Date: 2015-11-14
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the American Academy of Ophthalmology (AAO) 2015 Annual Meeting
Company: Spark Therapeutics (USA - PA)
Product: SPK-RPE65
Action
mechanism: gene therapy. SPK-RPE65 uses a neutralized virus as a vector, or delivery vehicle, to transport a functional RPE65 gene into the affected tissue in the eye. Once inside the eye, the new genetic material enables patients to produce the protein that is missing as a result of their genetic mutation.
Disease: RPE65-mediated inherited retinal dystrophies
Therapeutic area: Ophtalmological diseases - Genetic diseases - Rare diseases
Country:
Trial
details: The pivotal Phase 3 trial of SPK-RPE65 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 specified 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 statistical analysis plan included three secondary endpoints tested statistically in the following hierarchical order: FST (white light), which reflects underlying physiological function by measuring light sensitivity of the entire visual field. Change in MT score for the assigned first eye, which compares the MT 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. Visual acuity (VA) testing, which measures changes in central vision by assessing the ability of the subject to read a standard eye chart.
Latest
news: * On November 14, 2015, Spark Therapeutics announced that additional secondary endpoint data from the Phase 3 pivotal trial of SPK-RPE65 were presented at the American Academy of Ophthalmology (AAO) 2015 Annual Meeting. SPK-RPE65 is Spark’s lead product candidate for the treatment of RPE65-mediated inherited retinal dystrophies. As previously announced, the randomized controlled multicenter Phase 3 trial demonstrated a highly statistically significant improvement in the intervention group compared to the control group in the primary endpoint, the change in bilateral mobility testing (MT) between baseline and one year. The first two secondary endpoints – full-field light sensitivity threshold testing (FST) and MT for the assigned first eye – also showed highly statistically significant improvement. Principal Investigator Albert M. Maguire, MD, professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania, presented a comprehensive overview of results at AAO, including new detail highlighting the positive trends seen in the third secondary endpoint, visual acuity. These data showed that intervention subjects in the modified intent-to-treat efficacy analysis population achieved a mean improvement of approximately two lines (9.0 letters averaged across both eyes) on the logarithm of the minimum angle of resolution (logMAR) scale, a standard measure of visual acuity, compared with a slight improvement (1.6 letters) among control subjects. Over one-third of the intervention subjects (seven of 20) saw a 15-letter, or three-line, improvement in the first eye administered, compared with none in the control group. In the second eye administered, four of 20 intervention subjects reached a 15-letter improvement compared with none of the control subjects. Spark continues to conduct analyses of the changes seen in visual acuity. The pivotal Phase 3 trial of SPK-RPE65 is the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease. The multicenter 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. A summary of previously announced top-line efficacy results follows: * On October 10, 2015, Spark Therapeutics announced the presentation of additional data from the Phase 3 pivotal trial as well as continued durability data from an earlier Phase 1 study of SPK-RPE65, its lead product candidate for the treatment of RPE65-mediated inherited retinal dystrophies (IRDs). Principal Investigator Stephen R. Russell, MD, of the Stephen A. Wynn Institute for Vision Research at the University of Iowa, presented Phase 3 data highlighting the rate, breadth and magnitude of changes seen across the primary endpoint and first secondary endpoint following administration of SPK-RPE65. In addition, Dr. Russell presented data on the three-year durability of improvements in the same measures of functional vision and light sensitivity in a cohort of subjects from an earlier Phase 1 trial. This presentation builds on top-line results of a randomized controlled multi-center Phase 3 trial announced by Spark on October 5, which demonstrated a highly statistically significant improvement in the intervention group compared to the control group in the primary endpoint and two of three secondary endpoints (see below). There were no serious adverse events related to SPK-RPE65 in the Phase 3 trial. Data presented highlighted a mean improvement in the functional vision of intervention subjects (n=20) of 1.9 specified lux levels, compared with an improvement of 0.2 specified lux levels in control subjects (n=9) as measured by the change in bilateral mobility testing (MT) between baseline and one year in the modified intent-to-treat (mITT) population. The mITT