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Gene therapy for AMD?

Gene therapy as a drug delivery platform for non-inherited retinal issues

Dermot McGrath

Posted: Monday, November 2, 2020

Gene therapy offers transformative potential to greatly reduce treatment burden and potentially improve patient outcomes with a single intravitreal injection in patients with age-related macular degeneration, according to Szilard Kiss MD.
“The future is bright for intraocular gene therapy especially after the efficacy that was noted with voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) resulting in FDA approval of the first ocular gene therapy in the United States for patients with inherited retinal disease due to mutations in the RPE65 gene. There is every reason to hope that similar success may be obtained with gene therapy for non-inherited ocular disorders such as wet AMD, diabetic retinopathy (DR), diabetic macular oedema (DME) and retinal vein occlusion (RVO),” Dr Kiss said at the World Ophthalmology Congress 2020 Virtual.
In a broad overview of the progress made to date in gene therapy for non-inherited retinal diseases (IRD), Dr Kiss, Director of Clinical Research and Associate Professor at Weill Cornell Medical College, New York, said that initial trials of therapies such as RGX-314 (RegenexBio) and ADVM-022 (Adverum) have shown promise for the treatment of exudative AMD.
RGX-314, which uses an adeno-associated virus serotype 8 (AAV8) as a vector, contains a gene encoding for a monoclonal antibody fragment that binds to and neutralises VEGF. It is administered as a one-off subretinal injection, said Dr Kiss.
In the phase I/IIa trial, 42 wet AMD patients in five different dosing cohorts received a subretinal injection of RGX-314.
“The mean age was around 80 and patients received an average of nine anti-VEGF injections a year, so these are heavily treated macular degeneration patients. RGX was shown to be well tolerated in all dosing cohorts, with most adverse events rated mild in severity,” he said.
The best-corrected visual acuity remained stable and mean central retinal thickness improved over the course of the follow-up for patients in the fourth and fifth dose cohort. Five (42%) patients were injection-free over the follow-up in the fourth cohort, while nine of the patients (75%) remained injection-free in the fifth cohort.
Positive data also emerged from the OPTIC phase 1 dose-ranging study of ADVM-022, which aims to treat neovascular AMD by delivering long-term expression of therapeutic levels of anti-VEGF aflibercept protein.
ADVM-022 was found to be safe and well tolerated and showed consistent and sustained anatomic improvements in OCT and stable best-corrected visual acuity, noted Dr Kiss. No rescue injections were required. Some cases of intraocular inflammation associated with ADVM-022 were successfully treated with topical steroids.
Going forward, Dr Kiss said that dry AMD, for which no treatment is currently available, may also be amendable to gene therapy, with a number of promising therapeutic agents currently undergoing clinical trials.