GenSight Biologics announced that a phase 3 study of GS010 (rAAV2/2-ND4) in patients with Leber hereditary optic neuropathy (LHON) failed to meet its primary endpoint, with sham-treated eyes demonstrating similar improvements in vision compared to the gene therapy.
The topline results from the REVERSE phase 3 clinical trial evaluated the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 LHON commenced between 6 and 12 months prior to study treatment.
According to GenSight, topline results further highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters (-0.218 LogMAR) in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters (-0.211 LogMAR). Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks.
The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8 to 22% of patients with the G11778 ND4 mutation (Lam et al. 2014, Riordan-Eva et al. 1995). “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. 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,” Bernard Gilly, Chief Executive Officer of GenSight, said in a company news release.
“The fact that structural measures of the retina showed such a large statistical difference with treatment is compelling and objective evidence that this gene therapy protects the integrity of many retinal ganglion cells from the damage of LHON,” commented Pr. José-Alain Sahel, Director of the Institut de la Vision (Sorbonne-Universités/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 Medical Center, and co-founder of GenSight Biologics.
The objectively measured endpoints were the effects of GS010 on parameters measured with high resolution Spectral-Domain Optical Coherence Tomography (SD-OCT). The critical secondary endpoint of the change in retinal ganglion cell macular volume measured from baseline to week 48 demonstrated a statistically significant difference (P = 0.0189) between all GS010-treated eyes and all sham-treated eyes, with untreated eyes losing 0.038 cubic mm of macular ganglion cell volume while treated eyes preserved their ganglion cell volume (-0.003 cubic mm).
The secondary endpoint of change in thickness of the temporal quadrant and papillomacular bundle of the retinal nerve fiber layer from baseline to week 48 demonstrated a large statistically significant difference (P = 0.0359) between all GS010-treated eyes and all sham-treated eyes, with untreated eyes showing a loss of 3.4 μm while treated eyes showed a limited loss of 0.6 μm.
"Preliminary optical coherence tomography [OCT] results from the REVERSE trial indicate that the biological targets of the mitochondrial DNA gene therapy have been successfully engaged in the treated eye compared to the untreated eye. The bottom line: we have excellent news for LHON patients and their families about their vision, which is remarkable for a previously untreatable disease," Dr. Robert C. Sergott, Director, Wills Eye Hospital, Neuro-Ophthalmology and Director, William H. Annesley, Jr, EyeBrain Center, Thomas Jefferson University, Philadelphia, said in the news release.
Based on preliminary analysis of the safety data, GS010 was well tolerated after 48 weeks. The ocular adverse events most frequently reported in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation (accompanied by elevation of intraocular pressure in some patients) that is likely related to GS010, and which was responsive to conventional treatment and without sequelae. There were no withdrawals from the trial.
A full assessment of the data is ongoing, and detailed results are expected be presented at a major upcoming medical meeting.
GS010 is currently being investigated in two additional ongoing phase 3 trials, RESCUE and REFLECT, while patients in REVERSE continue to be followed for another 4 years. RESCUE is a randomized, double-masked, sham-controlled phase 3 trial designed to evaluate the safety and efficacy of a single intravitreal injection of GS010 in subjects affected by LHON with < 6 months of onset of vision loss. GenSight expects to report topline data for RESCUE in the third quarter of 2018. REFLECT is a randomized, double-masked, placebo-controlled phase 3 trial evaluating the safety and efficacy of bilateral injections of GS010 in patients with < 1 year of onset of vision loss in LHON. The first patient in REFLECT was treated in March 2018.