population (n=29) includes all subjects that received SPK-RPR65, and only those who continued beyond the baseline study visit. Two subjects in the intent-to-treat (ITT) population (n=31) that were randomized but never received SPK-RPE65 are excluded from this efficacy analysis population. Thirteen of the 20 subjects receiving SPK-RPE65 were able to pass the MT at one lux at year one, demonstrating maximum improvement measurable on the MT score. None of the nine control subjects followed was able to pass MT at one lux at year one. In a corresponding finding in the first secondary efficacy endpoint, full-field light sensitivity threshold testing (FST) for white light, intervention subjects demonstrated a highly statistically significant mean improvement of -2.06 log10 (candela second/m2) compared with decline of 0.04 log10 (candela second/m2) among control subjects (all analyses in mITT population). Dr. Russell presented additional top-line analyses from the pivotal Phase 3 trial showing the rapid and sustained impact of SPK-RPE65 throughout the entire one-year study period. Significant differences emerged in both MT and FST by the first study visit, at 30 days. These effects were reproduced consistently at each subsequent study visit (at days 90, 180 and one year). (Phase 3 Trial of SPK-RPE65: MT and FST Over Time (mITT) Dr. Russell also presented data on the durability of effect after three years as measured by MT and FST in a cohort of subjects that participated in the Phase 1 open-label 102 study, and would likely have met the eligibility criteria for the Phase 3 trial. All of these subjects continue to experience a durable improvement over three years from the time of administration to the contralateral, or second eye, with observation ongoing. These subjects received the same dose and volume of SPK-RPE65 that was used in the pivotal Phase 3 trial. The figures below reflect data from all subjects available for follow-up at each time point reported. Spark and the clinical investigators continue to follow study participants to evaluate the durability of response, and will provide further updates in the future through a series of peer-reviewed presentations and publications. (Phase 1 Trial of SPK-RPE65: Durability of MT and FST Over Time (102-injected eye). Principal Investigator Albert Maguire, MD, professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania, will present additional data about SPK-RPE65 during the American Academy of Ophthalmology Retina Sub-specialty meeting on November 14th in Las Vegas, NV. * On October 5, 2015, Spark Therapeutics announced positive top-line results from the Phase 3 pivotal trial of SPK-RPE65, for the treatment of RPE65-mediated inherited retinal dystrophies (IRDs). 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. 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. The pivotal Phase 3 trial of SPK-RPE65 is the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease. 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). Based on these results, Spark intends to file a Biologics License Application with the FDA in 2016 as the first step in executing its global regulatory and commercialization strategy. 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: Full-field light sensitivity threshold testing (FST), which reflects underlying physiological function by measuring light sensitivity of the entire visual field. Primary outcome (ITT) * On September 9, 2015, Spark Therapeutics announced database lock for the Phase 3 clinical trial of its lead program, SPK-RPE65, for the treatment of RPE65-mediated inherited retinal dystrophies. The datasets have been transferred to the company's independent external statistical consultants, who have initiated the analysis of the data. Spark anticipates that it will provide top-line results in October. In addition, Spark reported the following modifications to its final SAP: Designation of pupillary light reflex as an exploratory endpoint and the analysis of the mobility test change score for an assigned first eye as a secondary endpoint, resulting in three secondary endpoints -- full-field light sensitivity threshold testing, the first eye mobility test change score, and visual acuity -- which will be tested hierarchically in that order; and Adjustment to the intent-to-treat (ITT) population (n=31), which will be the main efficacy analysis population, as well as addition of a modified ITT population (n=29) and clarification of a per-protocol population (n=28), both of which will be used as sensitivity efficacy analysis groups. Primary outcome (ITT) MT change score, bilateral p = 0.001 Secondary outcomes (ITT) FST, averaged over both eyes p < 0.001 MT change score, assigned first eye p = 0.001 VA, averaged over both eyes p = 0.17
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.
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:
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
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.
