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RGX-314 gene therapy, a treatment for wet age-related macular degeneration delivered subretinally, showed dose-dependent sustained/improved vision and a good safety profile.
This article was reviewed by Jeffrey S. Heier, MD
RGX-314 (REGENXBIO) gene therapy, delivered subretinally to patients with neovascular age-related macular degeneration (AMD), who required a large number of prior injections of anti-vascular endothelial growth factor (VEGF) annually, provided a marked decrease in the number of injections needed and retained or improved the vision and anatomy in this challenging patient population.
RGX-314 uses a proprietary gene delivery platform that is hypothesized to deliver longer and higher protein expression with a lower immune response that earlier generation adeno associated viruses (AAVs) used for gene therapy.
“The AAV8 vector is encoded to deliver a gene that leads to anti-VEGF antibody fragment protein production within the retina,” said Jeffrey S. Heier, MD, co-president and director of Retinal Research, Ophthalmic Consultants of Boston.
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All 42 patients included in this study had undergone previous treatment for neovascular AMD and had a “high need” for anti-VEGF therapy, i.e., patients received more than 30 injections on average prior to coming in and an average of 9.6 annualized injections in the year prior to RGX-314.
In addition, the included patients had to have shown an anatomic response to anti-VEGF therapy during screening. After RGX-314 was delivered to the subretinal space, the patients were evaluated monthly to assess safety and the need for additional anti-VEGF therapy, Dr. Heier noted.
Re-treatment with an anti-VEGF drug could be provided beginning at four weeks after RGX-314 was delivered and then as needed every four weeks thereafter based on physician discretion, Dr. Heier explained. The criteria for retreatment was per investigator discretion which included choroidal neovascularization-related increased, new, or persistent fluid; vision loss of five or more letters as a result of fluid, or a new ocular hemorrhage.
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Following delivery of RGX-314, Dr. Heier reported that the drug was well tolerated. No serious adverse events were reported; most adverse events were classified as mild, i.e., grade 1 in 79% of cases. In addition, no clinically determined immune responses occurred.
Two deaths that occurred were not related to RGX-314. Two serious adverse effects that were related to the delivery procedure were reported, specifically, a peripheral retinal detachment that was repaired successfully and a case of endophthalmitis that occurred after collection of an aqueous sample.
“We observed a dose-dependent increase in RGX-314 protein across the five dose cohorts,” he reported. The protein levels were measured in aqueous samples collected one month after delivery of RGX-314.
Cohort 3, which included six eyes treated with a dose of 6 x 1010 genome copies (GC)/eye, did well.
“Cohort 3 had a gain in vision of +9 letters and stable anatomy of -40 Î¼m over 18 months despite relatively few injections,” Dr. Heier reported.
Three of the six patients in this cohort were injection-free at 18 months. They had a mean increase of +11 letters of vision at 18 months and a concomitant mean decrease in the central retinal thickness of -21 Î¼m. The RGX-314 protein levels were sustained over one year.
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Cohort 4, which included 12 eyes treated with a dose of 1.6 x 1011 GC/eye, also did well.
“The vision and anatomy in these patients were stable or improved,” according to Dr. Heier.
Five of the 12 patients were injection-free at 6 months. The average improvement at that time point was +2 letters and the decrease in the central retinal thickness was -42 Î¼m.
Two patients in this cohort continued to require anti-VEGF monthly injections as the result of incomplete responses to anti-VEGF therapy.
Cohort 5, which included 12 patients treated with a dose of 2.5 x 1011 GC/eye, demonstrated the highest clinical response seen in the trial with stable to improved vision and anatomic outcomes.
Nine of the 12 patients were injection-free at five to six months with vision of +5 letters and a decrease in central retinal thickness of -80 Î¼m over five months.
“This was the highest clinical response observed,” Dr. Heier commented.
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An interesting analysis of the injections administered to patients in cohort 5 in the year before they were treated with RGX-314 showed injections ranged from six to 13. After delivery of RGX-314, only three patients needed additional therapy, i.e., six injections for one patient with an incomplete anti-VEGF response, two injections for a second patient, and one injection to a third patient.
In the case of the cohort 5 patient who required 13 injections with persistent subretinal fluid at every visit in the year prior, Dr. Heier reported that following delivery of RGX-314, this patient remained dry and did not need rescue injections for five months.
Dr. Heier noted that based on the study findings, Regenxbio plans to move forward with phase IIb study of RGX-314 for wet AMD and an Investigational New Drug trial for diabetic retinopathy,. The company also will be investigating suprachoroidal delivery using the ClearSide Microinjector, which can be used in-office.
“Subretinal RGX-314 was well tolerated in the five study cohorts. A dose-dependent increase in ocular protein was observed across the cohorts,” he concluded. “Cohort 5 demonstrated the highest response among the cohorts; 75% of the patients were injection-free at five to six months.”
Jeffrey S. Heier, MD
Dr. Heier is a scientific advisor to REGENXBIO.