Voretigene neparvovec-rzyl for the treatment of biallelic RPE65 mutation–associated retinal dystrophy

ABSTRACT

Introduction: Inherited retinal dystrophies (IRDs) are the major cause of familial blindness in the Western world, and until recently, have been devoid of pharmacologic treatment options. Biallelic mutations in the RPE65 gene cause a progressive IRD characterized by decreased light sensitivity, constricted visual fields, and impaired visual acuity. Voretigene neparvovec-rzyl (VN), an adeno-associated viral vector gene therapy that delivers a normal copy of the RPE65 gene to retinal pigment epithelium cells lacking a functional version of the gene, was recently approved by the FDA.

Areas covered: The VN compound and its mechanism of action are described. Clinical efficacy, durability, and safety of VN from phase 1 follow-on and phase 3 trials of subjects who received the approved dose of 1.5 x 10¹¹ vector genomes are summarized.

Expert opinion: The VN phase 3 trial is the first randomized, controlled study completed in gene therapy for a genetic disease. This represents more than a decade of innovative research, including vector design, manufacturing and formulation, surgical delivery procedure, and clinical trial design, as well as the development of a novel end point. In addition to offering a proven therapy for patients with RPE65 mutation–associated IRD, this gene therapy platform is a springboard to developing investigational therapies for other debilitating genetic diseases.

KEYWORDS:

• Genetic therapy
• Leber congenital amaurosis
• night blindness
• retinal dystrophies
• retinitis pigmentosa
• transgenes

Box 1. Drug summary.

Declaration of interest

S Russell’s institution has received grants from Spark Therapeutics, Inc. and he has provided presentations on behalf of Spark Therapeutics, Inc. S Russell is a co-author on a copyrighted visual function questionnaire used in a study of voretigene neparvovec-rzyl. J Bennett has received grants from the Foundation Fighting Blindness, the National Institutes of Health, and Spark Therapeutics, Inc.; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; has two issued US patents and a related pending patent application licensed to Spark Therapeutics, Inc. for which she has waived financial interest; and is a co-author on a copyrighted visual function questionnaire used in a study of voretigene neparvovec-rzyl. AM Maguire has received grants from Spark Therapeutics, Inc., the National Institutes of Health, and the Foundation Fighting Blindness; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; and has two issued US patents and a related pending patent application licensed to Spark Therapeutics, Inc. for which he has waived financial interest. KA High is an employee of Spark Therapeutics, Inc. and has a pending patent application pertaining to the primary end point measure used in a study of voretigene neparvovec-rzyl and issued patents and pending patent applications related to adeno-associated virus vector (AAV) manufacturing. 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

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by Spark Therapeutics, Inc., Philadelphia, PA. Medical writing support was provided by Christina M. Ohnsman, MD, of CMO Medical Communications, LLC, and editorial support was provided by Lisa Feder, PhD of Peloton Advantage, Parsippany, NJ; both were funded by Spark Therapeutics, Inc.