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Phase III data is announced from a randomised controlled cross-over gene therapy trial for LCA treatment

Spark Therapeutics (NASDAQ:ONCE), a gene therapy company based in Philadelphia, USA, has announced the results of what the company claims to be the “first randomized, controlled phase 3 trial of a gene therapy for a genetic disease”. The company’s lead gene therapy product, termed “SPK-RPE65”, is a replacement gene therapy treatment for RPE65-mediated inherited retinal degeneration. According to the company, the pivotal trial conducted in 31 patients met its primary endpoint (p = 0.001), indicating improvement of functional vision in the treated patients, compared to the control subjects, “as measured by the change in bilateral mobility testing between baseline and one year”. The company intends to apply for a marketing BLA with the US FDA at some point in FY2016.


According to information released by the company, the clinical trial included 21 subjects in the intervention group and 10 in the control group which, by normal pharmaceutical standards, may appear to be an extremely small study. However, the company were of the view that the careful clinical design and statistical analysis plan were sufficient to provide statistically meaningful support for the efficacy of the treatment. With an increasing number of trials being conducted in orphan disease populations, considerable innovation and research is now conducted into novel mechanisms of study and analysis to accommodate small numbers of patients. Such designs include more novel and creative end-points, using repeated measure outcomes, longer trial durations to capture more data, cross-over study designs, use of Bayesian statistical measures and the use of data from a broader number of studies in order to leverage optimal benefits from meta-analyses.


In the SPK-RPE65 study, the primary endpoint involved assessing the patients’ performance in “navigating a mobility course under a variety of light levels ranging from one lux (equivalent to a moonless summer night) to 400 lux (a brightly lit office)”. Each attempt was recorded and, to ensure masking of treated subjects from controls, videos of the patients’ navigation attempts over a series of time points were sent to independent, centralized, masked graders who were tasked with assigning “a pass/fail score based on speed and accuracy with which the subjects navigated the course”. According to the trial results released by the company, the trial met its primary endpoint (p = 0.001). No serious adverse events were found and no deleterious immune responses were detected in any of the trial subjects. Secondary endpoints that were successfully met included full-field light sensitivity threshold testing (p < 0.001) and a mobility test change score for the first injected eye (p = 0.001). The last secondary end-point was visual acuity tested by a standard eye chart which did not show statistically significant evidence of benefit (p = 0.17).


While these are the first results, they represent a significant milestone in the field of gene therapy, marking the culmination of an enormous amount of time and effort invested by countless individuals across several decades of academic, commercial and government research. Peer review analysis of the results will be the next step and it is hoped that the company will make all participant level data available freely to independent reviewers, representing a gold-standard mechanism for advancing the scientific field in the best interests of patients, clinicians, industry and academe.