( 1 – 4 ). Although more recent analysis suggests a carrier rate of up to 1 in 1,000 of the most common causative genetic variants ( 5 , 6 ). The three most common variants in the mitochondrial genome - m.3460G > A (MTND1), m.11778G > A (MTND4), and m.14484T > C (MTDN6) – are identified as the causative variant in over 95% of LHON cases ( 7 , 8 ). LHON is characterised by centrocecal vision loss that can occur at any age but typically has two peaks of incidence in early adulthood and a smaller increase in incidence around late middle-age ( 7 , 9 ). Individuals tend to experience profound visual loss which is limiting on their daily activities and often adversely impacts their ability to work ( 10 ). There is, however, some evidence for spontaneous improvement of visual function over months to years following the initial decline in vision ( 8 ). This is reported to be more common amongst certain variants particularly the m.14484T > C variant ( 4 , 8 , 11 ). Up until recently there have been very limited management options beyond maximising residual vision with magnifying aids and supportive measures to improve quality of life ( 9 , 10 ). More recently several novel therapies have been trialled from oral supplements and medications to genetic therapies ( 12 – 14 ). Of particular interest is oral idebenone dosed at 300mg three times daily, which was approved by the European Medicines Agency and has been established in several European nations as standard therapy following a number of trials, including the RHODOS study and the LEROS study ( 3 , 15 – 18 ). Briefly the LEROS trial demonstrated benefits for those patients dosed with idebenone in terms of their clinically relevant recovery (CRR) deemed as improvement of 10 letters on chart or from off chart to a minimum of 5 letters on chart, with 46.0% demonstrating CRR when compared to those on placebo in the extended access programme and 31.9–47.9% demonstrating CRR in the LEROS trial depending on when therapy was initiated ( 3 , 15 ). Based on this evidence idebenone was recommended for use in the National Health Service in Wales for patient with LHON by the All Wales Medicines Strategy Group (AWMSG) in their final appraisal recommendation (Advice No: 0521 –March 2021) ( 19 ). The present study presents an overview of the outcomes of all patients treated with idebenone within the tertiary referral ophthalmic genetics clinic in University Hospital of Wales (UHW), Cardiff following their initiation of treatment from 2021 up until January 2025. Methods Patients attending the tertiary referral clinic for ophthalmic genetics within University Hospital of Wales in Cardiff with a diagnosis of LHON were identified. All patients were offered treatment as part of their routine clinical care in line with prescribing guidelines and authorisation in line with All Wales Medicines Strategy Group (AWMSG) advice. Idebenone was prescribed at 300mg orally three times daily (TDS). Demographic data was collected from patients’ medical records, as well as details of diagnosis and the outcome of genetic testing and data on visual outcomes. All patients were confirmed to have an established genetic diagnosis of LHON associated with one of the three primary variants in mitochondrial DNA by NHS genetic testing in the form of targeted gene sequencing, next-generation based gene panel, or mitochondrial gene sequencing. All data capture was finalised as of 29th January 2025. Visual acuity data was collected and converted to LogMAR units where not collected in this format. This was performed using the previously published calculator ( 20 ) based on the United Kingdom National Ophthalmology Database published values ( 21 ). From this clinically relevant recovery (CRR) was defined as improvement from “off-chart” to “on-chart” or “on-chart” improvement of at least 10 letters. This was adapted from previous studies of idebenone therapy in LHON ( 15 – 17 ) given the mixed methods of visual acuity assessment from “off-chart” to “on-chart” and subsequent conversion of some visual acuity outcomes recorded in metric Snellen format to LogMAR equivalent outcomes. This study was approved locally (Cardiff & Vale University Health Board Research & Development) and registered on the local Audit Management and Tracking (AMaT) system. It was conducted in accordance with the tenets of the Declaration of Helsinki. Results A total of 29 individuals with mitochondrial variants associated with LHON were identified in the ophthalmic genetics service. Six tested positive for the m.14484T > C variant and the remaining 23 tested positive for the m.11778G > A variant. All patients were offered treatment excluding those who had experienced prior spontaneous visual recovery or exhibited LHON with ‘plus’ features, such as one female patient with Harding’s syndrome. No restriction was placed on time from vision loss, although a number of those with the longest potential durations of disease were either not being routinely followed up, or had been lost to follow up, or been discharged some years before. Thus, 12 were initiated on idebenone therapy under the NHS ophthalmic genetics clinic in UHW in accordance with the AWMSG guidance. All were offered six monthly appointments to monitor vision and any side effects. One patient was excluded from the current analysis as they were restarted on therapy for only 6 months having previously been treated within the LEROS trial ( 15 ). There were 8 male and 4 female, with an average age when initiating therapy of 47.2 (±19.3) years ranging from 22 to 72 years of age. Prior to starting idebenone the mean duration of symptoms attributed to LHON was 31.5 (±59.5) months with a total range from 2 to 216 months. Four patients tested positive for the m.14484T > C pathogenic variant, and the remaining eight carried the m.11778G > A variant. Two treated patients had a known family history of LHON, one with the m.14484T > C variant and one carried the m.11778G > A variant. The remaining 10 patients had no clear family history and were suspected de novo variants, albeit not all family members have undergone genetic testing to investigate their carrier status. The cohort treated with idebenone had a mixed history of alcohol and tobacco usage. Six reported smoking more than 10 cigarettes a day, although two of these subsequently ceased smoking after their diagnosis of LHON. Four of the cohort reported drinking 10 or more units of alcohol per week with two reporting heavy use of 40 units or more. Of the entire cohort, no mention was made of significant tobacco usage or alcohol consumption in the case of three individuals, whereas two individuals reported zero tobacco smoking or alcohol consumption. At the point of data collection, the patients had received an average of 30.2 (±9.9) months of therapy ranging from 14–42 months in total. No side effects were