Dive Brief:

• GenSight Biologics SA on April 3 announced topline results from the Phase 3 REVERSE trial that evaluated a single, intravitreal injection of its gene therapy candidate GS010 in 37 subjects with an inherited, degenerative eye disease who began losing their vision shortly before the start of the study.
• The data showed a meaningful improvement of visual acuity in treated eyes at 48 weeks as compared to baseline for all 37 patients. Patients were given bilateral treatment, meaning one eye was injected with GenSight's candidate, and the other eye was injected with placebo. Curiously, an improvement in visual acuity was seen in both eyes of subjects.
• That improvement in untreated eyes caused the trial to miss its primary endpoint, which was based on the comparison between eyes. GenSight's stock trades on the Paris stock exchange and shares fell by nearly half in value Wednesday morning.

Dive Insight:

The field of transferring healthy genetic material to diseased cells has received new energy in recent years. One of the easiest targets seems to be the eye, as genetic material can be injected directly into it. This delivery method can be beneficial because the corrective genetic material is thought to have a better chance of being incorporated into the host's genome.

Spark Therapeutics Inc.'s recently approved Luxturna (voretigene neparvovec-rzyl), a gene-replacement therapy for inherited vision loss related to the RPE65 gene, is the highest-profile example of this type of treatment. Yet there are many experimental gene therapies currently in the works that also deal with disorders of the eye.

REVERSE enrolled patients with 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) who started losing their eyesight between six and 12 months prior to study. Investigators then compared improvement in visual acuity for GS010-treated eyes compared with sham-treated eyes at 48 weeks.

GS010 led to improved visual acuity in treated eyes by 11 letters on a scale known as ETDRS. Troubling for GenSight, however, is the nearly identical improvement seen in patients treated with the sham.

"This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease," GenSight CEO Bernard Gilly said in a statement. "We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood."

GenSight reasoned the gene therapy administered to one eye could have protected the integrity of many retinal ganglion cells in the other, placebo-treated eye, possibly explaining the benefit seen across all eyes.

Despite not meeting the study's primary endpoint, GenSight's candidate did slow the loss of thickness in the temporal quadrant and papillomacular bundle of the eye's retinal nerve fiber layer. Untreated eyes treated with placebo showed a loss of 3.4 μm, while treated eyes showed a loss of 0.6 μm.

The bilateral benefit GenSight described has actually been seen in other clinical trials looking at gene therapy for retinal disorders.

In a 2016 study looking at gene therapy for LHON, eight patients received unilateral gene therapy, and visual function improvement was observed in both treated eyes and untreated eyes. There was one patient who received bilateral gene therapy, and in this patient, both eyes improved — but visual acuity in the first eye that was treated decreased three months after that patient received gene therapy in the second eye, a phenomenon the researchers chalked up to either coincidence or a humoral immune response to the AAV2 delivery vector after gene therapy was administered in the first eye.

It is worth mentioning, however, that both trials looked at replacement of the G11778A ND4 mitochondrial mutation, the most common point mutation that leads to the development of LHON.

GenSight's study observed patients for a year post-treatment, and it says it will follow patients in the REVERSE trial for another four years. That may not be a long enough time period to actually conclude that eyesight has improved, however. In human models, gene therapy improves vision for only up to six years, according to a 2014 analysis.

The company's stock, which trades on the Paris stock exchange, plummeted nearly 50% to €2.96 per share from Tuesday's market close through Wednesday morning.