History and Development Story of Luxturna: Scientific and Regulatory Challenges

Until recently, there was no approved treatment for an inherited retinal degenerative disease (IRD). Reversal of blindness in a canine model of an IRD through the delivery of the wildtype copy of the disease-causing gene inspired several groups to initiate Phase I gene augmentation therapy clinical trials for Leber congenital amaurosis (LCA) due to RPE65 mutations. The wildtype human RPE65 cDNA was delivered through subretinal injection of a recombinant adeno-associated virus (AAV). Positive results were reported by the three groups in contemporaneous Phase I studies. However, only our group at The Children's Hospital of Philadelphia (CHOP) proceeded to drug approval. Successful navigation of the hurdles along the way and the positive data generated from the Phase III clinical trial led to the first FDA-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna™). Luxturna was then approved by the European Medicines Agency and is now available in the USA through Spark Therapeutics (now owned by Roche) and throughout much of the world through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but also it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This case study describes some hurdles in moving the studies from the laboratory to the clinic and beyond. It also describes how learnings from the Luxturna experience could benefit the development of additional gene-based treatments for blindness.