Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France.
Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France.
BioDrugs. 2021 Mar;35(2):201-214. doi: 10.1007/s40259-021-00468-9. Epub 2021 Feb 10.
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.
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.
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.
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 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.
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.
EUDRACT N° 2013-001405-90.
Leber 遗传性视神经病变（LHON）是一种母系遗传的线粒体疾病，其主要临床表现为双侧视力丧失。在欧洲，仅有一种名为 Idebenone 的药物被批准用于特殊情况下使用，而在美国则没有批准任何治疗方法。LHON 仍然是一种医疗需求未得到满足的疾病。
本报告介绍了一项开放标签、单中心、剂量递增研究，该研究评估了 lenadogene nolparvovec 在 15 名 LHON 患者中的安全性和耐受性，这些患者在单次玻璃体内注射后，在 4 个剂量水平下进行了长达 5 年的随访。
受试者按顺序入组，在剂量递增前，由独立的数据安全监测委员会（DSMB）评估安全性。
在 5 年的随访中，总体而言，治疗耐受性良好。没有认为与治疗相关的严重不良事件，没有发生意外不良事件，也没有报告 3 级或 4 级不良事件通用术语标准（CTCAE）的不良事件。前房炎症和眼内炎主要通过局部皮质类固醇治疗，根据受试者的获益/风险，DSMB 认为眼部炎症是剂量限制因素。用最小分辨角对数（LogMAR）视力分析治疗眼和未治疗眼，与基线相比，均显示出具有临床意义的持久改善。治疗眼和未治疗眼的平均改善分别为 -0.44 和 -0.49 LogMAR，治疗后 5 年的平均最终 LogMAR 值分别为 +1.96±0.60 和 +1.65±0.34。对于接受最佳剂量水平（9×10 病毒基因组[vg]/眼）治疗的 6 名受试者，治疗眼的平均视力从基线提高了 -0.68 LogMAR，未治疗眼提高了 -0.64 LogMAR，治疗后的最终 LogMAR 值分别为 +1.77±0.52 和 +1.78±0.34。尽管 REVEAL 受试者的视力有明显改善，但最终视力不如随后两项疾病早期治疗的关键性 III 期研究中所见。
在 5 年的随访中，lenadogene nolparvovec 具有良好的耐受性和良好的安全性，可为该 LHON 人群提供有意义的持久视力改善。
Eudract N° 2013-001405-90。
