Voretigene Neparvovec-rzyl Gene Therapy Continues to Improve IRD Patient Marks in Year 3


A three-year update of VN for patients with biallelic RPE65 mutation-associated inherited retinal disease improved on the common standard-of-care for retina disease.

A three-year follow-up to a phase 3 trial testing the efficacy of gene therapy voretigene neparvovec-rzyl (VN) in patients with biallelic RPE65 mutation-associated inherited retinal disease (IRD) reports that aspects of patient visual function also improved over time.

The data, presented at the American Society of Retina Specialists (ASRS) Annual Meeting in Vancouver, BC, on Tuesday, distinguishes from previous standards of care for IRD, author Stephen R. Russell, MD, told MD Magazine®.

“For the more common diseases we see, our first therapeutic attempt is to stabilize vision and prevent deterioration,” Russell said. “The thing that was unique about the RPE65 trials is not only did we prevent loss, we improved the situation.”

Russell—a professor of vitroretinal diseases and surgery services director at University of Iowa Hospital & Clinics—and colleagues randomized 29 patients with RPE65 mutation-associated IRD to either bilateral subretinal VN intervention (n= 20) or one-year control followed by VN (9). The study’s primary endpoint was set at bilateral multi-luminance mobility test (MLMT) at 7 standardized illumination levels.

Supplemental endpoints included full-field light sensitivity threshold (FST) testing, visual acuity (VA), Goldmann kinetic visual field (GVF), and various safety endpoints.

At 2 years, mean bilateral change in MLMT score was 1.8 levels for patients on VN intervention, and 2.1 levels for patients on initial control. More than 68% of patients passed MLMT, with lowest light level measured at 3 years for intervention patients and 2 years for control patients. Mean change in white light FST averaged over both patients eyes was -2.04 log10 (cd.s/m2; 1.43) at 3 years for intervention patients and -2.69 log10 (cd.s/m2; 1.41) at 2 years for control patients.

Sum total degree change on GVF III4e, averaged over both eyes, was +282 (257) for intervention patients, and +183 (31) in control patients. Both patient groups, at 3 and 2 years respectively, averaged consistent mean change in VA, as well as consistent safety profiles.

Researchers concluded the VN therapy’s benefit-risk profile was favorable to control/VN, with noted improvements in both routine functional vision and vision capability in subjects with biallelic RPE65 mutation-associated IRD. That said, control patients’ improvements in MLMT, FST, and GVF were consistent with those reported in treated patients.

The development of long-term data supporting VN comes at a time of an “explosion” of gene therapy research for ophthalmology, Russell said. Despite the variability of genes being targeted by researchers, he credits VN as being a form of true gene therapy: the augmenting of cell by putting in a functional gene copy where no copy previously existed.

That said, future endeavors may even improve on the methodology of VN.

“There are all kinds of manipulations where you might be able to affect the way the DNA is processed into RNA, how the RNA processing might occur,” Russell said. “There are a number of other ways in which gene therapy intervention may occur without just putting in a gene product.”

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