PARIS—Leber's hereditary optic neuropathy (LHON) is a rare, maternally inherited genetic disease that results in the degeneration of retinal ganglion cells. Patients with LHON, which consist of mostly adolescents and young adults, experience sudden loss of central vision in one eye, which is soon followed by the second eye, with poor functional visual recovery. In 97 percent of patients, vision loss in the second eye follows less than a year after vision loss in the first eye, and in 25 percent of cases, vision is lost in both eyes simultaneously.
GenSight Biologics is taking aim against this disease with GS010, and recently reported encouraging results from its Phase 3 REVERSE study.
GS010 seeks to treat LHON by leveraging a mitochondria targeting sequence proprietary technology platform. When linked with the gene of interest, this platform makes it possible to target defects within the mitochondria using an adeno-associated virus vector. This approach delivers the gene of interest into the cell where it is expressed and produces a functional protein, which is then transferred to the mitochondria to restore missing or deficient mitochondrial function.
REVERSE sought to evaluate the safety and efficacy of a single intravitreal injection of GS010 in 37 individuals who experienced vision loss due to 11778-ND4 Leber hereditary optic neuropathy (LHON) six to 12 months prior to treatment initiation. This is the last of the scheduled readouts for the trial.
In keeping with the results seen at weeks 48 and 72, best-corrected visual acuity (BCVA) in sham-treated eyes presented with a generally parallel trajectory, showing a mean improvement of -0.259 LogMAR over baseline, or a gain of +12.9 ETDRS letters equivalent at week 96. The mean BCVA improvement of sham-treated eyes was not statistically significant from that of GS010-treated eyes.
Similar to results seen in the RESCUE trial, REVERSE participants saw an initial point of low visual acuity (nadir), but recovered, with GS010-treated eyes having gained +28 more letters compared to nadir by week 96.
Low-contrast visual acuity, a second key visual function, demonstrated similar improvement in both GS010-treated and sham-treated eyes. Contrary to BCVA, however, the trajectories were not as similar, with GS010-treated eyes seeing more improvement over baseline.
Dr. Barrett Katz, chief medical officer of GenSight, noted in a conference call that “It’s important to measure contrast sensitivity and look at it because it, quite specifically, is a function of the ganglion cells, and it is the ganglion cells that are affected in this disease.”
“The data show that both the treated and the sham eye improved in both high and low contrast, defying the accepted natural history of this disease and improving upon it, based upon the clinical experiences of generations of neuro-ophthalmologists,” noted Dr. Robert C. Sergott, director, Wills Eye Hospital, Neuro-Ophthalmology and director, William H. Annesley, Jr, EyeBrain Center, Thomas Jefferson University. “The behavior of the untreated eye must also make us re-examine what we thought we knew as possibly dogma, and be open to the idea that gene therapy delivered into one eye may be able to access the contralateral eye.”
Continued efficacy was seen two years past injection, with BCVA maintaining a clinically meaningful improvement over baseline. GS010-treated eyes had a mean improvement of -0.308 LogMAR at week 96 compared to baseline, which is equivalent to +15.4 ETDRS letters or three lines on the standard ETDRS vision chart. This maintains the improvements of +14.7 ETDRS letters equivalent seen at week 72.
“We are reporting sustained improvements of visual acuity at levels that have not been achieved in any other clinical trials,” Bernard Gilly, co-founder and CEO of GenSight, said in a conference call regarding the results.
Sixty-five percent of GS010-treated eyes achieved at least a -0.2 LogMAR or +10 ETDRS letters equivalent improvement versus baseline at week 96, compared to 46 percent of sham-treated eyes. GS010-treated eyes were also more likely to improve by at least 15 ETDRS letters at week 96 from baseline, or avoid the U.S. legal blindness threshold of 20/200 at week 96 (32 percent vs. 16 percent).
In addition, a natural history study conducted by Santhera showed that 15 percent of patients with the 11778A mutation achieved spontaneous “clinically relevant recovery (CRR)” from baseline in at least one eye, which was defined by improvement by at least 10 ETDRS letters from on-chart visual acuity; or improvement from off-chart visual acuity to being able to read at least five ETDRS letters. By comparison, 68 percent of REVERSE participants achieved CRR in at least one eye at week 96.
The safety profile was encouraging, with no discontinuations and no serious adverse events in GS010-treated eyes. The most commonly reported adverse events were related to the injection procedure, as well as some cases of intraocular inflammation and increased intraocular pressure, which were likely related to GS010 and responsive to treatment.
The company is also evaluating GS010 in the Phase 3 REFLECT trial, and expects the last patient treatment to be administered in the second quarter of this year, with data from the 96-week readout of RESCUE, the second Phase 3 trial of GS010, to be available by the end of the third quarter.