reported. Two patients were excluded at this point of analysis due to being lost to follow up, leaving 10 patients continuing therapy. Additionally, one patient died whilst taking idebenone of coexistent medical comorbidities after 13 months of therapy. Two patients had ceased therapy after 30 and 35 months respectively by mutual consent on clinical review. One ceased due to no response over the 30 months of therapy. The second individual demonstrated CRR between 21 and 30 months, however by 35 months their vision deteriorated to baseline in both eyes and they elected to cease idebenone therapy. The primary outcome of the study was visual acuity, with patients having a mean visual acuity equivalent to 1.89 (±0.71, 24 eyes) LogMAR units at diagnosis of LHON. At the time of therapy initiation, the patients vision had deteriorated to 2.22 (±0.32, 24 eyes) LogMAR units. The most recent visual acuity for the 7 patients still receiving idebenone therapy is 1.69 (±0.72, 14 eyes) LogMAR units. The peak mean visual acuity within the first 36 months of therapy was at 27 months, which was 1.12 (± 0.77, 8 eyes) LogMAR units for the limited patients with a review at this time point. The time course of visual acuity is illustrated in Fig. 1 and Fig. 2 . In terms of CRR, 10% of a total of 10 patients (20 eyes) reaching 3 months therapy demonstrated CRR. This increased to a peak of 86% of 7 patients (14 eyes) reaching 27months of therapy, but declined thereafter with far fewer patients (3 patients, 6 eyes) reaching beyond 34 months of therapy. This is outlined in Fig. 3 . The individual patient who demonstrated CRR at 3 months has continued to improve up until 27 months with a peak visual acuity of -0.18 LogMAR units in the right eye and − 0.08 LogMAR untis in the left eye. This has, however, deteriorated up to 39 months where their vision was 0.18 LogMAR units in the right eye and 0.18 LogMAR units in the left eye. This is relative to a visual acuity of counting fingers (equivalent to 2.1 LogMAR units) in the right eye and 1.0 LogMAR units in the left eye at the point of initiating therapy. Examining the visual field tests of this individual demonstrated some improvement in terms of visual field index (VFI) and mean deviation (MD) on Humphrey 24 − 2 visual field testing using the SITA standard protocol. There was only a full field 120 point suprathreshold test available prior to treatment initiation which demonstrated a centrocecal scotoma within the central 20 degrees of both eyes. At 9 months after therapy initiation the individual achieved a VFI of 75% in the left eye and 59% in the right eye and a MD of -8.39 dB in the left eye and − 13.00 dB in the right eye. After a further 13 months of therapy, at 22 months total, they achieved a VFI of 77% in the left eye and 66% in the right eye as well as a MD of -7.50 dB in the left eye and − 10.09 dB in the right eye. Three cases were identified as developing vision loss with no previous visual symptoms in older male patients (63, 68 and 72 years of age, all from separate families) with the m.14484T > C pathogenic variant coincidentally subsequent to CoVID-19 vaccines. All three of these individuals started on idebenone within 4 to 8 months of the onset of symptoms. All three also demonstrated CRR at some time point during their treatment between 15 and 33 months. However, at most recent review, one had ceased therapy due to completing 36 months of treatment and not retaining CRR. Meanwhile the others continue therapy although one individual’s vision has returned to baseline and the other retains some vision at 1.36 and 1.34 LogMAR units in the right and left eyes respectively. Discussion The present cohort summarises the clinical outcomes of 12 patients treated for idebenone for LHON. In the somewhat heterogenous environment of real-world treatment there is a surprising degree of CRR within the cohort, with 86% (10 of 14 eyes) achieving this by 27 months. This is a somewhat long time period of treatment to gain maximum response, given that 5 individuals had not reached 27 months of therapy. It does, however, correlate with other observations of clinical response up to 2 years ( 15 , 17 ). In comparison the time course observed in the previous LEROS trial was briefer ( 15 ). Previous reports have highlighted the ongoing efficacy of idebenone therapy within patients started on idebenone therapy in the acute phase (less than 1 year from disease onset), in the early chronic phase (1–5 years from disease onset) or in the late chronic phase (> 5 years from disease onset) ( 22 , 23 ). In the current cohort there were 6 (50%) patients treated within the acute phase of whom 4 (67%) demonstrated CRR at any time point. Five (42%) patients were treated within the early chronic phase, only one of whom demonstrated CRR at any time point, however two of these patients had no further clinical details beyond baseline as they were lost to follow up, and one individual had only been on therapy for 12 months at the time of data collection. Only one (8%) patient was treated within the late chronic phase who did demonstrate CRR. Of interest one individual who demonstrated CRR attained this despite initiating idebenone therapy with a significant time period since disease manifestation of 18 years. This is outside the time limit defined by the LEROS trial of individuals being within 5 years of diagnosis ( 15 ) or the Extended Access Programme study, which had more stringent restrictions of patients being within 1 year of disease onset ( 3 , 17 ). This does not contravene current prescribing recommendations of the AWMSG which do not set a time limit of disease duration before starting therapy. This individual achieved CRR by 15 months and continues to demonstrate sustained improvement in VA up until their latest review at 27 months of therapy. This supports the finding in the LEROS trial suggesting VA improvement can continue to start until 24 months ( 3 , 15 , 22 ). The presented cohort notably had solely 12 individuals with LHON treated with idebenone, in spite of a pool of 29 individuals being identified within the population served by the clinic as carrying pathogenic variants causative of LHON. One individual was ineligible due to exhibiting “plus” features consistent with Harding’s syndrome. This presentation of LHON currently does not have evidence supporting the use of idebenone. Additionally, this includes those who may not benefit from idebenone because they have already experienced some spontaneous improvement or partial recovery of visual function, as was observed with approximately 30–40% of individuals within LHON in previous trials of idebenone ( 3 , 15 – 17 ). Furthermore, of the 17 individuals identified within the clinic as carrying pathogenic variants who did not start idebenone, 2 did not demonstrate any expression of the disease phenotype, 3 declined