Author: Mark Barakat
Co-authors:
Abstract
Purpose:In eyes with severe non-proliferative diabetic retinopathy (NPDR), anti-VEGF therapy by repeated intravitreal injections has been demonstrated to improve DR severity scores and reduce the development of vision threatening complications. In order to maintain optimal anatomic outcomes, however, multiple injections appear to be required resulting in a high treatment burden. RGX-314 is a gene therapy that utilizes an AAV8 vector to deliver a transgene for a soluble anti-VEGF fab designed to provide continuous anti-VEGF therapy following a single treatment. ALTITUDE is evaluating RGX-314 delivered into the suprachoroidal space (SCS) through an in-office procedure.
Setting/Venue:
This Phase II, multi-center, open-label, randomized, controlled, dose-escalation study of RGX-314 is being conducted at eighteen clinical retina practices in the United States.
Methods:
ALTITUDE is evaluating the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector® in patients with a DR diagnosis of moderately severe or severe nonproliferative DR (NPDR) or mild proliferative DR (PDR). 20 patients in Cohort 1 were randomized to receive RGX-314 at a dose level of 2.5x1011 genomic copies per eye (GC/eye) versus observational control at a 3:1 ratio. Cohort 2 includes 20 patients randomized to receive RGX-314 at an increased dose level of 5x1011 GC/eye versus observational control at a 3:1 ratio. Cohort 3 is evaluating RGX-314 at the same dose level as Cohort 2 in 20 patients who are neutralizing antibody (NAb) positive. Patients do not receive prophylactic immune suppressive corticosteroid therapy before or after receiving RGX-314. The primary outcome is the proportion of eyes with 2-step improvement in DR severity scale score (DRSS) at 48 weeks. Secondary outcomes include safety, and development and intervention of DR-related complications.
Results:
As of January 18, 2022, RGX-314 was well tolerated in 15 patients in Cohort 1. Two unrelated serious adverse events were reported, both of which were considered not drug-related. One case of mild episcleritis resolved with topical corticosteroids, and no intraocular inflammation was observed among Cohort 1 patients dosed with RGX-314. Common ocular treatment emergent adverse events in the study eye through six months were not considered drug-related and were predominantly mild, and included conjunctival hemorrhage and conjunctival hyperemia. 7 of the 15 patients (47%) demonstrated a 2-step or greater improvement in DRSS score from baseline at six months, compared to 0 of the 5 patients (0%) in the observational control group. In the 7 patients who had NPDR (DRSS 47-53) at baseline, 4 patients (57%) demonstrated a 2-step or greater improvement at six months.
Conclusions:
RGX-314 has the potential to provide sustained clinical outcomes in the treatment of diabetic retinopathy with a one-time treatment administered in-office. This treatment could deliver advantages over conventional treatments that may require repeated, life-long intraocular injections to prevent disease progression.
Financial Disclosures:
Speakers’ Bureau/Consultant/Research for Adverum Biotech, Alcon, Allegro, Allergan, Alimera, Annexon, Bausch and Lomb, Clearside Biomedical, EyePoint Pharma, Kodiak Sciences, Gemini Therapeutics, Genentech, Graybug, Gyroscope Therapeutics, Novartis, Palatin Technologies, Ocular Therapeutix, Regeneron, RegenxBio, ReNeuron, Ribomic, Stealth Biotherapeutics, Unity Biotechnology. Equity holder in Oxurion, NeuBase.
