Wednesday, October 14, 2015

Gene Therapy in Ophthalmology Update 22: First Spark Therapeutic Phase III Clinical Trial Results and Phase I Longevity Data

My article updating the latest information on the status of gene therapy clinical trials, What’s New in Gene Therapy for Ophthalmology? was published in the October issue of Retinal Physician. The final draft was submitted just prior to this important news from Spark Therapeutics providing information about their Phase III clinical trial results.

Principal Investigator Stephen R. Russell, MD, of the Stephen A. Wynn Institute for Vision Research at the University of Iowa, presented Phase III data highlighting the rate, breadth and magnitude of changes following administration of SPK-RPE65 to patients with Leber’s Congenital Amaurosis (LCA), at the Retina Society Meeting held in Paris on October 10th.

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 the earlier Phase I trial.

This presentation built on top-line results of a randomized controlled multi-center Phase III trial previously 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.

Significant Improvements and Strong Parallels in Mobility and Light Sensitivity Testing

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).

(*FST is a full-field light sensitivity threshold test. As RPE65-mediated retinal dystrophies primarily affect rod photoreceptors first, night blindness and loss of peripheral vision are typically the presenting symptoms; central vision may be relatively spared initially. Thus FST was the first hierarchically-arranged secondary as opposed, for example, to visual acuity. It is more reflective of the underlying pathophysiology of the disease.)

Dr. Russell presented additional top-line analyses from the pivotal Phase III 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).

Dr. Russell said, "It's exciting to see a consistency of improvement between the functional vision and visual function. The parallel effect seen in the prompt response in both the primary and first secondary endpoints highlights a critically important finding from the trial: that functional improvements measured through the mobility test change score correspond closely with the physiologic impact seen through FST."

Figure 1: Phase III Trial of SPK-RPE65: MT and FST Over Time (mITT)

In addition, Dr. Russell 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 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.

"We are pleased to provide these additional informative data, the totality of which highlight the rapid, sustained and durable effect associated with SPK-RPE65 across multiple functional and physiological parameters, at time points ranging from 30 days to three years," said Jeffrey D. Marrazzo, co-founder and chief executive officer of Spark. "We will continue to analyze the data from our groundbreaking pivotal Phase 3 trial in order to further elucidate the potential positive, meaningful impact that SPK-RPE65 can have on the lives of patients with RPE65-mediated blinding conditions."

Figure 2: Phase 1 Trial of SPK-RPE65: Durability of MT and FST Over Time

Pivotal, Phase 3 Trial Overview

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 (LCA) 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.

A summary of top-line efficacy results follows:

Primary outcome (ITT)    
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
VA, averaged over both eyes                p = 0.17

So What Does All This Mean?

In a story about the trial results published by Bloomberg Business News, the reporters commented, “A gene therapy maker showed this week it could make blind children and adults see. But the big question left is how long the effect will last.”

“Much depends on the answer, including how much the company can charge for the drug -- a price tag some say could be more than $1 million a patient.”

The company has shown the effect has lasted for as long as three years without degradation of vision in some patients, providing back functional vision to those nearly blind children treated in the initial clinical trial.

According to Dr. Russell, the principal investigator, "Investors will look at the data and are going to go, `Wow this is the best data we've seen, not just in the eye, but on gene therapy, period' and they're right,"

Yet he cautioned that more information is needed before the drug can be considered a cure. While it produces a missing enzyme needed to sense light, it can't restore light-sensing cells that have already died off due to this progressive disease. In the initial study results, released on October 5th, one standard measure of vision, visual acuity, didn't improve by a statistically significant amount. (But, functional vision did!)

Spark also hasn't finalized and published data on individual patients, and it's possible that some responded better than others. “Age in particular may be a factor in how much a patient can improve,” said Dr. Russell. The company said in its statement that no serious adverse events have been seen so far in the trial.

So, the question remains, is this the “forever fix”, as author Riki Lewis has written in her book on gene therapy, or something less? Time will tell. But this is certainly an important step forward for the treatment of an inherited retinal disease.


1.  What’s New in Gene Therapy for Ophthalmology?, Irv Arons, Retinal Physician, October 2015.

Stephen R. Russell MD, Retina Society Meeting, Paris, Stephen R. Russell MD, October 10, 2015.

5. 'Holy Grail' Seen as Gene Drug for Blind Produces Lasting Effect, Caroline Chen & Robert Langreth, Bloomberg Business News, October 10, 2015.


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