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Phase III clinical trial results with gene therapy AAV delivered RPE-65 show functional and sensitivity improvements.

A clinical study on a small number of patients with retinal degeneration cause by RPE-65 mutations, has reported positive results in respect of visual function and full-field sensitivity testing. An adeno-associated viral vector carrying engineered versions of the RPE-65 gene, manufactured by Spark Therapeutics (NASDAQ: ONCE) in the US and referenced as voretigene neparvovec, is in advance clinical studies in a crossover trial of 29 patients. Initial results, reported in October 2015, showed clinically significant improvement in the intervention group (20 subjects) compared to the control group (9 subjects) on the primary endpoint, change in bilateral mobility testing between baseline and 1 year. Two secondary endpoints (full-field light sensitivity threshold testing for white light and mobility testing for the assigned first eye) additionally indicated a statistically significant improvement however, visual acuity did not meet statistical significance.


More recently, a year after initial administration, eight of the nine subjects in the original control group that crossed over to the treatment arm showed improved mobility testing with eight responders demonstrating an ability to navigate an obstacle course at 1 lux. The sponsor reported that the mean improvement among all nine subjects in the crossover portion of the study was 2.1 lux levels, compared to the 1.9 lux level improvement seen in the original group of 20 subjects. On full-field light sensitivity threshold testing, eight of the nine subjects were reported to be improved, recording an average improvement of nearly 200-fold, compared to an approximate 100-fold improvement average seen in the original 20 study subjects. Subjects in the crossover study were also reported as demonstrated an average visual acuity improvement of 4.5 letters.


Commenting on the results, Dr. Katherine High, President and CSO of Spark Therapeutics stated, “we now have substantially more data at one year after administration of voretigene neparvovec across both the 301 and 302 Phase 3 studies, and have seen 27 of 29, or 93%, of subjects respond, importantly demonstrating gains in functional vision. We plan to include these additional Phase 3 data in the clinical modules of our rolling BLA submission, as well as to continue to analyze data from our clinical trials in order to further elucidate the potential for long-lasting benefit that voretigene neparvovec may have on the lives of patients with RPE65-mediated inherited retinal disease.” Although the patient numbers are small, the clinical testing is understood to be carefully designed and monitored to ensure that results move beyond statistical significance and into clinical significance. Spark believe they have made considerable contributions to designing new outcome measures, including mobility and navigation testing, to ensure real-world application of the novel potential treatments.