treatment through the clinic in UHW, 2 moved outside of Wales, and the remaining 10 did not respond to invitations to attend clinic to consider treatment. In the presented cohort of patients, it is unclear who may have exhibited spontaneous visual recovery if idebenone had been omitted, especially given the atypical presentation of three older male individuals who started treatment relatively early in their disease’s time course. This may somewhat bias results presented herein either due to more or fewer patients experiencing CRR than might have in the placebo groups of prior LHON trials due to underlying differences in the demographics and clinical presentations of those with LHON ( 3 , 7 , 8 ). A limitation of the current study is the measurement of VA using a mixture of both LogMAR and Snellen VA in the clinic setting, which has subsequently been converted to LogMAR for analysis. Historically before idebenone was a therapeutic option the patients had Snellen acuities as a routine, and increasinggly all were having Log MAR acuity as they returned for follow up. This has resulted in a subtly different definition of CRR in the presented study, which might allow for a higher reporting rate of CRR compared to those defined in LEROS, EAP and prior trials ( 15 , 17 ). That being said, in the context of the presented study reporting real world outcomes and the difficulties of how VAs are measured in the clinic setting, where it may be the case that less encouragement of patients to attain a ’better’ score compared to when those measuring VA have knowledge of an individual being a ‘trial’ patient and hence may prompt the participant to achieve a higher VA regardless of the test being used. In conclusion, the presented real-world cohort of patients treated with oral idebenone over a period of 14–42 months demonstrates rates of CRR comparable to those reported in the previously published trials of idebenone therapy in people with LHON. Further data collection is required to elucidate the optimal timeframe of therapy initiation as well as duration of therapy that continues to provide clinically-relevant benefit to patients with LHON. Abbreviations AMaT – Audit Management and Tracking AWMSG – All Wales Medicines Strategy Group CAVUHB – Cardiff and Vale University Health Board LHON – Leber Hereditary Optic Neuropathy NHS – National Health Service TDS – Ter Die Sumendum UHW - University Hospital of Wales Declarations Acknowledgements MV and FS would like to acknowledge the support of the Cardiff and Vale University Health Board Research and Development department for hosting this study. Funding This analysis received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Author Contribution Statement Both FS and MV have collected and analysed data. FS drafted the manuscript with review by MV. Synopsis An overview of 12 patients treated with idebenone for Leber Hereditary Optic Neuropathy for a range of 14 to 42 months. Competing Interests Statement MV received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici and Stoke Therapeutics. FS has no competing interests to declare. References Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England. Am J Hum Genet. 2003 Feb;72(2):333–9. Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet EJHG. 2007 Oct;15(10):1079–89. Klopstock T, Zeng LH, Priglinger C. Leber’s hereditary optic neuropathy – current status of idebenone and gene replacement therapies. Med Genet. 2025;37(1):57–63. Mascialino B, Leinonen M, Meier T. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Eur J Ophthalmol. 2012;22(3):461–5. Mackey DA, Ong JS, MacGregor S, Whiteman DC, Craig JE, Lopez Sanchez MIG, et al. Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low? Am J Hum Genet. 2023 Jan 5;110(1):170–6. Mackey DA, Staffieri SE, Lopez Sanchez MIG, Kearns LS. Family and genetic counseling in Leber hereditary optic neuropathy. Ophthalmic Genet. 2025 Jan 20;1–9. Poincenot L, Pearson AL, Karanjia R. Demographics of a Large International Population of Patients Affected by Leber’s Hereditary Optic Neuropathy. Ophthalmology. 2020 May;127(5):679–88. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011 Mar;30(2–2):81–114. Stramkauskaitė A, Povilaitytė I, Glebauskienė B, Liutkevičienė R. Clinical Overview of Leber Hereditary Optic Neuropathy. Acta Medica Litu. 2022;29(1):9–18. Kirkman MA, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, et al. Quality of life in patients with leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3112–5. Harding AE, Riordan-Eva P, Govan GG. Mitochondrial DNA diseases: genotype and phenotype in Leber’s hereditary optic neuropathy. Muscle Nerve Suppl. 1995;3:S82-84. Chen BS, Yu-Wai-Man P, Newman NJ. Developments in the Treatment of Leber Hereditary Optic Neuropathy. Curr Neurol Neurosci Rep. 2022;22(12):881–92. Hage R, Vignal-Clermont C. Leber Hereditary Optic Neuropathy: Review of Treatment and Management. Front Neurol. 2021 May 26;12:651639. Chen BS, Newman NJ. Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities. Curr Opin Neurol. 2025 Feb;38(1):79. Yu-Wai-Man P, Carelli V, Newman NJ, Silva MJ, Linden A, Van Stavern G, et al. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell Rep Med. 2024 Feb 29;5(3):101437. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011 Sep;134(9):2677–86. Catarino CB, von Livonius B, Priglinger C, Banik R, Matloob S, Tamhankar MA, et al. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy. J Neuroophthalmol. 2020 Dec;40(4):558–65. Raxone | European Medicines Agency (EMA) [Internet]. 2015 [cited 2025 Apr 2]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/raxone All Wales Therapeutics and Toxicology Centre [Internet]. [cited 2025 Apr 2]. idebenone (Raxone®). Available from: https://awttc.nhs.wales/accessing-medicines/medicine-recommendations/idebenone-raxone/ Moussa G, Bassilious K, Mathews N. A novel excel sheet conversion tool from Snellen fraction to LogMAR including ‘counting fingers’, ‘hand movement’, ‘light perception’ and ‘no light perception’ and focused review of literature of low visual acuity reference values. Acta Ophthalmol (Copenh). 2021;99(6):e963–5. Day AC, Donachie PHJ, Sparrow JM, Johnston RL, Royal College of Ophthalmologists’ National Ophthalmology Database. The Royal College of Ophthalmologists’ National Ophthalmology Database study of cataract surgery: report 1, visual outcomes and complications. Eye Lond Engl. 2015 Apr;29(4):552–60. Pemp B, Kircher K, Reitner A. Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2019 Dec;257(12):2751–7. Pemp B, Mitsch C, Kircher K, Reitner A. Changes in Visual Function and Correlations with Inner Retinal Structure in Acute and Chronic Leber’s Hereditary Optic Neuropathy Patients after Treatment with Idebenone. J Clin Med. 2021 Jan 4;10(1):151. Additional Declarations There is conflict of interest Cite Share Download PDF Status: Published Journal Publication published 17 Sep, 2025 Read the published version in Eye → Version 1 posted Editorial decision: revise 02 Jun, 2025 Review # 1 received at journal 19 May, 2025 Reviewer # 1 agreed at journal 06 May, 2025 Reviewers invited by journal 30 Apr, 2025 Editor assigned by journal 24 Apr, 2025 Submission checks completed at journal 17 Apr, 2025 First submitted to journal 16 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6465259","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":450041705,"identity":"1cd05310-ecf1-4266-b4de-d3b07e92637a","order_by":0,"name":"Francis Sanders","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYJACCRDB3sDD+ABI8/ARrYXnAA+zAYhmI0ULG5hBUIt8+9mDNz7uqWPgkcg9Vvk1x06GjYH54aMbeLQYnMlLtpzx7DBQS17abdltyUCHsRkb5+DTwpBjJs1z4ACDvXSO2W3JbcxALTxs0vi0yPe/MZP+cwDoMKCWYslt9YS1MNwA2sJwgBmshfHjtsOEtRjceGNs2XPgMA+P/LtkacZtx3nYmAn4Rb4/x/DGjwN1cjw8Zw9+/Lmt2p6fvfnhY7wOgwIeEMEMIYlQDgeMP0hRPQpGwSgYBSMGAAAoqkDCAV75AQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1625-7487","institution":"University Hospital of Wales","correspondingAuthor":true,"prefix":"","firstName":"Francis","middleName":"","lastName":"Sanders","suffix":""},{"id":450041706,"identity":"b6cde7f4-77d6-416a-82b9-8fe654c28e50","order_by":1,"name":"Marcela Votruba","email":"","orcid":"https://orcid.org/0000-0002-7680-9135","institution":"School of Optometry \u0026 Vision Sciences","correspondingAuthor":false,"prefix":"","firstName":"Marcela","middleName":"","lastName":"Votruba","suffix":""}],"badges":[],"createdAt":"2025-04-16 16:16:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6465259/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6465259/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41433-025-03993-x","type":"published","date":"2025-09-17T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82272164,"identity":"3ef8f0bb-00d9-4dc3-941a-7fde1c81298c","added_by":"auto","created_at":"2025-05-08 14:22:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36797,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eThe mean visual acuity (LogMAR) of 12 patients with LHON treated with idebenone over time (months). Displayed as mean ± standard error of the mean.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1300.png","url":"https://assets-eu.researchsquare.com/files/rs-6465259/v1/b442439a4ed107c8da889f84.png"},{"id":82272162,"identity":"05e0d0a9-a8de-4424-83da-c955b71b4cd5","added_by":"auto","created_at":"2025-05-08 14:22:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":123864,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eThe measured visual acuity (LogMAR) of each eye in all 12 patients treated with idebenone over time (months). OD – right eye; OS – left eye.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2300.png","url":"https://assets-eu.researchsquare.com/files/rs-6465259/v1/db096b13adbe846c391db181.png"},{"id":82273771,"identity":"a7d643eb-5e85-4d1e-b953-06c76ee6e6ea","added_by":"auto","created_at":"2025-05-08 14:30:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44876,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eNumber of eyes within the cohort of patients treated with idebenone demonstrating clinically relevant recovery (CRR) at each time point (months). The total number of eyes within the cohort that reach each timepoint after initiation is represented to demonstrate the relative proportion of eyes reaching a time point that demonstrate CRR. CRR is defined as improvement in vision from “off chart” to at least 1 letter “on chart”, or improvement of at least 10 letters “on chart”.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure3300.png","url":"https://assets-eu.researchsquare.com/files/rs-6465259/v1/483f52d6f6cb3992a86654c8.png"},{"id":91616805,"identity":"defac7c7-8c47-454e-8fe5-5bb5a51ab794","added_by":"auto","created_at":"2025-09-18 10:40:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":538117,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6465259/v1/fd372869-ea1f-4dcb-9d59-254cb11216d3.pdf"}],"financialInterests":"There is conflict of interest","formattedTitle":"Outcomes of Idebenone Therapy for Leber Hereditary Optic Neuropathy in a cohort of patients from Wales","fulltext":[{"header":"Summary Box","content":"\u003cp\u003e\u003cem\u003eWhat was known before\u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eLeber hereditary optic neuropathy is a debilitating condition resulting in severe visual disability with emerging new therapies\u003c/li\u003e\n \u003cli\u003ePrior clinical trials have demonstrated the efficacy of idebenone in treating patients with Leber hereditary optic neuropathy and providing some meaningful improvement in visual function\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eWhat this study adds\u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eReal world outcomes from treatment with oral idebenone in a cohort of patients with a diverse background shows clinically relevant recovery of visual acuity in a majority of patients reaching 27 months of therapy\u003c/li\u003e\n \u003cli\u003eThe presented study provides evidence for an extended course of therapy with idebenone, potentially to continue beyond 3 years given the recovery in visual acuity did not present in some individuals until the 27 month time point\u003c/li\u003e\n\u003c/ul\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eLeber hereditary optic neuropathy (LHON) is a rare disease but one of the most commonly described hereditary optic neuropathies with a prevalence of 1 in 31,000 to 1 in 68,000 (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Although more recent analysis suggests a carrier rate of up to 1 in 1,000 of the most common causative genetic variants (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The three most common variants in the mitochondrial genome - m.3460G\u0026thinsp;\u0026gt;\u0026thinsp;A (MTND1), m.11778G\u0026thinsp;\u0026gt;\u0026thinsp;A (MTND4), and m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C (MTDN6) \u0026ndash; are identified as the causative variant in over 95% of LHON cases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLHON is characterised by centrocecal vision loss that can occur at any age but typically has two peaks of incidence in early adulthood and a smaller increase in incidence around late middle-age (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Individuals tend to experience profound visual loss which is limiting on their daily activities and often adversely impacts their ability to work (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). There is, however, some evidence for spontaneous improvement of visual function over months to years following the initial decline in vision (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This is reported to be more common amongst certain variants particularly the