Pivotal subretinal gene therapy trial begins

This article is reviewed by Allen C. Ho, MD.

RGX-314 subretinal gene therapy (RE­GENXBIO Inc) is being tested in the first pivotal gene therapy trial for exu­dative age-related macular degenera­tion (AMD). Interim results indicate 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. Allen C. Ho, MD, a professor of ophthalmology at Wills Eye Hospital in Philadelphia, and Thomas Jeffer­son University in Plymouth Meeting, Pennsylva­nia, reported the findings.

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, he explained.

Phase 1/2a first-in-human trial

A total of 42 patients have been enrolled in the RGX- 314-001 study (NCT03066258) 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 5 dosing cohorts, all of which were well balanced demographically.

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

Related: Subretinal gene therapy for neovascular AMD showing efficacy and safety

The primary outcome was determination of the safety and tolerability of RGX-314 through 6 months. Secondary outcomes included determination of trans­gene protein production, effect on vision and ocular anatomy, and need for additional injections. The retreatment criteria included the presence of any fluid, visual loss of 5 or more letters associated with fluid, and presence of hemorrhages.

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

Surgical incision conjunctival hemorrhages 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.

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 below. 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.

Long-term follow-up study

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. 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 out to 3 years.

Related: How gene therapy clinical trials are addressing retinal diseases at the core

Pivotal 2b/3 trial

Based on these findings, REGENXBIO has begun ATMOSPHERE, a subretinal pivotal trial in neo­vascular AMD. Investigators will evaluate 2 doses of RGX-314 compared with monthly injections of ranibizumab in pseudophakic patients with a base­line VA of 20/32 to 20/160. The study will enroll about 300 patients at 60 clinical sites. The primary end point is the mean change in BCVA relative to ranibizumab at week 54.

REGENXBIO 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 programs will be announced for the phase 2 AAVIATE (neovascu­lar AMD; NCT04514653) and ALTITUDE (diabetic retinopathy; NCT04567550) trials.

Allen C. Ho, MD

E: achomd@gmail.com

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

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