Published in Pipeline

REGENXBIO shares 2-year data on gene therapy injection for wet AMD

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5 min read

REGENXBIO Inc. announced that The Lancet has published 2-year data from a phase 1/2a dose-escalation study on its gene therapy candidate ABBV-RGX-314 for the treatment of wet age-related macular degeneration (AMD).

Let’s start with ABBV-RGX-314.

The gene therapy is being developed via a partnership between RegenxBio and AbbVie as a potential one-time, subretinal injection treatment for patients with certain retinal conditions who have been treated with (and demonstrated a meaningful response to) anti-vascular endothelial growth (VEGF) in the past:

  • Wet AMD
  • Diabetic retinopathy (DR)
    • See here for positive 1-year data from the phase 2 ALTITUDE trial, released in November 2023.
  • Other chronic retinal conditions

Explain how this therapy works.

ABBV-RGX-314 leverages a novel adenosine-associated virus (N + AAV= NAV for short) vector that is administered via injection or infusion.

The therapeutic goal: Reaching the target cells, delivering the gene, and enabling the cells to potentially manufacture the deficient protein(s) for various rare diseases.

Go on…

The gene therapy includes the NAV adeno-associated virus 8 (AAV8) vector that contains a gene encoding for a monoclonal antibody fragment.

Via protein expression, this modified AAV vector has been designed to neutralize VEGF activity and block the pathway where new, leaky blood vessels may grow and cause fluid to accumulate in the retina.

Any previous clinical trials know about?

Yes, there are! Three in total:

  • Phase 2b/3 ATMOSPHERE (NCT04704921) and phase 3 ASCENT (NCT05407636) are evaluating two doses of ABBV-RGX-314 (compared to an active comparator)
  • Phase 2 AAVIATE trial (NCT04514653) is assessing the gene therapy in three doses/dose combinations.

And the data so far?

Positive interim data from the AAVIATE trial reported in January 2024 found ABBV-RGX-314 to be well tolerated among all patients at three dose levels (across six cohorts):

  • Cohort 1
    • Dose 1 (2.5x1011 genome copies per eye [GC/eye])
  • Cohorts 2 & 3
    • Dose 2 (5x1011 GC/eye)
  • Cohorts 4-6
    • Dose 3 (1x1012 GC/eye)

Follow-up clinic visits: Participants were observed one day and one week after injection, then on a monthly basis for 2 years (up to 106 weeks).

Gotcha. Now talk about this dose-escalation study.

The open-label, multiple-cohort, multicenter, phase 1/2a dose-escalation study (NCT03066258) enrolled 42 wet AMD patients aged 50-89 who were previously treated with anti-VEGF injections (see here for full participant criteria).

Participants were divided into five cohorts of five different ABBV-RGX-314 doses:

  • Cohort 1
    • Dose 1 (3x109 GC/eye)
  • Cohort 2
    • Dose 2 (1x1010 GC/eye)
  • Cohort 3
    • Dose 3 (6x1010 GC/eye)
  • Cohort 4
    • Dose 4 (1·6x1011 GC/eye)
  • Cohort 5
    • Dose 5 (2·5x1011 GC/eye)

Follow-up clinic visits: Participants were observed one day and one week after injection, then on a monthly basis for 2 years (up to 106 weeks).

What was measured?

Primary outcome was safety of ABBV-RGX-314 , as measured by ocular and nonocular adverse events (AEs) through 26 weeks.

Measured at Week 106, secondary outcomes included:

  • Safety of ABBV-RGX-314
  • Change from baseline in:
    • Best-corrected visual acuity (BCVA)
    • Central retinal thickness (CRT)
  • Supplemental injections
  • Mean change from baseline in area of choroidal neovascularization (CNV)

And the findings?

Per the investigators, a total of 20 serious AEs were observed in 13 participants, with one potentially related to the gene therapy: “pigmentary changes in the macula with severe vision reduction 12 months after injection of (ABB-RGX-314) at a dose of 2·5x1011 GC/eye.”

What else?

For dose 3 (6x1010 GC/eye) and up (including dose 4 [1·6x1011 GC/eye] and dose 5[2·5x1011 GC/eye]), asymptomatic pigmentary changes were most commonly noted in participants’ inferior retinal periphery several months after injection.

Further, these doses also “resulted in sustained concentrations of (ABB-RGX-314) protein in aqueous humour” as well as stable or improved BCVA and CRT, with few or no supplemental anti-VEGF-A injections in most participants.

Any inflammation?

Nope! The study authors reported no clinically determined immune responses or inflammation other than what was expected after routine vitrectomy.

And this all means…

Overall, the gene therapy was generally well-tolerated, providing a “novel approach for sustained VEGF-A suppression” in wet AMD patients with the potential to “control exudation, maintain vision, and reduce treatment burden after a single administration.

And the significance?

Per Jeffrey S. Heier, MD, principal investigator of the trial, a single injection of ABBV-RGX-314 could potentially “provide long-lasting treatment outcomes and a strong safety profile would offer a novel approach to treating this serious and blinding disease."