Spark Therapeutics announced findings from three post-hoc analyses of data from the phase 3 clinical trial of Luxturna (voretigene neparvovec-rzyl) at the American Academy of Ophthalmology annual meeting in Chicago. Luxturna is a 1-time gene therapy for the treatment of patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and viable retinal cells. One of these analyses, “Visual Acuity Outcomes in the Voretigene Neparvovec Phase 3 Trial” was presented on Monday at AAO.
In the phase 3 clinical trial of Luxturna, visual acuity was measured using a scale adapted from the Holladay method, which assigns LogMAR values for off-chart vision measurements. Best-corrected (with optimal glasses/contact lens prescription) visual acuity improvement averaged over both eyes for participants in the intervention group was not statistically significant as compared to the control group (P=0.17) at year 1. In this post-hoc analysis, visual acuity data were revisited using the Lange method, which is a less conservative off-chart vision scale when quantifying the difference between counting fingers and hand motions. Results at year 1 using this method showed a statistically significant improvement from baseline versus the control group in best-corrected visual acuity averaged over both eyes (nominal P<0.05).
No adverse events associated with a reduction in visual acuity have been reported across the Luxturna clinical development program. In the post-marketing setting, one adverse event of reduced visual acuity has been reported within the immediate postoperative period following administration. It was considered non-serious and is reported to be resolving.
“These data further deepen our understanding of the biology of RPE65 mutation-associated inherited retinal disease and the phase 3 clinical trial of Luxturna,” Katherine A. High, MD, president and head of research & development at Spark Therapeutics, said in a company news release. “An important component of clinical research is to complete additional analyses on data to gain further insight into the current understanding of the science. This is particularly important in gene therapy, where there is the potential to restore function in the setting of previously untreatable diseases. We look forward to our continued engagement with the ophthalmology clinical and research communities as a leader in gene therapy research.”
Spark Therapeutics also presented two posters at the meeting. One explored potential correlations between mutation subtype and baseline visual function, response to Luxturna treatment and adverse events. Among the 29 participants who received Luxturna in the phase 3 clinical trial, 25 unique genotypes were reported. For this post-hoc analysis, the mutations were characterized into subtypes based on both the mutation type and the likeliness of pathogenicity. No correlations were found between RPE65 mutation subtype and baseline visual function, treatment response or adverse events associated with administration.
The second poster reports an analysis suggesting that administration of Luxturna resulted in improvements in the function of retinal cone cells, one of the two primary cell types supporting visual function in the retina (in addition to the other primary cell type, rod cells). Cone cells are responsible for sharpness and color vision, while rod cells are responsible for light sensitivity and peripheral vision. RPE65 mutation-associated inherited retinal disease has been understood to be primarily a rod-mediated disease. Without the properly functioning protein encoded by the RPE65 gene, the visual cycle is disrupted with an inability to regenerate visual pigment, which leads to the accumulation of toxic materials and byproducts, particularly compromising light capture in rod cells, which lack another process for regenerating visual pigment.
Mean values averaged over both eyes for white light FST testing that assesses rod function, blue light FST testing that assesses rod and cone function and red light FST testing that assesses cone function all demonstrated statistically significant improvements from baseline versus the control group at year one (P<0.001, nominal P=0.002 and nominal P<0.001, respectively). The improvements in rods were greater than in cones. This analysis provides scientific support for why some patients may experience improvement in cone function including color and sharpness of vision in addition to improvement in light sensitivity and peripheral vision after treatment with Luxturna.