Gene Therapies Move One Step Closer to Reality

Positive top-line results from a pivotal Phase III study may result in the first gene therapy to win U.S. regulatory approval, and sent shares of the developer skyrocketing. Earlier this week, Spark Therapeutics (Philadelphia) announced its lead candidate, SPK-RPE65, was able to improve functional vision in patients with a rare form of a genetic disorder known as RPE65-mediated inherited retinal dystrophies.

SPK-RPE65 is intended to treat rare blinding conditions caused by mutations in the RPE65 gene, which is linked to subtypes of Leber congenital amaurosis (LCA type 2) and retinitis pigmentosa (RP type 20). Wall St. approved as well–Spark shares rose almost 60% to $70 in trading before the market opened the day of the announcement.

The study results represent the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease, Spark executives said. The trial enrolled 31 patients, 21 of whom received SPK-RPE65. The study met its primary endpoint of demonstrating improvement in the treated group as measured by the change in bilateral mobility testing between baseline and one year (p=.001). The treated group also outperformed control subjects across the first two secondary endpoints: full-field light sensitivity threshold testing (p<.001) and the mobility test change score for the first injected eye (p=.001). The third secondary endpoint, visual acuity, did not show statistically significant evidence of benefit (p=.17).

In the mobility test, subjects were evaluated at baseline, 30, 60, 90, 180, and 365 days 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. Patients in the treated group gained almost two light-levels of improvement; the control group gained only 0.2 levels, according to the company, and two-thirds of those treated were able to complete the course under the lowest lighting levels. Additional data will be presented this upcoming weekend at the Retina Society Annual Scientific Meeting in Pairs.

Spark estimates there are 3,500 people in the United States and five major European countries with these inherited retinal dystrophy conditions, though the treatment would not be expected to help people whose disease had progressed past a certain point.

How SPK-RPE65 differs
Theories abound that other gene thereapies have used weaker vectors than Spark’s does, and that would explain the time-limited visual improvements in other therapies that do not seem to occur with SPK-RPE65. Spark also uses a surfactant to ensure the vector doesn’t stick to the vial after injection; that may also result in a higher dose of RPE65 entering the retinal cells. To date, the vision gains seem to be stable for more than 7.5 years.

“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,” said Albert M. Maguire, MD, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania.

However, this study did not meet the secondary end point of improved visual acuity; an investor conference call suggested the company has not yet analyzed that data. Other ophthalmologists were reported as saying the therapy is primarily aimed at improving night and peripheral vision, and therefore a substantial improvement in VA was not expected.

Katherine High, MD, and colleagues at the Children’s Hospital of Philadelphia originally developed the therapy; Dr. High co-founded Spark in 2013. In a somewhat unusual move, CHOP invested $50 million in Spark’s launch and now owns more than a third of the company, a stake estimated at around $400 million.

What’s next
After the first year, patients in the control group were allowed to crossover to the SPK-RPE65 arm; results from that study (dubbed the “302 trial”) are expected some time next year.

Spark received orphan drug designation in both the United States and the European Union for the treatment of patients with a diagnosis of Leber congenital amaurosis (LCA) and retinitis pigmentosa due to RPE65 mutations. In November 2014, Spark announced that SPK-RPE65 had also received breakthrough therapy designation from the U.S. Food and Drug Administration for the treatment of nyctalopia in patients with LCA due to mutations of the RPE65 gene.

Spark plans on filing a Biologics License Agreement with the FDA in 2016.
If approved, pricing for the gene therapy may be more than off-putting for the small number of patients the therapy can potentially treat. According to Bloomberg Business, some analysts are projecting pricing at around $1 million, making it far and away the most expensive one-time treatment. (Another gene therapy launched last year in Europe for a metabolic disorder is priced at about $1.23 million per patient).

Avalanche Biotechnologies, another company investigating gene therapies for ophthalmic disorders, saw its stock plummet after results from its age-related macular degeneration gene therapy could not eliminate the need for intravitreal injections and it announced it would not move ahead with further studies.
Only time will tell if SPK-RPE65 will follow suit and have limited results over the longer term or if it will truly be the first successful gene therapy for inherited retinal dystrophies.