m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C variant (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUp until recently there have been very limited management options beyond maximising residual vision with magnifying aids and supportive measures to improve quality of life (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). More recently several novel therapies have been trialled from oral supplements and medications to genetic therapies (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Of particular interest is oral idebenone dosed at 300mg three times daily, which was approved by the European Medicines Agency and has been established in several European nations as standard therapy following a number of trials, including the RHODOS study and the LEROS study (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBriefly the LEROS trial demonstrated benefits for those patients dosed with idebenone in terms of their clinically relevant recovery (CRR) deemed as improvement of 10 letters on chart or from off chart to a minimum of 5 letters on chart, with 46.0% demonstrating CRR when compared to those on placebo in the extended access programme and 31.9\u0026ndash;47.9% demonstrating CRR in the LEROS trial depending on when therapy was initiated (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Based on this evidence idebenone was recommended for use in the National Health Service in Wales for patient with LHON by the All Wales Medicines Strategy Group (AWMSG) in their final appraisal recommendation (Advice No: 0521 \u0026ndash;March 2021) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe present study presents an overview of the outcomes of all patients treated with idebenone within the tertiary referral ophthalmic genetics clinic in University Hospital of Wales (UHW), Cardiff following their initiation of treatment from 2021 up until January 2025.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatients attending the tertiary referral clinic for ophthalmic genetics within University Hospital of Wales in Cardiff with a diagnosis of LHON were identified. All patients were offered treatment as part of their routine clinical care in line with prescribing guidelines and authorisation in line with All Wales Medicines Strategy Group (AWMSG) advice. Idebenone was prescribed at 300mg orally three times daily (TDS).\u003c/p\u003e \u003cp\u003eDemographic data was collected from patients\u0026rsquo; medical records, as well as details of diagnosis and the outcome of genetic testing and data on visual outcomes. All patients were confirmed to have an established genetic diagnosis of LHON associated with one of the three primary variants in mitochondrial DNA by NHS genetic testing in the form of targeted gene sequencing, next-generation based gene panel, or mitochondrial gene sequencing. All data capture was finalised as of 29th January 2025.\u003c/p\u003e \u003cp\u003eVisual acuity data was collected and converted to LogMAR units where not collected in this format. This was performed using the previously published calculator (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) based on the United Kingdom National Ophthalmology Database published values (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). From this clinically relevant recovery (CRR) was defined as improvement from \u0026ldquo;off-chart\u0026rdquo; to \u0026ldquo;on-chart\u0026rdquo; or \u0026ldquo;on-chart\u0026rdquo; improvement of at least 10 letters. This was adapted from previous studies of idebenone therapy in LHON (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) given the mixed methods of visual acuity assessment from \u0026ldquo;off-chart\u0026rdquo; to \u0026ldquo;on-chart\u0026rdquo; and subsequent conversion of some visual acuity outcomes recorded in metric Snellen format to LogMAR equivalent outcomes.\u003c/p\u003e \u003cp\u003eThis study was approved locally (Cardiff \u0026amp; Vale University Health Board Research \u0026amp; Development) and registered on the local Audit Management and Tracking (AMaT) system. It was conducted in accordance with the tenets of the Declaration of Helsinki.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 29 individuals with mitochondrial variants associated with LHON were identified in the ophthalmic genetics service. Six tested positive for the m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C variant and the remaining 23 tested positive for the m.11778G\u0026thinsp;\u0026gt;\u0026thinsp;A variant.\u003c/p\u003e \u003cp\u003eAll patients were offered treatment excluding those who had experienced prior spontaneous visual recovery or exhibited LHON with \u0026lsquo;plus\u0026rsquo; features, such as one female patient with Harding\u0026rsquo;s syndrome. No restriction was placed on time from vision loss, although a number of those with the longest potential durations of disease were either not being routinely followed up, or had been lost to follow up, or been discharged some years before. Thus, 12 were initiated on idebenone therapy under the NHS ophthalmic genetics clinic in UHW in accordance with the AWMSG guidance. All were offered six monthly appointments to monitor vision and any side effects. One patient was excluded from the current analysis as they were restarted on therapy for only 6 months having previously been treated within the LEROS trial (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). There were 8 male and 4 female, with an average age when initiating therapy of 47.2 (\u0026plusmn;19.3) years ranging from 22 to 72 years of age. Prior to starting idebenone the mean duration of symptoms attributed to LHON was 31.5 (\u0026plusmn;59.5) months with a total range from 2 to 216 months. Four patients tested positive for the m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C pathogenic variant, and the remaining eight carried the m.11778G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. Two treated patients had a known family history of LHON, one with the m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C variant and one carried the m.11778G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. The remaining 10 patients had no clear family history and were suspected de novo variants, albeit not all family members have undergone genetic testing to investigate their carrier status.\u003c/p\u003e \u003cp\u003eThe cohort treated with idebenone had a mixed history of alcohol and tobacco usage. Six reported smoking more than 10 cigarettes a day, although two of these subsequently ceased smoking after their diagnosis of LHON. Four of the cohort reported drinking 10 or more units of alcohol per week with two reporting heavy use of 40 units or more. Of the entire cohort, no mention was made of significant tobacco usage or alcohol consumption in the case of three individuals, whereas two individuals reported zero tobacco smoking or alcohol consumption.