Gensight Biologics uses allotopic expression of a mitochondrial gene, ND4, to attempt to treat the inherited blindness condition Leber hereditary optic neuropathy, in which this gene is mutated and dysfunctional. An altered copy of ND4 is introduced into the cell nucleus, and the protein produced is delivered back to the mitochondria where it is needed for correct function. A fairly standard gene therapy is used to deliver this payload into the retina. Unfortunately, after promising results from earlier trials and technology demonstrations, their late stage trials are failing.
It remains to be seen as to why this is the case. Earlier work makes it clear that the technology works in principle. It is possible that intervening too late cannot clear out enough of the damage already done, and that damage makes further decline inevitable, or recovery difficulty. This is a systemic problem for many conditions, given the way in which the structure and enormous cost of clinical trial regulation pushes companies towards the late stage of the disease, rather than earlier, preventative treatment. Equally, it may be that this formulation of the allotopic expression gene therapy isn't achieving a great enough coverage of retinal cells to produce reliable benefits. There are many possible reasons for failure.
A phase 3 trial of GenSight Biologics' Leber hereditary optic neuropathy (LHON) gene therapy has missed its primary endpoint. The AAV gene therapy was no better than placebo at improving vision at 48 weeks, leading GenSight to look to future updates to salvage the study. GenSight designed GS010 to improve the vision of patients with a particular mutation in the mitochondrial ND4 gene and moved the gene therapy into a pair of phase 3 trials in 2016. One trial enrolled patients who had suffered vision loss for 6 to 12 months. The other recruited people whose vision loss began less than six months ago. Both trials missed their primary endpoints.
The latest clinical setback involves LHON patients with six months or less of vision loss enrolled in the RESCUE trial. As in the other study, GenSight set out to link GS010 to a 15-letter improvement over placebo on a vision test. Each subject received GS010 in one eye and a sham injection in the other. This time around, the eyes treated with GS010 deteriorated by 19 letters over the first 48 weeks of the trial, compared to a 20-letter decline in the control cohort. The top-line figures hide a trend that shows vision in both arms of the trial declined before improving. Eyes treated with GS010 improved by 13 letters from their low point, while the placebo group recorded an 11-point improvement.
The trial failed to show GS010 is statistically superior to placebo against secondary endpoints, too. After 48 weeks, GS010 statistically had no more effect on the temporal retinal nerve fiber layer, papillomacular bundle thickness and ganglion cell volume than placebo. While GS010 outperformed the sham treatment on some other measures, the overall data set offers little encouragement that the gene therapy is effective at 48 weeks. The question is whether it will become effective as more weeks pass. GenSight thinks it will, in part because of its experience with the other phase 3 trial.