Investigators start pivotal subretinal gene therapy trial

Reviewed by Dr Allen C. Ho.

RGX-314 subretinal gene therapy (Regenxbio) is being tested in the first pivotal gene therapy trial for exudative age-related macular degeneration (AMD). Interim results indicate that the treatment is generally well tolerated, with stable to improved visual acuity (VA) and reductions in anti-vascular endothelial growth factor (VEGF) injection burden of up to 1.5 to 3 years, depending on the cohort.

Dr Allen C. Ho, a professor of ophthalmology at Wills Eye Hospital in Philadelphia, Pennsylvania, United States, and Thomas Jefferson University in Plymouth Meeting, Pennsylvania, reported the findings. As Dr Ho explained, RGX-314 uses an adeno-associated viral 8 vector to deliver a gene encoding for a therapeutic anti-VEGF Fab protein and is designed to produce continuous anti-VEGF therapy.

Phase 1/2a first-in-human trial

A total of 42 patients have been enrolled in the RGX-314-001 study, with up to 3 years of follow-up. The drug continues to be well tolerated with stable-to-improved vision and has resulted in clinically meaningful decreases in anti-VEGF injections in cohorts 3, 4 and 5 of the five dosing cohorts, all of which were well balanced demographically.

The patients with neovascular AMD had been treated previously with an average of 10 injections annually for 4–5 years and were required to respond to a baseline injection of ranibizumab (Lucentis, Genentech) before receiving RGX-314. These patients do not receive systemic corticosteroids during the study; anti-VEGF rescue injections were permitted beginning 4 weeks into the study if needed.

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The primary outcome was determination of the safety and tolerability of RGX-314 over a period of 6 months. Secondary outcomes included determination of transgene protein production, effect on vision and ocular anatomy and need for additional injections. The re-treatment criteria included the presence of any fluid, visual loss of five or more letters associated with fluid, and presence of haemorrhages.

“RGX-314 continues to be generally well tolerated across all doses” Dr Ho said. “Importantly, no clinically determined immune responses, drug-related ocular inflammation or post-surgical inflammation were seen beyond what is expected following routine vitrectomy.”

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Surgical incision conjunctival haemorrhages and pigmentary changes in the retinal pigment epithelium (RPE) occurred, both of which were mostly mild events. One patient had RPE changes through the macula that were associated with visual loss.

Dr Ho presented interim data for cohorts 4 and 5 at 1.5 years and cohort 3 at up to 2 years. An additional year of follow-up for cohort 3 is described as follows.

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Changes in best-corrected VA (BCVA) showed improved vision over 2 years for cohort 3, and this patient group had a significant reduction in the need for rescue therapy over the 2 years; in cohorts 4 and 5, the vision was stable or improved and the patients needed fewer rescue injections over a period of 1.5 years.

For cohorts 3, 4 and 5, retinal thickness was stable on optical coherence tomography images over time and VA was stable or improved, including in those who did not need rescue therapy. Evaluation of the protein levels in cohorts 3, 4 and 5 showed durable and dose-dependent increases in protein production over 2 years for cohort 3, and over 1 year for cohorts 4 and 5.

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This study will follow patients for an additional 3 years beyond the Phase 1/2a trial, for a total of 5 years of follow-up after receiving RGX-314. Dr Ho also presented the third year of data for cohort 3.

Thus far, investigators have reported no new drug-related ocular adverse events. In cohort 3, patients continue to show stable-to-improved VA and have shown a mean of 12 letters of improvement and a reduction in the need for rescue injections up to 3 years.

Pivotal Phase 2b/3 trial

Based on these findings, Regenexbio has begun ATMOSPHERE, a subretinal pivotal trial in neovascular AMD. Investigators will evaluate two doses of RGX-314 compared with monthly injections of ranibizumab (Lucentis, Genentech/Novartis) in pseudophakic patients with a baseline VA of 20/32 to 20/160.

The study will enroll around 300 patients at 60 clinical sites. The primary endpoint is the mean change in BCVA relative to ranibizumab at week 54.

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Regenexbio is also conducting studies using the in-office SCS Microinjector to deliver RGX-314 to the suprachoroidal space in patients with neovascular AMD and diabetic retinopathy. Upcoming results from these suprachoroidal programmes will be announced for the Phase 2 AAVIATE (neovascular AMD) and ALTITUDE (diabetic retinopathy) trials.

Allen C. Ho, MD

e: achomd@gmail.com

This article is adapted from Dr Ho’s presentation at the Bascom Palmer Eye Institute Angiogenesis, Exudation and Degeneration 2021 virtual meeting. Dr Ho reported receiving research grants from Regenexbio, Inc., and he serves as a scientific advisor to the company.

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