Dilsher Dhoot, MD: RGX-314 Improves Diabetic Retinopathy in Phase 2 ALTITUDE Study

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Presented at ASRS 2023, study data showed a single, in-office injection of RGX-314 gene therapy may have long-lasting improvements in diabetic retinopathy severity.

A one-time injection of RGX-314 gene therapy could potentially provide long-lasting improvement in the severity of diabetic retinopathy and reduce the risk of vision-threatening complications, according to results from the phase 2 ALTITUDE study.

The data, presented at the American Society of Retina Specialists (ASRS) 41st Annual Meeting, showed the in-office gene therapy was generally well-tolerated, with no observed cases of chorioretinal vasculitis, occlusion, or hypotony.

“The ability to provide a one-time injection to reduce diabetic retinopathy severity and also reduce the odds of having a vision-threatening complication has big implications, so it’s a very exciting time,” presenting author Dilsher Dhoot, MD, California Retina Consultants, told HCPLive at ASRS 2023. “If we’re able to provide a single injection in the office in the suprachoroidal space, I think that’s going to be a big game-changer for our patients.”

For eyes with severe nonproliferative diabetic retinopathy (NPDR), the use of repeated intravitreal anti-VEGF therapy has been shown to improve diabetic retinopathy severity scores (DRSS) and reduce vision-threatening developments. A gene therapy that uses an AAV8 vector to deliver a transgene for a soluble anti-VEGF fab, RGX-314 is designed to provide continuous anti-VEGF therapy following a single treatment.

The phase 2 controlled, open-label, randomized, dose-escalation ALTITUDE trial evaluated the efficacy, safety, and tolerability of RGX-314 delivered into the suprachoroidal space using an in-office procedure in eyes with moderately severe or severe NPDR or mild proliferative diabetic retinopathy (PDR). Enrollment was completed for cohorts 1–3: cohort 1 evaluated RGX-314 at a dose of 2.5x1011 genomic copies per eye (GC/eye); cohort 2 and 3 evaluated RGX-314 at an increased dose level of 5x1011 GC/eye; cohort 3 evaluated RGX-314 in patients who are NAb positive.

The trial is also enrolling an additional dose (1x1012 GC/eye) with short-course, ocular steroids following RGX-314, and the 2 cohorts (4 and 5) will be stratified by DRSS levels. The primary outcome was identified as the proportion of eyes with a 2-step improvement in the diabetic retinopathy severity scale score (DRSS) at 48 weeks; secondary outcomes were safety and the development and intervention for related complications.

Upon analysis, as of October 2022, RGX-314 was well tolerated in 50 patients included in cohorts 1 - 3 (dose 1: 15 patients; dose 2: 35 patients). The investigative team observed no cases of chorioretinal vasculitis, occlusion, or hypotony. A total of 3 cases of mild intraocular inflammation through 6 months were observed and resolved with the use of topical corticosteroids.

At the 6-month timepoint, data showed 20% of patients (dose 1: 40%; dose 2: 11%) achieved a >2-step improvement in DRSS versus 10% in control. On the other hand, 54% of patients (dose 1: 60%; dose 2: 51%) achieved any DRSS improvement compared to 20% in control, and 0% of patients worsened >2 steps versus 20% in control.

“This is a phase 2 trial, so next, assuming the results continue to be promising as they are, you can expect to see this develop into a phase 3 trial,” Dhoot told HCPLive.

Relevant disclosures for Dr. Dhoot include Apellis, Genentech, Novartis, RegenXBio, and others.