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Patient reported outcomes in retinal gene therapy study make significant impact on regulatory assessment

An October meeting of the Food and Drug Administration’s (FDA) Cellular, Tissue and Gene Therapies Advisory Committee has unanimously recommended (16-0) approval of a new treatment, “LUXTURNA” (voretigene neparvovec), a gene therapy for the treatment of patients with biallelic RPE65-mediated inherited retinal disease. The approval of the new treatment was supported by patient testimony, understood to have contextualised a number of objective readouts used as outcome measures in the trial. The sponsor of the new treatment. Spark Therapeutics Inc., had developed a novel outcome measure – a multi-luminance mobility test (MLMT) – designed to assess an individual’s ability to navigate an obstacle course at several different light intensities. However, FDA panel members expressed uncertainty indicating that it may be difficult to interpret the clinical utility of light intensity changes on MLMT scores. Commenting on the assessment, Wilson Bryan, director of the Office of Tissues and Advanced Therapies at Center for Biologics Evaluation and Research (CBER) stated, “[w]e are uncertain of the product’s activity on this novel endpoint and whether it represents a true improvement in the lives of patients.”


To address such concerns, patient testimony was heard to understand what level of clinical significance could be ascribed to such functional outcome measures. FDA panel members heard from six patients who received the gene therapy in a Phase III trial, and additionally heard from clinicians and caregivers of a further two patients. Speaking of his positive experience with the treatment, Christian Guardino, an LCA patient explained: “[t]he first 12 years of my life were spent in darkness. It was difficult for me to see and, socially, I couldn’t relate because I couldn’t see people’s facial expressions. I couldn’t get around in restaurants, theaters or on stage (Mr. Guardino is a stage performer). At dusk, I was completely blind. This gene therapy has literally made my day so much brighter.” Laura Gatz, the mother of a young patient, Angelina, explained how her daughter needed one-to-one assistance at school and would have difficulty seeing food on her plate. However, following treatment, Angelina sight was reported to have improved by three light levels. Laura Gatz told the FDA panel that, “just a few months after treatment, her vision improved so much. She no longer needed any of those items at school or the aid. She can function independently.” Such personal testimony is not normally part of FDA panel drug authorisation meetings however, the initiative was welcomed by Stephen Rose, Chief Research Officer of Foundation Fighting Blindness. Speaking to BioCentury after the panel meeting, Dr. Rose stated that, “[t]here are no validated PROs (patient reported outcomes) that the FDA is accepting for ophthalmic diseases, so it took the testimony of the individuals who received the therapy to demonstrate what it means to them personally. Numbers aren’t going to express what these individuals are experiencing. But what you are seeing now is that FDA is really going the route of listening to individuals.”


Such patient testimony appeared to be additionally welcomed by some panel members in its ability to provide real world perspective to the MLMT model. The incorporation of such supporting evidence into regulatory assessment may be particularly beneficial in some indications however, it is not yet clear how such data might fit into pharmacoeconmic assessments. The pricing of gene therapy medicines has proved controversial in the past and so it will be instructive to see how national re-imbursement systems manage the road ahead.