\u003c/p\u003e \u003cp\u003eAt the point of data collection, the patients had received an average of 30.2 (\u0026plusmn;9.9) months of therapy ranging from 14\u0026ndash;42 months in total. No side effects were reported. Two patients were excluded at this point of analysis due to being lost to follow up, leaving 10 patients continuing therapy. Additionally, one patient died whilst taking idebenone of coexistent medical comorbidities after 13 months of therapy. Two patients had ceased therapy after 30 and 35 months respectively by mutual consent on clinical review. One ceased due to no response over the 30 months of therapy. The second individual demonstrated CRR between 21 and 30 months, however by 35 months their vision deteriorated to baseline in both eyes and they elected to cease idebenone therapy.\u003c/p\u003e \u003cp\u003eThe primary outcome of the study was visual acuity, with patients having a mean visual acuity equivalent to 1.89 (\u0026plusmn;0.71, 24 eyes) LogMAR units at diagnosis of LHON. At the time of therapy initiation, the patients vision had deteriorated to 2.22 (\u0026plusmn;0.32, 24 eyes) LogMAR units. The most recent visual acuity for the 7 patients still receiving idebenone therapy is 1.69 (\u0026plusmn;0.72, 14 eyes) LogMAR units. The peak mean visual acuity within the first 36 months of therapy was at 27 months, which was 1.12 (\u0026plusmn; 0.77, 8 eyes) LogMAR units for the limited patients with a review at this time point. The time course of visual acuity is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn terms of CRR, 10% of a total of 10 patients (20 eyes) reaching 3 months therapy demonstrated CRR. This increased to a peak of 86% of 7 patients (14 eyes) reaching 27months of therapy, but declined thereafter with far fewer patients (3 patients, 6 eyes) reaching beyond 34 months of therapy. This is outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe individual patient who demonstrated CRR at 3 months has continued to improve up until 27 months with a peak visual acuity of -0.18 LogMAR units in the right eye and \u0026minus;\u0026thinsp;0.08 LogMAR untis in the left eye. This has, however, deteriorated up to 39 months where their vision was 0.18 LogMAR units in the right eye and 0.18 LogMAR units in the left eye. This is relative to a visual acuity of counting fingers (equivalent to 2.1 LogMAR units) in the right eye and 1.0 LogMAR units in the left eye at the point of initiating therapy.\u003c/p\u003e \u003cp\u003eExamining the visual field tests of this individual demonstrated some improvement in terms of visual field index (VFI) and mean deviation (MD) on Humphrey 24\u0026thinsp;\u0026minus;\u0026thinsp;2 visual field testing using the SITA standard protocol. There was only a full field 120 point suprathreshold test available prior to treatment initiation which demonstrated a centrocecal scotoma within the central 20 degrees of both eyes. At 9 months after therapy initiation the individual achieved a VFI of 75% in the left eye and 59% in the right eye and a MD of -8.39 dB in the left eye and \u0026minus;\u0026thinsp;13.00 dB in the right eye. After a further 13 months of therapy, at 22 months total, they achieved a VFI of 77% in the left eye and 66% in the right eye as well as a MD of -7.50 dB in the left eye and \u0026minus;\u0026thinsp;10.09 dB in the right eye.\u003c/p\u003e \u003cp\u003eThree cases were identified as developing vision loss with no previous visual symptoms in older male patients (63, 68 and 72 years of age, all from separate families) with the m.14484T\u0026thinsp;\u0026gt;\u0026thinsp;C pathogenic variant coincidentally subsequent to CoVID-19 vaccines. All three of these individuals started on idebenone within 4 to 8 months of the onset of symptoms. All three also demonstrated CRR at some time point during their treatment between 15 and 33 months. However, at most recent review, one had ceased therapy due to completing 36 months of treatment and not retaining CRR. Meanwhile the others continue therapy although one individual\u0026rsquo;s vision has returned to baseline and the other retains some vision at 1.36 and 1.34 LogMAR units in the right and left eyes respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present cohort summarises the clinical outcomes of 12 patients treated for idebenone for LHON. In the somewhat heterogenous environment of real-world treatment there is a surprising degree of CRR within the cohort, with 86% (10 of 14 eyes) achieving this by 27 months. This is a somewhat long time period of treatment to gain maximum response, given that 5 individuals had not reached 27 months of therapy. It does, however, correlate with other observations of clinical response up to 2 years (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In comparison the time course observed in the previous LEROS trial was briefer (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious reports have highlighted the ongoing efficacy of idebenone therapy within patients started on idebenone therapy in the acute phase (less than 1 year from disease onset), in the early chronic phase (1\u0026ndash;5 years from disease onset) or in the late chronic phase (\u0026gt;\u0026thinsp;5 years from disease onset) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In the current cohort there were 6 (50%) patients treated within the acute phase of whom 4 (67%) demonstrated CRR at any time point. Five (42%) patients were treated within the early chronic phase, only one of whom demonstrated CRR at any time point, however two of these patients had no further clinical details beyond baseline as they were lost to follow up, and one individual had only been on therapy for 12 months at the time of data collection. Only one (8%) patient was treated within the late chronic phase who did demonstrate CRR.