Long-term gene therapy for wet AMD promising

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The first results from a phase I trial of gene therapy for exudative age-related macular degeneration using a subretinal injection suggest that the treatment is safe and well tolerated even in the elderly population and may eliminate the need for frequent reinjection with anti-vascular endothelial growth factor agents.

Reviewed by Elizabeth Rakoczy, MSc, PhD

Perth, Australia-Preliminary encouraging data on long-term gene therapy for exudative age-related macular degeneration (AMD) have been released. In the phase I trial, a single subretinal injection of rAAV.sFlt-1-a viral vector used to deliver a gene that expresses a therapeutic protein in the eye-was safe and well tolerated.

Treated subjects showed gains in visual acuity and a reduction in center point retinal thickness, and rescue therapy was rarely needed.

“The safety is excellent, and we have seen long-term benefits for the patients from this approach,” said Elizabeth Rakoczy, MSc, PhD, professor and director of molecular ophthalmology at the Centre for Ophthalmology and Visual Science, the University of Western Australia, Perth. “Patients who receive our treatment do not need any retreatments, or very few, and the growth of new blood vessels in the eye can be controlled without any additional intervention.”

Dr. Rakoczy presented an analysis of the first 8 of 40 subjects enrolled in the safety and efficacy, dose escalation study.

Understanding the study

In the ongoing study, enrolled subjects receive an injection containing genes that encode sFlt-1, a protein that inhibits vascular endothelial growth factor (VEGF). The approach is fundamentally different from the anti-VEGF therapies currently used to treat wet AMD, which require frequent reinjections.

In the gene therapy approach, the recombinant virus is taken up by some of the cells in the eye and starts acting as a “biofactory,” secreting sFlt-1 continuously, Dr. Rakoczy said.

“This is vastly superior to what we normally use because you have a steady, biologically active level of the pharmaceutical agent, which happens to be a natural molecule present in the eye, inhibiting the negative effects of VEGF,” she continued.

California-based Avalanche Technologies is developing the proprietary drug delivery system.

The trial enrolled partial responders to AMD therapy who had relied on frequent anti-VEGF therapy to maintain stable vision. Two subgroups of patients were included in the initial analysis. The first group comprised three subjects who received the low dose, 10E10 vg, along with one control subject. Three other subjects were randomly assigned to receive the high dose, 10E11 vg, and also were matched with a control. Since rAAV.sFit-1 does not reach optimal anti-VEGF expression until 6 to 8 weeks after injection, all patients were given standard of care ranibizumab at day zero and at week 4.

“We wanted to make sure that during that time they were protected against the harmful effects of neovascularization in the eye,” Dr. Rakoczy said. After that, ranibizumab was provided only as rescue therapy.

The mean age of the study population at baseline was 77 years, and mean visual acuity was 38 letters. Mean central retinal thickness was 588 µm, and the average number of anti-VEGF injections prior to the trial was 17.

Analyzing the results

At one year, the investigators found no evidence of systemic or intraocular inflammation, IOP elevation, retinal detachment, arterial thromboembolic events, drug-related adverse events, or clinically significant changes in laboratory assessments. The vector was not found outside of the injected eye, although it was detected transiently in the tears of 2 of 6 subjects one day after surgery.

Subjects who received the sustained delivery device had an average 6 to 9-letter gain in best-corrected visual acuity versus a 3-letter loss in the control group. The mean visual acuity at baseline was 42 EDTRS letter compared to 49 letters at one year. In all, 5 of the 6 treated subjects gained vision. The patient who did not had baseline scarring under the fovea and may not have had the capacity to gain vision.

The mean center point retinal thickness of rAAV.sFlt-1-treated patients decreased by 35% at one year.

Although rescue therapy with ranibizumab was allowed, only 2 of a possible 66 injections were given in the active treatment group. In the control group, one patient needed 5 injections, while the other received 1.

Dr. Rakoczy, who has been studying disease mechanisms and developing treatment for blinding eye diseases for more than 20 years, observed that the evolution of the AMD product has been lengthy and is far from over.

“This is the result of very thorough scientific research which spans 25 or 30 years,” she said. “We are potentially looking at the dawn of a completely new way of treating disease with recombinant viruses. Gene therapy has been used for genetic diseases, which usually have relatively low prevalence.

“Here we are using it for a highly prevalent, complex disease, so this is conceptually different from the original role imagined for gene therapy 20 years ago,” Dr. Rakoczy continued. “It’s a very important scientific leap.”

Elizabeth Rakoczy, MSc, PhD

E: [email protected]

This article is adapted from Dr. Rakoczy’s presentation at the 2014 meeting of the Association for Research in Vision and Ophthalmology. Dr. Rakoczy has a commercial relationship with Avalanche Biotechnologies.