Gene therapy for LHON

Researchers encouraged by clinical trial results, but puzzled by outcomes

Sean Henahan

Posted: Thursday, November 1, 2018

Despite some unexpected but very promising results in late-stage clinical studies, researchers remain optimistic about the therapeutic potential for a novel gene therapy candidate for the treatment of Leber hereditary optic neuropathy (LHON).

José-Alain Sahel MD presented an update on clinical trials with rAAV2/2-ND4 (GS010, GenSight Biologics), a gene therapy that targets LHON. He presented Phase I/II 18-month results at the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting in Honolulu. Speaking immediately before ARVO, Dr Sahel also presented Phase III data from the REVERSE trial at the 5th Annual Retinal Cell and Gene Therapy Innovation Summit. In June 2018, he presented more extensive data at the World Ophthalmology Congress in Barcelona.

The apparent good news is that patients receiving a single intravitreal injection of GS010 in the worse seeing eye showed clinically meaningful improvement of +11 ETDRS letters at the 48-week mark. The confounding news is that fellow eyes receiving sham injections did almost as well, showing an improvement of +10 ETDRS letters, not expected given all that is known about the natural history of the disease. The lack of statistically significant difference between the groups meant that the study did not meet its primary endpoint, defined as a 15-letter difference in visual acuity between active and sham-treated eyes. The study did not include a true control or untreated group.

Nonetheless, the study did meet secondary endpoints, measured as a change in ganglion cell layer macular volume as demonstrated with spectral domain optical coherence tomography (SD-OCT). These measurements showed a statistically significant difference in retinal ganglion cell macular volume measured from baseline in GS010-treated eyes compared to sham-treated eyes. Eyes receiving the sham injection showed a loss of 0.038 cubic mm of macular ganglion cell volume, while treated eyes preserved their ganglion cell volume. A statistically significant difference was also observed between GS010– and sham-treated eyes for the change in thickness of the temporal quadrant of the retinal nerve fibre layer – where the ever-important papillo-macular bundle lives – showing relative preservation from baseline to week 48. These findings would appear to be the first case of a treatment producing neuroprotection of neurons and central nervous system axons in human genetic disease.

Eyes receiving the experimental agent also showed clinically significant improvement in contrast sensitivity, a meaningful metric of visual function more applicable to real-life conditions, while those receiving sham injections remained stable. Pelli-Robson evaluations indicated that logCS, a measure of contrast sensitivity, almost doubled in the GS010-treated eyes compared to sham-treated eyes.

This conglomeration of evidence suggests that GS010 treatment had a direct biologic and physiological impact of GS010 on the anatomy relevant to LHON, according to Dr Sahel, who is the director of The Vision Institute, Paris, France and Chairman of the Department of Ophthalmology at the University of Pittsburgh. Dr Sahel is also a scientific co-founder of GenSight Biologics.

The researchers also found hopeful hints in post hoc analyses. For example, those patients who began the study with better visual acuity showed a trend towards better outcomes, improving by 12 letters at 48 weeks compared with the sham group’s four-letter improvement.

Another interesting observation was that visual acuity improvement was far more likely to occur in patients with a history of vision loss of less than nine months prior to treatment. Patients less than 21 years old also tended to do better.

All 37 participants in the REVERSE trial will be evaluated again at 96 weeks. Those data are expected to be reported in early 2019. Follow-up studies will be conducted out to five years.

LHON is a maternally inherited disorder associated with a mutation in mitochondrial DNA. GS010 was designed to rescue retinal cells affected by the G11778A mutation of the mitochondrial ND4 gene. It is delivered by a single intravitreal injection via an adeno-associated virus vector. The therapeutic gene produces a functional protein that restores the deficit in mitochondrial function.

The REVERSE study is one of three ongoing Phase III clinical studies now under way with GS010. The patients enrolled in REVERSE have a history of vision loss of six months to one year, while the RESCUE trial is applying the identical approach in patients presenting with vision loss of six months or less prior to treatment.

A multi-centre randomised double-blind, placebo-controlled study, dubbed the REFLECT study, is now enrolling patients. That study plans to enrol 90 LHON patients who will receive either bilateral intravitreal injections of GS010, or an injection of GS010 in one eye and a placebo injection in the fellow eye.

José-Alain Sahel: