Phase III studies of a gene therapy for Leber hereditary optic neuropathy have generated some unexpected positive findings. There is biologic plausibility to explain the data.
Reviewed by Robert C. Sergott, MD
RESCUE, the phase III study investigating GS010 (GenSight Biologics) for Leber hereditary optic neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation in patients with up to six months of vision loss, did not meet its primary endpoint. Data from secondary outcome measures and from a longer follow-up in RESCUE and in a completed phase 3 trial that enrolled patients with a longer history of vision loss (REVERSE), however, provide strong signals of efficacy, including a potential benefit in untreated fellow eyes. The collective clinical trial experience also shows that the gene therapy is well-tolerated and has an acceptable safety profile.
“The GS010 phase III trials are rigorously designed and conducted studies, and any well-done clinical trial often generates unexpected findings,” said Robert C. Sergott, MD, director, Wills Eye Hospital, Neuro-Ophthalmology and founding director, William H. Annesley, Jr., EyeBrain Center, Thomas Jefferson University, Philadelphia, which is the central reading center for the GS010 phase III studies.
Dr. Sergott said the researchers could not fully explain the results from the GS010 trials. “There is reason to be encouraged, however, and to be hopeful that as we go forward and more data become available, we will begin to better understand the outcomes,” he explained. GS010 is a recombinant adeno-associated viral vector serotype 2 containing the wild-type ND4 gene.
In both RESCUE and REVERSE, enrolled patients received a single intravitreal injection of GS010 in one randomly selected eye and a sham injection in the fellow eye. The primary outcome measure in RESCUE looked at ETDRS best-corrected visual acuity (BCVA) at week 48 post-injection. To meet the primary endpoint, the results had to show a +15-letter difference in BCVA favoring the GS010-treated eyes compared to sham.
The primary endpoint analysis showed, however, that there was essentially no difference between groups. Eyes treated with GS010 had a mean BCVA loss of 19 ETDRS letters compared with baseline while on average, sham-treated eyes had a loss of 20 ETDRS letters. As expected and consistent with the natural history of LHON, mean BCVA in both groups declined after study entry and reached a nadir.
The GS010- treated eyes achieved a mean BCVA improvement of 13 ETDRS letters relative to the nadir while shamtreated eyes improved by a mean of 11 letters. Data from RESCUE that supports the efficacy of GS010 included the finding that GS010-treated eyes were threefold more likely than sham-treated eyes to have 20/200 or better BCVA at week 48 (p=0.0247).
In addition, an analysis comparing outcomes between fellow eyes in individual patients showed that the change from baseline of high-contrast visual acuity was at least 0.3 LogMar (15 ETDRS letters) better in the treated eye than in the sham-treated eye in 24% of subjects. A similar result was obtained in an analysis comparing improvements in low-contrast visual acuity, which is a more sensitive measure of visual function than high-contrast visual acuity, said Dr. Sergott.
Robert C. Sergott, MD
Dr. Sergott did not indicate any proprietary interest in the subject matter.