GenSight Biologics reported additional results from the REVERSE phase 3 clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4)in patients with Leber Hereditary Optic Neuropathy (LHON). The study involved 37 patients with visual loss due to 11778-ND4 LHON.
Topline results, reported in April, showed that the clinically significant improvement of +11 ETDRS letters (-0.218 logMar) in GS010-treated eyes was matched by an unexpected improvement of +10 ETDRS letters (-0.211 LogMAR) in the sham-treated eyes. This caused the study not to meet its primary endpoint predefined as a +15 ETDRS letters difference in visual acuity between GS010- and sham-treated eyes.
At the same time, the study successfully met secondary endpoints defined by Spectral-Domain Optical Coherence Tomography (SD-OCT) parameters, specifically the change in ganglion cell layer macular volume measured from baseline to week 48 and change in thickness of the temporal quadrant of the retinal nerve fiber layer from baseline to week 48. These results demonstrated a direct biologic and physiological impact of GS010 on the anatomy relevant to LHON.
Further analyses now demonstrate that, although some secondary endpoints did not show significant or meaningful changes, contrast sensitivity as determined by Pelli-Robson low‑vision testing almost doubled in the GS010‑treated eyes compared to sham‑treated eyes. GS010‑treated eyes started with lower contrast sensitivity (0.25 LogCS on average) than sham-treated eyes (0.35 LogCs on average). At week 48, GS010‑treated eyes gained on average +0.20 LogCS, and the contrast sensitivity in sham-treated eyes remained stable (+0.08 LogCS on average).
As per protocol, all 37 subjects will be evaluated again at 96 weeks, and data will be reported in the first quarter of 2019.
In addition, post hoc analyses revealed trends that suggest GS010 may have a larger positive impact on the visual acuity of patients at relatively less advanced or severe stages of the disease:
- Subjects who entered study with better vision (on-chart eyes) tended to have better clinical outcomes. At week 48, in on‑chart best-seeing eyes, GS010‑treated eyes gained on average +12 ETDRS letters (-0.236 LogMAR) compared to +4 ETDRS letters (-0.075 LogMAR) in sham‑treated eyes.
- Subjects whose vision loss was less than 9 months tended to have better clinical outcomes. 75% of GS010-treated eyes that showed a trend in visual acuity improvement at week 48 had vision loss for less than 9 months at time of treatment administration.
- Subjects who were younger (< 21 years) at enrollment tended to have better clinical outcomes
“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,” Dr. Barrett Katz, Chief Medical Officer of GenSight, said in a company news release. “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.”
“Although the clinically meaningful bilateral improvement of visual acuity observed in most subjects remains to be further explained, it is undoubtedly a wonderful outcome for patients and their families,” commented Bernard Gilly, Chief Executive Officer of GenSight. “We are now going to discuss the full results with regulatory authorities so that we are aligned on how best to bring GS010 to market with our existing phase 3 program within our defined timelines.”
The full set of data and post hoc findings will be presented and discussed at a Key Opinion Leader (KOL) Event today in New York City from 8.30 a.m. – 11:00 a.m. EST. Medical experts, consisting of specialists who were investigators in the trial and key opinion leaders in neuro-ophthalmology and ophthalmology, will introduce LHON and its natural history, present the findings and discuss their significance in a panel discussion. Lissa Poincenot, a leading patient advocate, will present her perspectives on what the results mean for patients and their caregivers. To conclude the session, Bernard Gilly will share the company’s regulatory strategy and upcoming consultations with the FDA and EMA to remain on track with its goal of submitting dossiers as planned in Q2 2019.