PARIS—Additional results shared in June from GenSight Biologics’ Phase 3 clinical trial, REVERSE, are building on previous encouraging data for its GS010 compound. REVERSE is a randomized, double-masked, sham-controlled pivotal Phase 3 trial evaluating the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 Leber hereditary optic neuropathy (LHON) patients with the G11778A mutation in the mitochondrial ND4 gene.
LHON is a rare maternally inherited mitochondrial genetic disease in which the degeneration of retinal ganglion cells leads to irreversible vision loss. Vision is suddenly lost in one eye, and the second eye is sequentially impaired—while 97 percent of patients experience bilateral involvement at less than one year of the beginning of their vision loss, a quarter of patients lose vision in both eyes simultaneously. An estimated 1,400 to 1,500 individuals lose their sight as a result of LHON in the United States and Europe every year.
GS010 uses a mitochondrial targeting sequence proprietary technology platform that resulted from research performed at the Institut de la Vision. When linked with a gene of interest, the platform can specifically target defects in mitochondria using an AAV vector. The gene of interest is transported into the cell, where it is expressed and produces a functional protein, which is then moved to the mitochondria to restore missing/deficient mitochondrial function.
GenSight shared top-line results in April that demonstrated that the improvement of +11 ETDRS letters (-0.218 logMar on average) in GS010-treated eyes, which was clinically significant, was matched by an improvement of +10 ETDRS letters (-0.211 LogMAR) in the sham-treated eyes. This fell short of the study’s primary endpoint of a +15 ETDRS letters difference in visual acuity between GS010- and sham-treated eyes.
The study did meet its secondary endpoints based on spectral-domain optical coherence tomography (SD-OCT) parameters, such as the change in ganglion cell layer macular volume from baseline to week 48, and the change in thickness of the temporal quadrant of the retinal nerve fiber layer from baseline to week 48. In addition, contrast sensitivity—per Pelli-Robson low-vision testing, a more sensitive method of evaluating visual function—almost doubled in GS010-treated eyes compared to sham-treated eyes.
“-0.21 log units is about 11 to 12 letters,” Dr. Robert Sergott, professor of neurology and ophthalmology at Thomas Jefferson University, remarked in the webcast. “We set a high bar this trial—15 letters. If you get a 15-letter improvement, you double your visual angle, and regulatory agencies will allow you to label your product as one that gives vision improvement. The most common intravitreal injections are the anti-VEGF agents in the retinal community, for diabetes, macular degeneration of the wet variety. How much improvement do they get? Seven letters; this far exceeded [that].” Sergott is also the director of neuro-ophthalmology at Wills Eye Hospital and director of the William H. Annesley, Jr. EyeBrain Center.
The exact cause of the improvement in the sham-treated eyes is unknown, but it could be based in part on the fact that molecules can travel from one eye to the contralateral optic nerve, GenSight noted in its presentation. The company hypothesizes that GS010 is systemically absorbed, and as such, a smaller dose makes its way to the untreated eye.
As noted in the presentation, this is the first demonstration of neuro-protection of both central nervous system AXONS and neurons in a human genetic disease.
“Examining the totality of the data, the REVERSE results suggest a therapy that may provide meaningful bilateral improvement of vision for our subjects, which is not what would be expected from the natural history of this disease. Our planned follow-up of REVERSE subjects will enable us to monitor the observed continuous bilateral improvement after another year,” said Dr. Barrett Katz, chief medical officer of GenSight. “GS010-treated eyes were significantly more likely to achieve vision of 20/200 or better when compared to sham-treated eyes. In addition, trends suggest a potentially larger benefit for subjects at earlier stages of LHON. We eagerly await what data from the RESCUE trial will show.”
Based on post-hoc analyses, it is thought that patients at less advanced stages of LHON could see a better benefit from GS010. Participants who enrolled with better vision had better clinical outcomes, and 75 percent of GS010-treated eyes that saw improvement at week 48 were those that had had vision loss for less than nine months at the time of treatment.
Study subjects will be evaluated again at 96 weeks, with that data set to be available in the first quarter of 2019.
Bernard Gilly, co-founder and CEO of GenSight, said in the webcast that “The company—myself, and the management of this company—is absolutely determined to move this product into the approval process ...We will move this forward to the European Agency, and to the FDA as well. We are going to make all effort possible to make this happen, to make this become a product available to the patient as soon as we can.” Per the presentation, GenSight intended to send out a Scientific Advice packet on June 5 to regulatory bodies, with a response expected in the third or fourth quarter.
