Gene therapy company Spark Therapeutics announced that The Lancet has published phase 3 clinical trial data of voretigene neparvovec, an investigational, potential one-time gene therapy candidate for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). In the trial, investigational voretigene neparvovec improved functional vision, light sensitivity, and visual field in study participants with RPE65-mediated IRD. A natural history study has shown that people with this IRD eventually progress to complete blindness.
Functional vision refers to a person's ability to perform, on his or her own, visually dependent activities of daily living. This is typically measured per person rather than per eye, and may be thought of as the performance output of various aspects of visual function. Visual function is measured by tests performed on each eye individually, such as light sensitivity, visual acuity (determined by the smallest letters one can read on a standardized eye chart from a specified distance), and visual field (which refers to the area in which objects can be detected in the periphery while the eye is focused on a central point). This clinical trial evaluated both functional vision and various aspects of visual function.
The publication presents the results of the phase 3 trial, including the intent-to-treat population of all randomized subjects, through the 1-year timepoint. Results showed a statistically significant and clinically meaningful difference between intervention (n=21) and control participants (n=10) at 1 year, per the clinical trial’s primary endpoint, mean bilateral multi-luminance mobility testing (MLMT) change score (difference of 1.6; 95% CI, 0.72, 2.41; P = .0013). Participants maintained functional gains observed 30 days post-administration at the 1-year primary endpoint. MLMT evaluates functional vision by documenting the participants' ability to navigate a mobility course under a variety of specified light levels ranging from one lux (equivalent to, for example, a moonless summer night) to 400 lux (equivalent to, for example, an office environment).
Improvements seen in MLMT were accompanied by statistically significant improvements in two secondary endpoints, including full-field light sensitivity threshold (FST) testing averaged over both eyes (P = .0004). A third secondary endpoint, the change in visual acuity averaged over both eyes, was not statistically significant between intervention and control participants (P = .17). An additional protocol-specified endpoint using the Goldmann III4e test stimulus to measure the visual field area of the original intervention group showed significant improvement (P = .0059), nearly doubling at year 1, while a slight decrease was observed in the control group over the same time period.
No serious adverse events (SAEs) associated with voretigene neparvovec or deleterious immune responses were observed. Most ocular events were mild in severity with the most common ocular adverse events (AEs) being transient mild ocular inflammation, transient elevated IOP, cataracts, and intraoperative retinal tears. Two participants in the intervention group, one with a pre-existing complex seizure disorder and another who experienced complications from oral surgery, had SAEs unrelated to study participation.
Please refer to the paper, “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in subjects with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label Phase 3 trial,” for additional results from the pivotal phase of this study.
“These data from the first randomized, controlled phase 3 gene therapy clinical trial ever conducted for a genetic disease are supportive of the potential role that investigational voretigene neparvovec may play in the treatment of IRD caused by biallelic mutations in the RPE65 gene,” Stephen R. Russell, MD, of the Stephen A. Wynn Institute for Vision Research at the University of Iowa, who was a principal investigator for the phase 3 trial, said in a company news release. “The data show clinically meaningful and statistically significant improvements in ability to navigate independently in low to moderate light conditions, as well as marked improvements in full-field light sensitivity and peripheral vision. As a treating physician, it’s exciting to see these types of results in a disease area where no approved pharmacologic treatment options currently exist.”
In May 2017, Spark Therapeutics completed the rolling submission of a Biologics License Application (BLA) with the FDA for voretigene neparvovec for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal disease. FDA has 60 days to review the submission to determine if it is complete. If deemed complete, the application will be considered filed and the review period will begin. Voretigene neparvovec has received breakthrough therapy designation from FDA, given to drugs when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies based on one or more clinically significant endpoints, and orphan product designations from FDA and European Medicines Agency (EMA), granted to drugs that treat a rare disease or condition