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Phase III results of experimental gene therapy treatment for RPE-65 mediated retinal dystrophy report statistical and clinically meaningful benefit

Findings from a clinical research study published in the Lancet (Jul 13, 2017) show that patients with RPE-65 mediated retinopathy had a “statistically significant and clinically meaningful difference” in the primary trial endpoint of “multi-luminance mobility testing” (MLMT). The endpoint itself represents an innovation built into the study and approved by regulators as a meaningful test to assess functional outcomes in such studies. The treatment, called voretigene neparvovec, is an AAV (adeno-associated virus) vector carrying a modified human RPE 65 cDNA gene sequence, designed for expression in the retinal tissue to replace the endogenous non-functioning gene and thereby correct the primary defect. The treatment is expected to essentially “cure” the disease with a single adminstration of the therapeutic and represents a landmark achievement in both the field of gene therapy and in the commercial development of a gene therapy product in the United States. If approved by the FDA, the treatment will represent the first such approved drug in North America.


The Phase III study was small, 29 patients in total, and was designed to assess the saftey and efficacy of the new treatment in an open label randomised clinical trial. Conducted at two sites in the US, patients were deemed elgible for the study if each eye had a BCVA of 20/60 or worse, or a visual field less than 20 degrees in any meridian, or both. In addition, eligible patients needed to have a confirmed genetic diagnosis of biallelic RPE65 mutations. Assessment of the primary endpoint was by way of “standardised multi-luminance mobility test”, essentially a carefully designed and modifiable navigation course with alterable luminance ranges used to assess the functional outcome of the treatment on a clinically meaningful basis. A subretinal injection of 1·5 × 10¹¹ vector genomes of voretigene neparvovec in 300uL total volume was administered to randomized participants (2:1) using a standardized surgical procedure. The primary efficacy endpoint was the 1-year change in MLMT performance, measuring functional vision at specified light levels. At the 1 year time point, the mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group, versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). In addition, 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux).


The authors of the research report conclude their study stating, “the data presented here, which add to the evolving safety and efficacy profile of voretigene neparvovec, show improved light sensitivity, visual fields, and navigational ability under dim lighting conditions in patients with RPE65-mediated inherited retinal dystrophy, a population with no approved pharmacological treatment options. Data from the follow-on phase 1 study suggest that this effect might last at least 3 years; observation is ongoing. These results underscore the need for access to genetic screening to identify patients with inherited retinal dystrophy who might benefit from this and other potential future gene therapies. “