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Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study
BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease whose primary clinical manifestation is bilateral visual loss. Only a single therapy, idebenone, is approved in Europe for use in exceptional circumstances and no therapy is currently approved in the...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952288/ https://www.ncbi.nlm.nih.gov/pubmed/33566264 http://dx.doi.org/10.1007/s40259-021-00468-9 |
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author | Vignal-Clermont, Catherine Girmens, Jean-François Audo, Isabelle Said, Saddek Mohand Errera, Marie-Hélène Plaine, Lise O’Shaughnessy, Denis Taiel, Magali Sahel, José-Alain |
author_facet | Vignal-Clermont, Catherine Girmens, Jean-François Audo, Isabelle Said, Saddek Mohand Errera, Marie-Hélène Plaine, Lise O’Shaughnessy, Denis Taiel, Magali Sahel, José-Alain |
author_sort | Vignal-Clermont, Catherine |
collection | PubMed |
description | BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease whose primary clinical manifestation is bilateral visual loss. Only a single therapy, idebenone, is approved in Europe for use in exceptional circumstances and no therapy is currently approved in the USA. LHON remains a disease with a high unmet medical need. OBJECTIVE: This is a report of an open-label, single-center, dose-escalation study that evaluated the safety and tolerability of lenadogene nolparvovec in 15 subjects with LHON for up to 5 years following a single intravitreal injection at four dose levels. METHODS: Subjects were enrolled sequentially in four cohorts followed by an additional cohort at the dose selected, and safety was assessed by an independent data safety monitoring board (DSMB) prior to any dose escalation. RESULTS: Overall, the treatment was well tolerated during the 5-year follow-up. No serious adverse events were considered related to treatment, no unexpected adverse events occurred, and no grade 3 or 4 Common Terminology Criteria for Adverse Events were reported. Anterior chamber inflammation and vitritis were mostly managed with topical steroids, and ocular inflammation was considered to be dose limiting by the DSMB based on the benefits/risks for the subjects. Analysis of the logarithm of the minimal angle of resolution (LogMAR) visual acuity in both treated and untreated eyes showed clinically relevant and durable improvements compared with baseline. Mean improvements of − 0.44 and − 0.49 LogMAR for treated and untreated eyes, respectively, were noted, with a mean (± standard deviation) final value of LogMAR + 1.96 ± 0.60 and + 1.65 ± 0.34, respectively, at 5 years post-treatment administration. For the six subjects treated with the optimal dose level (9 × 10(10) viral genomes [vg]/eye), the mean visual acuity improvement from baseline reached − 0.68 LogMAR for treated eyes and − 0.64 LogMAR for untreated eyes, with a mean final value of LogMAR + 1.77 ± 0.52 and + 1.78 ± 0.34, respectively. While there was a meaningful improvement in visual acuity for REVEAL subjects, the final visual acuity was less favorable than that seen in the two subsequent pivotal phase III studies in which subjects were treated earlier during the course of their disease. CONCLUSION: Lenadogene nolparvovec was well tolerated with a good safety profile during 5 years of follow-up and may offer meaningful lasting improvements in vision for this LHON population. CLINICAL TRIAL NUMBER: EUDRACT N° 2013-001405-90. |
format | Online Article Text |
id | pubmed-7952288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-79522882021-03-28 Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study Vignal-Clermont, Catherine Girmens, Jean-François Audo, Isabelle Said, Saddek Mohand Errera, Marie-Hélène Plaine, Lise O’Shaughnessy, Denis Taiel, Magali Sahel, José-Alain BioDrugs Original Research Article BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease whose primary clinical manifestation is bilateral visual loss. Only a single therapy, idebenone, is approved in Europe for use in exceptional circumstances and no therapy is currently approved in the USA. LHON remains a disease with a high unmet medical need. OBJECTIVE: This is a report of an open-label, single-center, dose-escalation study that evaluated the safety and tolerability of lenadogene nolparvovec in 15 subjects with LHON for up to 5 years following a single intravitreal injection at four dose levels. METHODS: Subjects were enrolled sequentially in four cohorts followed by an additional cohort at the dose selected, and safety was assessed by an independent data safety monitoring board (DSMB) prior to any dose escalation. RESULTS: Overall, the treatment was well tolerated during the 5-year follow-up. No serious adverse events were considered related to treatment, no unexpected adverse events occurred, and no grade 3 or 4 Common Terminology Criteria for Adverse Events were reported. Anterior chamber inflammation and vitritis were mostly managed with topical steroids, and ocular inflammation was considered to be dose limiting by the DSMB based on the benefits/risks for the subjects. Analysis of the logarithm of the minimal angle of resolution (LogMAR) visual acuity in both treated and untreated eyes showed clinically relevant and durable improvements compared with baseline. Mean improvements of − 0.44 and − 0.49 LogMAR for treated and untreated eyes, respectively, were noted, with a mean (± standard deviation) final value of LogMAR + 1.96 ± 0.60 and + 1.65 ± 0.34, respectively, at 5 years post-treatment administration. For the six subjects treated with the optimal dose level (9 × 10(10) viral genomes [vg]/eye), the mean visual acuity improvement from baseline reached − 0.68 LogMAR for treated eyes and − 0.64 LogMAR for untreated eyes, with a mean final value of LogMAR + 1.77 ± 0.52 and + 1.78 ± 0.34, respectively. While there was a meaningful improvement in visual acuity for REVEAL subjects, the final visual acuity was less favorable than that seen in the two subsequent pivotal phase III studies in which subjects were treated earlier during the course of their disease. CONCLUSION: Lenadogene nolparvovec was well tolerated with a good safety profile during 5 years of follow-up and may offer meaningful lasting improvements in vision for this LHON population. CLINICAL TRIAL NUMBER: EUDRACT N° 2013-001405-90. Springer International Publishing 2021-02-10 2021 /pmc/articles/PMC7952288/ /pubmed/33566264 http://dx.doi.org/10.1007/s40259-021-00468-9 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Original Research Article Vignal-Clermont, Catherine Girmens, Jean-François Audo, Isabelle Said, Saddek Mohand Errera, Marie-Hélène Plaine, Lise O’Shaughnessy, Denis Taiel, Magali Sahel, José-Alain Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title | Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title_full | Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title_fullStr | Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title_full_unstemmed | Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title_short | Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study |
title_sort | safety of intravitreal gene therapy for treatment of subjects with leber hereditary optic neuropathy due to mutations in the mitochondrial nd4 gene: the reveal study |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952288/ https://www.ncbi.nlm.nih.gov/pubmed/33566264 http://dx.doi.org/10.1007/s40259-021-00468-9 |
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