RGX-314 Gene Therapy for nAMD Well-Tolerated in Phase 1/2a Study

Jeffrey S. Heier, MD

Credit: Ophthalmic Consultants of Boston

Subretinal delivery of ABBV-RGX-314, a potential one-time gene therapy, was well-tolerated, with no clinically recognized immune response, in the treatment of neovascular (wet) age-related macular degeneration (nAMD), according to phase 1/2a results published in The Lancet.¹

The publication detailed two-year data suggesting the novel approach of RGX-314 for sustained vascular endothelial growth factor (VEGF)-A suppression, with the potential to safely maintain vision and reduce treatment burden in patients with nAMD after a single dose.

“Wet AMD is a chronic, life-long disease and real-world evidence shows patients are losing significant vision over time, and the burden of frequent anti-VEGF injections needed to manage their wet AMD is a major reason why,” Jeffrey S. Heier, MD, director of the vitreoretinal service and retina research, Ophthalmic Consultants of Boston and the primary study investigator, said in a statement.² “A single treatment of ABBV-RGX-314 that can potentially provide long-lasting treatment outcomes and a strong safety profile would offer a novel approach to treating this serious and blinding disease.”

Frequent anti-VEGF-A injections lessen the risk of rapid, severe vision loss among patients with nAMD, but the frequency-related burden could lead to undertreatment, and thus, vision loss over time.³ Sustained suppression of the VEGF-A pathway may provide the maintenance of vision and a reduction in the associated treatment burden.

RGX-314, an adeno-associated virus serotype 8 vector expressing an anti-VEGF-A antigen-binding fragment, is developed to allow continuous VEGF-A suppression after a single administration.² REGENXBIO is investigating two separate routes of administration of RGX-314 to the eye, including standard subretinal delivery and suprachoroidal delivery.

Current results from the phase 1/2a, open-label, dose-escalation study reported the safety and efficacy of the subretinal delivery of five dose cohorts of RGX-314 for patients with nAMD.¹ Between May 2017 and May 2019, investigators screened 110 patients with previously treated nAMD for eligibility criteria. The trial’s primary outcome was the safety of RGX-314 delivered by subretinal injection up to week 26.

After enrolling 68 individuals into the trial, 42 participants met the required anatomic response to intravitreal ranibizumab and received a single RGX-314 injection (dose range 3x10⁹ to 2.5x10¹¹ genome copies per eye). Participants were observed 1 day and 1 week after administration, then monthly for 2 years.

Analyses revealed 20 serious adverse events in 13 participants, with one event considered potentially related to RGX-314. The event was pigmentary changes in the macular with severe vision reduction 12 months after injection of RGX-314 at a dose of 2.5 x 10¹¹ genome copies per eye.

Heier and colleagues observed asymptomatic pigmentary changes in the inferior retinal periphery months after subretinal RGX-314, primarily at doses of 6x10¹⁰ genome copies per eye or higher. In addition, the analysis demonstrated no clinically determined immune responses or inflammation outside of those expected after routine vitrectomy.

Overall, the doses of 6 x 10¹⁰ genome copies per eye or higher led to sustained concentrations of RGX-314 protein in the aqueous humor, as well as stable or improved BCVA and central retinal thickness, with little to no supplemental anti-VEGF injections administered in most participants.

Heier and colleagues noted these results inform the pivotal program to assess RGX-314 for the treatment of nAMD further. Two pivotal trials, ATMOSPHERE and ASCENT, are currently evaluating RGX-314 in patients with wet AMD with on-target enrollment.

RegenXBio expects these data to support regulatory submission with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in late 2025 through early 2026.²

“To have these Phase I/IIa data published in The Lancet highlights the groundbreaking work of our scientists and investigators, and further validates the clinically transformative nature of ABBV-RGX-314 as a potential one-time gene therapy for wet AMD that may help patients maintain or improve their vision,” Kenneth T. Mills, president and chief executive officer of REGENXBIO, added in a statement.²

References

1. _{Campochiaro PA, Huddleston SM, Ho AC, Brown DM, Avery R. Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study. The Lancet. March 27, 2024. Accessed March 28, 2024. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00310-6/abstract.}
2. _{Regenxbio announces lancet publication of phase I/IIA study evaluating ABBV-RGX-314 as a one-time gene therapy for WET AMD. Regenxbio Inc. March 28, 2024. Accessed March 28, 2024. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-lancet-publication-phase-iiia-study.}
3. _{Campochiaro PA, Aiello LP, Rosenfeld PJ. Anti-Vascular Endothelial Growth Factor Agents in the Treatment of Retinal Disease: From Bench to Bedside. Ophthalmology. 2016;123(10S):S78-S88. doi:10.1016/j.ophtha.2016.04.056}