Kid with glasses

Ocular treatment likely to become first Gene Therapy approved in U.S.

Spark Therapeutics has announced positive results from the Phase 3 pivotal trial of its lead gene therapy product candidate, SPK-RPE65, for the treatment of RPE65-mediated inherited retinal dystrophies (IRDs). These results represent the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease.

The pivotal trial met its primary endpoint (p = 0.001), demonstrating improvement of functional vision in the intervention group compared to the control group, as measured by the change in bilateral mobility testing between baseline and one year. In addition, subjects who received SPK-RPE65 outperformed control subjects across the first two secondary endpoints: full-field light sensitivity threshold testing (p < 0.001) and the mobility test change score for the first injected eye (p = 0.001). The third secondary endpoint, visual acuity, did not show statistically significant evidence of benefit (p = 0.17). All reported p-values reflect results from the intent-to-treat (ITT) population, the most stringent efficacy analysis population described in the statistical analysis plan (SAP).

Ocular gene therapy - routes of administration


The multicenter, pivotal phase 3 trial randomized 31 subjects with confirmed RPE65 gene mutations. The ITT population included 21 subjects in the intervention group and 10 in the control group. For the primary endpoint, subjects were evaluated at multiple time points over the course of one year for their 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) using the bilateral testing condition. Each attempt was recorded, and the videos were sent to independent, centralized, masked graders to assign a pass/fail score based on speed and accuracy with which the subjects navigated the course.

In addition to the primary endpoint, the SAP included three secondary endpoints tested statistically in the following hierarchical order:

  1. Full-field light sensitivity threshold testing (FST), which reflects underlying physiological function by measuring light sensitivity of the entire visual field.
  2. Change in mobility test score for the first eye injected, which compares the mobility test performance between baseline and year one for the first eye injected for the intervention group and, for the control group during the control year, the first eye injected after they crossed over.
  3. Visual acuity testing, which measures changes in central vision by assessing the ability of the subject to read a standard eye chart.

A summary of top-line efficacy results follows:

Primary outcome (ITT):

  • Mobility test (MT) change score, bilateral (p = 0.001)

Secondary outcomes (ITT):

  • FST, averaged over both eyes (p < 0.001)
  • MT change score, first injected eye (p = 0.001)
  • Visual acuity, averaged over both eyes (p = 0.17)

There were no serious adverse events related to SPK-RPE65 or deleterious immune responses observed in the trial. Overall, adverse events related to the administration procedure were consistent with observations in earlier studies of SPK-RPE65.

Additional data from this clinical trial will be presented in a series of scientific meetings in the coming months, beginning with a presentation at the Retina Society Annual Scientific Meeting on October 10th in Paris by Principal Investigator Stephen R. Russell, MD, of the Stephen A. Wynn Institute for Vision Research at the University of Iowa.

Based on these results, Spark intends to file a Biologics License Application with the U.S. Food and Drug Administration in 2016.


Albert M. Maguire, MD, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania: “We saw substantial restoration of vision in patients who were progressing toward complete blindness. The majority of the subjects given SPK-RPE65 derived the maximum possible benefit that we could measure on the primary visual function test, and this impressive effect was confirmed by a parallel improvement in retinal sensitivity. If approved, SPK-RPE65 should have a positive, meaningful impact on the lives of patients with this debilitating condition.”

Jean Bennett, MD, PhD, professor of ophthalmology and director of the Center for Advanced Retinal and Ocular Therapeutics at the Perelman School of Medicine of the University of Pennsylvania: “These results are the culmination of more than a decade of work of many dedicated individuals to correct the underlying cause of RPE65-mediated blindness through the one-time administration of a gene therapy. We are excited about the potential impact that the results will have on the treatment of this and other blinding conditions.”

Gordon Gund, Chairman of the Foundation Fighting Blindness: “This is a watershed moment in the long-time pursuit of innovative gene therapy solutions for a range of blinding retinal degenerative diseases. Spark, The Children’s Hospital of Philadelphia, the Foundation Fighting Blindness and a long list of collaborators in the non-profit, academic and government sectors are to be commended for diligently persevering over many years in their aim to realize the potential of gene therapy in the fight against blindness.”


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