\u003c/p\u003e \u003cp\u003eOf interest one individual who demonstrated CRR attained this despite initiating idebenone therapy with a significant time period since disease manifestation of 18 years. This is outside the time limit defined by the LEROS trial of individuals being within 5 years of diagnosis (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) or the Extended Access Programme study, which had more stringent restrictions of patients being within 1 year of disease onset (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This does not contravene current prescribing recommendations of the AWMSG which do not set a time limit of disease duration before starting therapy. This individual achieved CRR by 15 months and continues to demonstrate sustained improvement in VA up until their latest review at 27 months of therapy. This supports the finding in the LEROS trial suggesting VA improvement can continue to start until 24 months (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presented cohort notably had solely 12 individuals with LHON treated with idebenone, in spite of a pool of 29 individuals being identified within the population served by the clinic as carrying pathogenic variants causative of LHON. One individual was ineligible due to exhibiting \u0026ldquo;plus\u0026rdquo; features consistent with Harding\u0026rsquo;s syndrome. This presentation of LHON currently does not have evidence supporting the use of idebenone. Additionally, this includes those who may not benefit from idebenone because they have already experienced some spontaneous improvement or partial recovery of visual function, as was observed with approximately 30\u0026ndash;40% of individuals within LHON in previous trials of idebenone (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Furthermore, of the 17 individuals identified within the clinic as carrying pathogenic variants who did not start idebenone, 2 did not demonstrate any expression of the disease phenotype, 3 declined treatment through the clinic in UHW, 2 moved outside of Wales, and the remaining 10 did not respond to invitations to attend clinic to consider treatment. In the presented cohort of patients, it is unclear who may have exhibited spontaneous visual recovery if idebenone had been omitted, especially given the atypical presentation of three older male individuals who started treatment relatively early in their disease\u0026rsquo;s time course. This may somewhat bias results presented herein either due to more or fewer patients experiencing CRR than might have in the placebo groups of prior LHON trials due to underlying differences in the demographics and clinical presentations of those with LHON (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA limitation of the current study is the measurement of VA using a mixture of both LogMAR and Snellen VA in the clinic setting, which has subsequently been converted to LogMAR for analysis. Historically before idebenone was a therapeutic option the patients had Snellen acuities as a routine, and increasinggly all were having Log MAR acuity as they returned for follow up. This has resulted in a subtly different definition of CRR in the presented study, which might allow for a higher reporting rate of CRR compared to those defined in LEROS, EAP and prior trials (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). That being said, in the context of the presented study reporting real world outcomes and the difficulties of how VAs are measured in the clinic setting, where it may be the case that less encouragement of patients to attain a \u0026rsquo;better\u0026rsquo; score compared to when those measuring VA have knowledge of an individual being a \u0026lsquo;trial\u0026rsquo; patient and hence may prompt the participant to achieve a higher VA regardless of the test being used.\u003c/p\u003e \u003cp\u003eIn conclusion, the presented real-world cohort of patients treated with oral idebenone over a period of 14\u0026ndash;42 months demonstrates rates of CRR comparable to those reported in the previously published trials of idebenone therapy in people with LHON. Further data collection is required to elucidate the optimal timeframe of therapy initiation as well as duration of therapy that continues to provide clinically-relevant benefit to patients with LHON.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAMaT \u0026ndash; Audit Management and Tracking\u003c/p\u003e\n\u003cp\u003eAWMSG \u0026ndash; All Wales Medicines Strategy Group\u003c/p\u003e\n\u003cp\u003eCAVUHB \u0026ndash; Cardiff and Vale University Health Board\u003c/p\u003e\n\u003cp\u003eLHON \u0026ndash; Leber Hereditary Optic Neuropathy\u003c/p\u003e\n\u003cp\u003eNHS \u0026ndash; National Health Service\u003c/p\u003e\n\u003cp\u003eTDS \u0026ndash; Ter Die Sumendum\u003c/p\u003e\n\u003cp\u003eUHW - University Hospital of Wales\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMV and FS would like to acknowledge the support of the Cardiff and Vale University Health Board Research and Development department for hosting this study.\u003c/p\u003e\n\n\n\n\u003cp\u003e\u003cem\u003eFunding \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis analysis received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eAuthor Contribution Statement \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBoth FS and MV have collected and analysed data. FS drafted the manuscript with review by MV. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSynopsis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn overview of 12 patients treated with idebenone for Leber Hereditary Optic Neuropathy for a range of 14 to 42 months.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003eCompeting Interests Statement\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMV received consultation fees from Santhera Pharmaceuticals, Chiesi Farmaceutici and Stoke Therapeutics. FS has no competing interests to declare.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMan PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England. Am J Hum Genet. 2003 Feb;72(2):333\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePuomila A, H\u0026auml;m\u0026auml;l\u0026auml;inen P, Kivioja S, Savontaus ML, Koivum\u0026auml;ki S, Huoponen K, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet EJHG. 2007 Oct;15(10):1079\u0026ndash;89. \u003c/li\u003e\n\u003cli\u003eKlopstock T, Zeng LH, Priglinger C. Leber\u0026rsquo;s hereditary optic neuropathy \u0026ndash; current status of idebenone and gene replacement therapies. Med Genet. 2025;37(1):57\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eMascialino B, Leinonen M, Meier T. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Eur J Ophthalmol. 2012;22(3):461\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eMackey DA, Ong JS, MacGregor S, Whiteman DC, Craig JE, Lopez Sanchez MIG, et al. Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low? Am J Hum Genet. 2023 Jan 5;110(1):170\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMackey DA, Staffieri SE, Lopez Sanchez MIG, Kearns LS. Family and genetic counseling in Leber hereditary optic neuropathy. Ophthalmic Genet. 2025 Jan 20;1\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePoincenot L, Pearson AL, Karanjia R. Demographics of a Large International Population of Patients Affected by Leber\u0026rsquo;s Hereditary Optic Neuropathy. Ophthalmology. 2020 May;127(5):679\u0026ndash;88. \u003c/li\u003e\n\u003cli\u003eYu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies \u0026ndash; Disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011 Mar;30(2\u0026ndash;2):81\u0026ndash;114. \u003c/li\u003e\n\u003cli\u003eStramkauskaitė A, Povilaitytė I, Glebauskienė B, Liutkevičienė R. Clinical Overview of Leber Hereditary Optic Neuropathy. Acta Medica Litu. 2022;29(1):9\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eKirkman MA, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, et al. Quality of life in patients with leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3112\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eHarding AE, Riordan-Eva P, Govan GG. Mitochondrial DNA diseases: genotype and phenotype in Leber\u0026rsquo;s hereditary optic neuropathy. Muscle Nerve Suppl. 