Real-World Study Confirms Long-Term Efficacy of Luxturna Gene Therapy for Inherited Retinal Disease
核心洞察
The PERCEIVE real-world study of 323 patients across 26 countries demonstrated sustained improvement in light sensitivity at 5 years following voretigene neparvovec treatment.
Chorioretinal atrophy (搜索) occurred in 36.5% of patients but did not significantly impact the therapy's effectiveness in improving visual function.
No new safety signals were identified beyond the known profile, supporting the long-term durability of this first-approved gene therapy for inherited retinal dystrophy (搜索).
A comprehensive 5-year interim analysis of the PERCEIVE real-world study has demonstrated sustained improvement in light sensitivity among patients treated with voretigene neparvovec-rzyl (Luxturna), the first approved gene therapy for inherited retinal disease. The findings, presented at the Euretina congress in Paris, represent the largest real-world analysis of the therapy outside the United States.
Robust International Evidence Base
The PERCEIVE study enrolled 323 patients with biallelic RPE65 (搜索) mutation-associated inherited retinal dystrophy (搜索) from 26 countries, with the majority from continental Europe including Italy (14.2%), France (12.7%), Germany (10.5%), and Spain (9.6%). The mean patient age was 23.7 years, with more than half being adults and an equal distribution between males and females. The mean follow-up period was 2.3 years, with some patients followed for up to 5 years.
"This is the biggest real-world analysis of voretigene neparvovec," said Dominik Fischer, MD, at the Euretina congress. "It's the post-approval registry that captures all patients outside the U.S."
Sustained Visual Function Improvements
The study's primary finding centered on the full-field light sensitivity threshold (FST) test using white light, which served as a primary endpoint in the pivotal phase 3 trial. Results showed a robust, sustained elevation of light sensitivity throughout the observation period. An increase in mean white light sensitivity from baseline was observed as early as month 1, with the highest gain recorded at 4 years. Notably, no significant change in visual acuity was reported during the study period.
Safety Profile and Chorioretinal Atrophy
The analysis revealed that 87.4% of patients received the full recommended dose of 300μL, while approximately 10% received a lower dose and 2.5% received a higher dose than recommended. Ocular adverse events were reported in 217 patients (67.2%), with the most frequent being retinal degeneration, intraocular pressure increase, and injection site atrophy.
A significant finding was the occurrence of chorioretinal atrophy (搜索) (CRA) in 36.5% of patients and 34.1% of eyes. Fischer explained that CRA encompasses various conditions under Medical Dictionary for Regulatory Activities (MedDRA) terminology, including retinal degeneration, injection site atrophy, retinal depigmentation, retinal dystrophy, injection site discoloration, and macular degeneration.
Importantly, when comparing FST results between eyes with CRA changes versus those without, the analysis revealed that eyes with atrophy "actually outperformed, or at least did not underperform, compared to the group without the CRA," according to Fischer. "This suggests that the CRA does not have a significant impact on light sensitivity."
Clinical Implementation Experience
The University Eye Hospital of Ludwig Maximilian University Munich (搜索), which became the first center in German-speaking Europe to begin clinical treatments with voretigene neparvovec-rzyl in 2019, has provided valuable insights into real-world implementation. The center has treated a growing number of pediatric and adult patients, with particular focus on preschool-aged children where early intervention is critical for functional benefit and long-term visual development.
Clinical outcomes have been encouraging, with children and young adults reporting improved light sensitivity and navigational vision within weeks of bilateral subretinal injection. However, the therapy has limitations: it does not halt retinal degeneration, may lead to progressive chorioretinal atrophy (搜索), and is most effective when applied early while sufficient viable photoreceptors and retinal pigment epithelial cells remain.
Expanding Gene Therapy Landscape
Beyond RPE65 (搜索)-targeted therapy, the gene therapy landscape for inherited retinal diseases is expanding rapidly. Several promising candidates are progressing through clinical trials, including RPGR (搜索)-targeted therapies for X-linked retinitis pigmentosa (搜索), with multiple AAV-based candidates in phase 2/3 trials showing encouraging safety and efficacy signals.
The University Eye Hospital of LMU Munich is preparing to initiate a phase 1 clinical trial investigating gene therapy for ABCA4 (搜索)-related disease, including Stargardt disease (搜索), the most common form of juvenile hereditary retinopathy. This trial will utilize a novel adeno-associated virus (AAV)-based dual vector technology developed by VeonGen Therapeutics (搜索), designed to overcome delivery limitations of conventional AAVs and enable efficient transduction of photoreceptors with larger transgene payloads.
Long-Term Outlook
The PERCEIVE study, which began enrollment in 2019 and will reach completion in 2029, continues to provide crucial real-world evidence on the long-term durability of vision improvements observed with voretigene neparvovec treatment. Fischer concluded that "safety findings are aligned with the known safety profile of voretigene neparvovec and no new safety signals were identified. Most patients, including those with CRA changes, had sustained improvement in visual function during this observation period."