When Spark Therapeutics announced positive topline results from the Phase III pivotal trial of its lead gene candidate, SPK-RPE65, last month, investigators and investors alike paid close attention because this is the first randomized, controlled Phase III trial of a gene therapy for genetic disease.

SPK-RPE65 targets the RPE65 gene, mutations in which have been linked to subtypes of Leber’s congenital amaurosis and retinitis pigmentosa. RPE65 is an enzyme that helps enable the conversion of light into electrical signals that the brain recognizes as vision. When this enzyme isn’t present or doesn’t work correctly, the inputs for vision get disrupted.

Besides meeting its primary endpoint demonstrating improvement of functional vision, the trial also showed SPK-RPE65 recipients performed better than controls across two secondary endpoints: full-field light sensitivity threshold testing and in completing an obstacle course with the worse eye.

Principal investigator (PI) Stephen R. Russell, MD, clinical director of the Stephen A. Wynn Institute for Vision Research at the University of Iowa, presented Phase III data along with data on the three-year durability of results from an earlier Phase I trial at the 48th Retina Society Scientific Meeting in Paris. Dr. Russell and co-PI Albert M. Maguire, MD, of the University of Pennsylvania, are scheduled to present more data at the American Academy of Ophthalmology 2015 meeting. Dr. Maguire, along with Jean Bennett, MD, PhD, of the University of Pennsylvania, have worked with Children’s Hospital of Philadelphia in their research.

Here, Dr. Russell provides insight into the SPK-RPE65 trials.

The mechanism of action in his words:

RPE65 is the rhodopsin kinase, the enzyme that converts vitamin A from its inactive form, which is the all-trans form, into the active high-energy form, which is the 11-cis retinal form of vitamin A. Even in patients who have mutations of the RPE65 gene, they may have some residual function, so we’ve actually called this RPE65 augmentation gene therapy.

Essentially what we’re trying to do is to instill the genes with the enzymes to create active copies of the RPE65 with as much excess as possible to drive this reaction, to create the activated vitamin A for visual transduction.

The analogy I use is that vitamin A is kind of like a mousetrap. In its extended form, it has a lot of energy built up in the molecule, and when it gets hit with the photons, like a mousetrap gets hit by a pingpong ball, that starts the cascade of visual transduction.

A comment on the topline Phase III results:

A rendering of the effect retinitis pigmentosa has on vision.
Courtesy National Eye Institute.
The mobility course results  were unequivocally positive and they matched nicely the light sensitivity increases that these patients experienced of approximately two orders of magnitude: the FST (white light), the mean difference was 2.1 log10 units, which is a little more than a 100-fold difference in light sensitivity between those that received SPK-RPE65 and those that did not; and, although the mobility test course is not precisely correlated in a geometric scale, unfortunately, it approximates that, so it was basically a 1.6 light level difference between those that received SPK-RPE65 and those that did not.

Results of the secondary endpoints:

The FST, the full field light sensitivity, was one of those endpoints, and it was confirmatory of the primary endpoint. The p values of the obstacle course result of a 1.6 light level gain (p=0.004) and for light sensitivity (p=0.001)  were outstanding for a small study with a very small number of patients.

As for the other secondary endpoints, one was the obstacle course for the first treated eye. The Food and Drug Administration was concerned with trying to differentiate whether the bilateral obstacle course results were driven by only the better-seeing eye; they wanted to see what the poorest-seeing eye contributed. In general we treated the poorer eye first and then the better-seeing eye to try to minimize any effect of amblyopia because we were recruiting subjects down to age 4. That result also was highly statistically positive.

The other secondary endpoint that got a lot of attention was visual acuity. This topline result did not show a statistically significant difference—an eight-letter difference between those that received SPK-RPE65 and those that did not—but there may have been many explanations for why there was not a statistically significant result. But, that was not one of the goals of the surgery.

The other important result of the trial:

We did not find any severe adverse events associated with either the surgery or the agent in first year. There were some minor mild to moderate adverse events, but they mostly consisted of what one might expect in the postoperative period: irritation; redness; some mild inflammation; and so on. There was no persistent inflammation, which was a concern based on the results of one of the other RPE65 trials.

How these results can help inform other trials of gene therapy:

The first thing people have been waiting on in gene therapy was to see one sort of “dart on the board” to be an example you could point to that would meet the satisfaction of the scientific community and, hopefully, the FDA (although that’s still to be determined). At least to the scientific community, we agree this appears to be efficacious, safe and of reasonable duration (although we don’t know how long term it is going to be).

The study met that criteria, and I think that’s what a lot of people have been waiting for. At this point, this is the largest success so far with gene therapy, period—not just the eye. I think that’s sort of the green light for a lot of investors, interested parties and for other investigators both within ophthalmology and outside of it.  RS