1995;3:S82-84. \u003c/li\u003e\n\u003cli\u003eChen BS, Yu-Wai-Man P, Newman NJ. Developments in the Treatment of Leber Hereditary Optic Neuropathy. Curr Neurol Neurosci Rep. 2022;22(12):881\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eHage R, Vignal-Clermont C. Leber Hereditary Optic Neuropathy: Review of Treatment and Management. Front Neurol. 2021 May 26;12:651639. \u003c/li\u003e\n\u003cli\u003eChen BS, Newman NJ. Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities. Curr Opin Neurol. 2025 Feb;38(1):79. \u003c/li\u003e\n\u003cli\u003eYu-Wai-Man P, Carelli V, Newman NJ, Silva MJ, Linden A, Van Stavern G, et al. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell Rep Med. 2024 Feb 29;5(3):101437. \u003c/li\u003e\n\u003cli\u003eKlopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebo-controlled trial of idebenone in Leber\u0026rsquo;s hereditary optic neuropathy. Brain. 2011 Sep;134(9):2677\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eCatarino CB, von Livonius B, Priglinger C, Banik R, Matloob S, Tamhankar MA, et al. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy. J Neuroophthalmol. 2020 Dec;40(4):558\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eRaxone | European Medicines Agency (EMA) [Internet]. 2015 [cited 2025 Apr 2]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/raxone\u003c/li\u003e\n\u003cli\u003eAll Wales Therapeutics and Toxicology Centre [Internet]. [cited 2025 Apr 2]. idebenone (Raxone\u0026reg;). Available from: https://awttc.nhs.wales/accessing-medicines/medicine-recommendations/idebenone-raxone/\u003c/li\u003e\n\u003cli\u003eMoussa G, Bassilious K, Mathews N. A novel excel sheet conversion tool from Snellen fraction to LogMAR including \u0026lsquo;counting fingers\u0026rsquo;, \u0026lsquo;hand movement\u0026rsquo;, \u0026lsquo;light perception\u0026rsquo; and \u0026lsquo;no light perception\u0026rsquo; and focused review of literature of low visual acuity reference values. Acta Ophthalmol (Copenh). 2021;99(6):e963\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eDay AC, Donachie PHJ, Sparrow JM, Johnston RL, Royal College of Ophthalmologists\u0026rsquo; National Ophthalmology Database. The Royal College of Ophthalmologists\u0026rsquo; National Ophthalmology Database study of cataract surgery: report 1, visual outcomes and complications. Eye Lond Engl. 2015 Apr;29(4):552\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003ePemp B, Kircher K, Reitner A. Visual function in chronic Leber\u0026rsquo;s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2019 Dec;257(12):2751\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003ePemp B, Mitsch C, Kircher K, Reitner A. Changes in Visual Function and Correlations with Inner Retinal Structure in Acute and Chronic Leber\u0026rsquo;s Hereditary Optic Neuropathy Patients after Treatment with Idebenone. J Clin Med. 2021 Jan 4;10(1):151. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6465259/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6465259/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLeber hereditary optic neuropathy (LHON) poses a significant burden to patients with with the majority not showing significant spontaneous improvement in their vision. The recent validation of idebenone as a therapy provides some avenue for benefit for patients with LHON in Wales, where it has been approved for use within the NHS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom March 2021 all patients being seen in a tertiary referral clinic and diagnosed with LHON by targeted genetic testing were offered treatment with idebenone and commenced on idebenone as part of standard care. For such patients their clinical records were used to collect demographic and outcome data. Visual acuity was analysed for clinically relevant recovery (CRR) defined as improvement from \u0026ldquo;off-chart\u0026rdquo; to \u0026ldquo;on-chart\u0026rdquo; or \u0026ldquo;on-chart\u0026rdquo; improvement of at least 10 letters.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 12 (67% male) individuals were treated with idebenone 300mg TDS for LHON for a mean period of 30.2 (\u0026plusmn;9.9) months. Two patients were lost to follow up after initiation of therapy, and two patients ceased therapy after 30 and 35 months respectively. Mean visual acuity at initiation of therapy was 2.22 (\u0026plusmn;0.32) LogMAR, improving to a peak of 1.12 (\u0026plusmn;0.77) LogMAR at 27 months. This timepoint was coincident with the maximum CRR achieved with 86% demonstrating CRR.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe present cohort demonstrates evidence of CRR in a high proportion of patients reaching 27 months of treatment. Further follow up and a larger cohort of patients will provide further insight into the real-world efficacy of idebenone in LHON.\u003c/p\u003e","manuscriptTitle":"Outcomes of Idebenone Therapy for Leber Hereditary Optic Neuropathy in a cohort of patients from Wales","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 14:22:31","doi":"10.21203/rs.3.rs-6465259/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-06-02T13:33:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-05-20T02:17:07+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-05-06T11:50:45+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-04-30T06:51:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-24T14:16:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-17T10:44:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2025-04-16T16:11:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"699d3b5b-c9f9-4df5-a58d-2f4ba9e6e0cb","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47889801,"name":"Health sciences/Medical research/Outcomes research"},{"id":47889802,"name":"Health sciences/Health care/Therapeutics/Drug therapy/Chemotherapy"}],"tags":[],"updatedAt":"2025-09-18T10:40:37+00:00","versionOfRecord":{"articleIdentity":"rs-6465259","link":"https://doi.org/10.1038/s41433-025-03993-x","journal":{"identity":"eye","isVorOnly":false,"title":"Eye"},"publishedOn":"2025-09-17 04:00:00","publishedOnDateReadable":"September 17th, 2025"},"versionCreatedAt":"2025-05-08 14:22:31","video":"","vorDoi":"10.1038/s41433-025-03993-x","vorDoiUrl":"https://doi.org/10.1038/s41433-025-03993-x","workflowStages":[]},"version":"v1","identity":"rs-6465259","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6465259","identity":"rs-6465259","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}