LHON: Gene therapy for Leber’s hereditary optic neuropathy

Pivotal efficacy studies under way evaluating novel platform that restores mitochondrial function

Cheryl Guttman Krader

Posted: Monday, December 5, 2016


Phase III trials are now under way evaluating gene therapy for Leber’s hereditary optic neuropathy (LHON) due to the G11778A mitochondrial ND4 DNA mutation, said Scott Uretsky MD at the 2016 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Seattle, USA.
The investigational therapy, GS010 (GenSight Biologics, SIGHT.PA), is administered by intravitreal injection. It is a recombinant adeno-associated viral vector serotype 2 carrying the wild-type mitochondrial ND4 gene (rAAV2/ND4) and uses novel proprietary technology that allows localisation of the wild-type protein to the mitochondrion in order to restore mitochondrial function.
The double-masked phase III trials, RESCUE and REVERSE, each plan to enrol 36 patients at sites in Europe and the USA. Patients will receive a single injection of GS010 (dose 9E10 viral genomes/90 μL) in one randomly selected eye and sham procedure in the contralateral fellow eye. RESCUE is enrolling patients with vision loss duration of up to six months, and patients eligible for REVERSE will have vision loss duration ranging from >six months to one year. The primary outcome measure in both studies is change in ETDRS visual acuity (VA) from baseline to week 48.
“ND4 is the most common mutation in LHON and carries the worst clinical prognosis. We hope that treatment with rAAV2/ND4 can halt, reverse, or even prevent further vision loss in patients with LHON caused by the ND4 mutation,” said Dr Uretsky, Medical Director, GenSight Biologics, Paris, France.
“Results from a phase I/IIA trial showed that intravitreal GS010 had a good safety and tolerability profile. The study was not powered for efficacy, but the preliminary findings were encouraging, and not surprisingly showed that shorter vision loss duration and better baseline status impacted the magnitude of the treatment effect. This information supports the protocol strategy of the phase III programme based on the notion that time is vision,” he added.
The single-centre phase I/IIA safety and tolerability study had an open-label dose-escalating design. Eligible patients had VA worse than 20/200 and received a single intravitreal injection of rAAV2/ND4 in the worse-functioning eye.
No systemic or serious adverse events related to the gene therapy were recorded. The most common ocular adverse events were intraocular pressure (IOP) elevation and ocular inflammation.
“Despite anterior chamber paracentesis pre-injection, IOP elevation was not unexpected considering the injection volume of 180μL is two to three times the volume administered for most intravitreous medications. We have lowered injection volume in the phase III studies that will reduce the occurrence of IOP elevations, of which all have been fully reversed and controlled,” Dr Uretsky said.
Elevated IOP levels ranged from 23 to 38mmHg, but the elevations were transient and either resolved spontaneously or were reversible with topical IOP-lowering treatment. No patient required paracentesis post-injection.
Ocular inflammation, manifesting in the anterior chamber or vitreous, was also expected, based on findings in preclinical studies. It was mostly mild, and in two patients the reaction was severe and oral corticosteroid treatment was given. Other patients received topical anti-inflammatory therapy, and there were no visual or ocular sequelae related to the inflammatory events.
Immunogenicity was also assessed through assays of AAV2 neutralising antibodies in the serum. Ten patients had an increased titre post-injection that neither correlated with the baseline antibody level or GS010 dose.
“Importantly, there was no consistent correlation between the occurrence or severity of ocular inflammation with either baseline immune status or change of immune status after injection,” Dr Uretsky said.

Analyses of logMAR VA data from patients who had reached week 48 of follow-up showed that in eyes with vision loss of less than two years, there was a three-line difference in mean change from baseline comparing the treated and untreated eyes. Visual field and colour vision outcomes were also better when duration of vision loss was less than two years.
“These outcomes are consistent with LHON being a neurodegenerative disease. In stroke patients, we say ‘time is brain’. In LHON, we think time is vision,” Dr Uretsky said.
“Now we will see if these promising efficacy findings are sustained when data from all the phase I/IIA patients are analysed and in the ongoing phase III trials.”

Scott Uretsky:

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