PARIS—GenSight Biologics recently announced results from the first scheduled readout, at Week 48, of the RESCUE Phase 3 clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 39 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) occurred up to 6 months prior to study treatment. These subjects received GS010 in one eye and a sham injection in the other eye, with drug treatment randomized between best- and worst-affected eyes.
Visual loss in LHON usually progresses such that vision reaches a nadir in 3 to 5 months, before stabilizing; the duration of this progression to nadir varies from patient to patient. In RESCUE, mean best-corrected visual acuity (BCVA) of GS010-treated eyes and sham-treated eyes evolved with similar trajectories, worsening to a low point before showing an improvement at Week 48.
At Week 48, change from baseline for GS010-treated eyes was -19 ETDRS letters equivalent, while that for sham-treated eyes -20 ETDRS letters equivalent. These figures incorporate a recovery from the nadir of vision loss for drug- and sham-treated eyes: mean improvement over the nadir of vision loss was +13 ETDRS letters equivalent in GS010-treated eyes and +11 ETDRS letters equivalent in sham-treated eyes. The primary efficacy endpoint, defined as a +15-letter difference in visual acuity improvement for GS010-treated eyes compared to sham-treated eyes at 48 weeks, was not met.
“The powerful and rapid degeneration of neurons early in the disease, combined with the time needed for GS010 to cause functioning proteins to be expressed, may be confounding efficacy measurements early in the active progression phase,” noted Dr. José-Alain Sahel, Director of the Institut de la Vision (Sorbonne-Université/Inserm/CNRS), Paris; Chairman of the Department of Ophthalmology at Centre Hospitalier National d’Ophtalmologie des XV-XX, Paris; Professor and Chairman of the Department of Ophthalmology at University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center (UPMC); and co-founder of GenSight.
Planned analysis of other visual functions and anatomic measures showed results broadly consistent with the direction of BCVA evolution: similar trajectories for GS010-treated and sham-treated eyes with the difference in change from baseline not being statistically significant at Week 48. The difference between GS010-treated and sham-treated eyes in change from baseline of temporal retinal nerve fiber layer missed statistical significance (p=0.0513). The changes from baseline in GS010-treated eyes of papillo-macular bundle thickness and ganglion cell volume were numerically superior to those in sham-treated eyes, though not statistically significant (p values > 0.05).
Even at an early readout at Week 48, some trends point toward GS010 efficacy. GS010-treated eyes were significantly more likely than sham-treated eyes to have 20/200 or better vision, the threshold for legal blindness (statistically significant with p=0.0347; odds ratio = 2.9). Subject responder analysis showed that in 24% of subjects, the change from baseline of high-contrast visual acuity in GS010-treated eyes was at least 0.3 LogMAR (15 ETDRS letters) better than in sham-treated eyes. Another subject responder analysis showed that in 24% of subjects, the change from baseline of low-contrast acuity (measured on the Pelli-Robson scale) in GS010-treated eyes was at least 0.3 LogCS better than in sham-treated eyes.
“In our REVERSE trial, which included patients with vision loss between 6 and 12 months prior to treatment, we saw more improvement in both anatomic measures and visual functions as the disease entered its chronic phase. The planned readouts of RESCUE data at Weeks 72 and 96 should confirm GS010’s efficacy,” added Dr. Barrett Katz, Chief Medical Officer of GenSight.
Based on preliminary analysis of the safety data, GS010 was well-tolerated through 48 weeks. There were no serious ocular adverse events or discontinuations due to ocular issues. The most frequently seen ocular adverse events were related to the injection procedure itself. Transient elevations of intraocular pressure were occasionally seen but were thought secondary to intraocular inflammation and thought likely due to administration of GS010. Such episodes were without sequelae and responded to conventional treatment. There were no systemic serious adverse events or discontinuations related to study treatment or study procedure.
RESCUE subjects will be evaluated again at 72 and 96 weeks; results are expected to be available in Q2 (April) and Q3 2019, respectively. Week 96 data will be available in Q2 (May) 2019 for the REVERSE trial; its data will be unblinded at this evaluation, allowing subject-level analyses to be conducted.
“As expected, the RESCUE results at Week 48 present a more complex picture because of the intense, brutal and extremely rapid onset of the retinal ganglion cells’ degeneration,” said Bernard Gilly, co-founder and Chief Executive Officer of GenSight. “But as with REVERSE, later readouts are likely to confirm our confidence in the efficacy of GS010. We eagerly await these upcoming readouts, even as we prepare to discuss the results with the relevant authorities. We remain committed to bringing GS010 as early as possible to the market so that LHON patients can have an effective treatment for their relentlessly blinding disease.”
The third interventional study for GS010, REFLECT, is a randomized, double-masked, placebo-controlled Phase 3 trial evaluating the safety and efficacy of bilateral injections of GS010 in patients up to one year from onset of vision loss due to LHON. The first patient in REFLECT was treated in March 2018.