Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development

ABSTRACT

Introduction: Over a decade of research and development culminated in the 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN) for RPE65 mutation-associated inherited retinal disease (IRD), the first approved gene therapy for a hereditary genetic disease in the US, and the first and only pharmacologic treatment for an IRD.

Areas covered: VN serves as a model for ocular gene therapy development, while RPE65 mutation-associated IRD serves as an example of a well-suited candidate disorder. This review also discusses development considerations for viral vector gene augmentation, and, studies that led to VN’s FDA approval. Subretinal injection of VN resulted in improved performance on the novel multi-luminance mobility test (MLMT), light sensitivity, and visual fields in patients with RPE65 mutation-associated IRD, which predominantly impairs rod function. Additionally, the dosage, administration technique, pharmacokinetics, and safety data of VN are reviewed.

Expert Opinion: As a model for development, special challenges associated with the introduction of this first ocular gene therapy include limited genetic testing in clinical practice, novel surgical complexity of ocular gene therapy administration, new functional vision endpoints, as well as unique development, launch, and reimbursement considerations associated with orphan therapies and one-time gene therapies.

KEYWORDS:

• Gene therapy
• adeno-associated virus
• inherited retinal disease
• Leber’s congenital amaurosis
• retinitis pigmentosa
• voretigene neparvovec-rzyl
• luxturna
• RPE65

Article highlights

• The 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN, Luxturna, Spark Therapeutics), the first US gene therapy for a genetic disease, marked a new cycle of innovation in ophthalmic therapies. VN serves as a model for the development of gene therapies to treat other IRDs. However, autosomal recessive RPE65 mutation-associated inherited retinal disease (IRD) may have been particularly well-suited for gene therapy development, as it involves a key enzymatic defect, and augmentation of even a small amount of enzymatic activity can sometimes restore phenotype, while it does not cause irreversible degneration until later in its course; development efforts also benefited from a large animal model.

• Voretigene neparvovec-rzyl is a non-replicating adeno-associated virus (AAV) serotype 2, which has been genetically modified to express the human RPE65 transgene; it has been approved for the one-time treatment of confirmed biallelic RPE65 mutation-associated IRD with viable retinal cells as determined by treating physicians. VN restores the visual cycle via functional retinoid isomerohydrolase, a 65-kD protein expressed in the RPE.

• The efficacy of VN was established on the basis of multi-luminance mobility testing (MLMT) score change from Baseline to Year 1. While practitioners have historically relied on visual acuity (VA) as a primary endpoint, many IRDs primarily affect rods and peripheral vision with late effects on VA. Tests of functional vision, the ability to conduct visually dependent activities of daily living, are important because they correlate with quality of life. The MLMT was designed to measure changes in functional vision, as assessed by the ability of a subject to navigate a mobility course accurately and at a reasonable pace in different levels of environmental illumination. MLMT and other tests of functional vision will become increasingly important as additional gene therapies for IRDs undergo clinical study and potential commercialization.

• Patients in the phase 3 trial of VN have shown durability of response to 4 years. Mean changes in MLMT at Year 1 were maintained at Year 4 for the original intervention group.

• VN administration to the RPE involves pars plana vitrectomy (PPV) followed by transretinal injection into the subretinal space. Precise subretinal administration of gene therapy via PPV is an evolving procedure, and its novel surgical complexity represented a challenge in the introduction of VN. For rare genetic disorders, ocular gene therapy treatment centers consolidate care, to facilitate safety and treatment optimization, as consistent patient and procedural volume in rare disease drives a virtuous cycle of expertise and positive outcomes.

• Gene therapy requires a genetic diagnosis, yet there has been limited clinical use of genetic testing in retina practices, representing another hurdle in the launch of VN. Educational efforts to address the complexity of genetic testing results must be continued for the successful adoption of precision medicine.

• Orphan therapy development, launch, and reimbursement considerations represented another group of challenges in the launch of VN, as ophthalmologists generally have not been exposed to treatments approved for orphan diseases. The launch of VN spurred the development of multiple innovative solutions.

This box summarizes key points contained in the article.

Declaration of Interest

TA Ciulla has had an employment relationship in VP roles with Iveric Bio and Spark Therapeutics. He currently has an employment relationship as Chief Medical Officer at Clearside Biomedical Inc. However, this manuscript was written during his work as a Volunteer Clinical Professor of Ophthalmology at Indiana University School of Medicine, and none of the work herein represents any official position or opinion of any of these companies or its management. RM Hussain has served on an advisory board for Alimera Sciences. AM Berrocal serves on advisory boards for Dutch Ophthalmic Research Center (DORC), Allergan, Novartis, Alcon, Zeiss, Phoenix, and Visunex Medical Systems. A Nagiel serves as a consultant for REGENXBIO. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One of the peer reviewers on this manuscript was involved in the clinical development of VN and is currently an ophthalmologist at Spark Therapeutics. Two additional peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.