AAO 2019: Encouraging results revealed from early trial of subretinal gene therapy for wet AMD


According to Jeffrey Heier, MD, RGX-314 administered by subretinal injection was well tolerated. In addition, it was associated with dose-dependent increase in ocular protein expression and evidence of clinical benefit.

Key takeaways from the RGX-314 (Regenxbio) phase I/IIa clinical trial indicate that the novel gene therapy is a promising approach for treating wet age-related macular degeneration (AMD). The messages were presented by Jeffrey Heier, MD, at the American Academy of Ophthalmology 2019 Retina Subspecialty Day meeting.

The investigational agent is designed to deliver a gene encoding for an anti-VEGF fab protein and uses a novel viral vector (adeno-associated virus 8; AAV8). The phase I/IIa dose-escalating trial enrolled 42 patients across five dose cohorts.

Eligible patients had severe wet AMD requiring frequent anti-VEGF injections and were required to have demonstrated a level of response to anti-VEGF therapy. They received a single subretinal injection of RGX-314 and were followed monthly for safety and need for rescue therapy.

Subretinal injections

Dr. Heier, co-president and medical director, director of the Vitreoretinal Service, and director of Retina Research, Ophthalmic Consultants of Boston, Boston, MA, reported that RGX-314 administered by subretinal injection was well tolerated. In addition, it was associated with dose-dependent increase in ocular protein expression and evidence of clinical benefit. Overall, patients in the middle dose cohort were demonstrating good vision and anatomic outcomes during follow-up reaching 18 months; three of the six patients in the middle cohort had received no rescue injections.

Twelve patients were enrolled in the next higher dose cohort, and they demonstrated stable to improved anatomic and visual outcomes with a reduction in injection burden. Among the 12 patients in the highest RGX-314 dose cohort, 75% were injection free during available follow-up of five to six months, and vision and central retinal thickness overall remained stable or was improved.

“Based on these findings, the sponsor is moving into a phase IIb trial for wet AMD, starting a trial for diabetic retinopathy, and looking at evaluating suprachoroidal delivery (SCS Microinjector, Clearside Biomedical),” said Dr. Heier.

The 42 patients enrolled in the trial had a mean age of 80 years. Baseline BCVA was 55.7 ETDRS letters and baseline central retinal thickness on OCT was 399 μm. On average, the patients had been on anti-VEGF therapy for 56 months and had an average annualized injection burden of 9.6.

Safety favorable

The novel proprietary gene delivery platform utilized for RGX-314 is hypothesized to deliver longer and higher protein expression than the AAV2 vector, but also to be associated with a lower immune response.

Patients in the trial are not receiving routine treatment with any topical or systemic medications for immunosuppression, and Dr. Heier said that there has not been any need for immunosuppression.

Dr. Heier reported that most adverse events recorded in the trial were assessed as mild. There were no drug-related serious adverse events, observed clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation beyond what is expected following routine vitrectomy. There were two ocular procedure-related serious adverse events, including a peripheral retinal detachment that was repaired.

Dr. Heier said that caution and care are critical for success with the subretinal injection.

“We spent almost two years in preparation for this study, standardizing the approach, and working on it in the laboratory,” he said. “We have looked at videos of every case to learn pearls and pitfalls from every surgeon. Sharing experience is critical.”


Jeffrey Heier, MD
Dr. Heier is scientific advisor to Regenxbio.

Related Videos
Deepak L. Bhatt, MD, MPH, MBA, on Incorporating AI into Genetic Research for Cardiovascular Disease
Jeffrey Chamberlain, PhD, on Helping Progress Cell and Gene Therapy Development
Jonathan W. Weinsaft, MD, on Integrating Genetic Research into Cardiovascular Medicine
Jacques Galipeau, MD, on Highlights from ISCT 2024’s Presidential Plenary
Vanee Pho, PhD, the senior director of product management, cell and gene therapy, at Mission Bio
Michael Wang, MD, a professor in the Department of Lymphoma/Myeloma at MD Anderson Cancer Center
Robert J. Hopkin, MD, on Looking Deeper into Fabry Disease Biology
Steven W. Pipe, MD, on Confirming Efficacy, Safety of Hemgenix Gene Therapy in Hemophilia B Populations
Rawan Faramand, MD, an assistant professor at Moffit Cancer Center
Marcus Conant, MD, on More Research Needed With HIV Therapies
© 2024 MJH Life Sciences

All rights reserved.