RegenxBio Inc. released positive interim data from its phase 2 trial on its gene therapy candidate ABBV-RGX-314 for the treatment of wet age-related macular degeneration (AMD).
Refresh me on ABBV-RGX-314.
Currently in development via a partnership between RegenxBio and AbbVie, ABBV-RGX-314 is in being clinically evaluated as a potential one-time, subretinal injection treatment for patients with the following 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
To note, the investigational candidate leverages a novel adenosine-associated virus (N + AAV= NAV for short) vector.
How does this NAV vector work?
The NAV vector is administered via injection or infusion, with the therapeutic goal of reaching the target cells and delivering the gene—thus allowing the cells to make the necessary body’s needed protein for various rare diseases.
And in ABBV-RGX-314?
ABBV-RGX-314 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.
See here for the company’s other investigational candidates featuring the NAV Technology Platform.
So what’s the clinical data on it thus far?
For wet AMD, there’s two ongoing trials that have yet to report data.
The phase 2b/3 ATMOSPHERE (NCT04704921) and phase 3 ASCENT (NCT05407636) are evaluating two doses of ABBV-RGX-314 (compared to an active comparator), with the primary endpoints being mean change in best-corrected visual acuity (BCVA) relative to ranibizumab (ATMOSPHERE) or aflibercept (ASCENT).
Both trials are scheduled to conclude in 2024: March (ATMOSPHERE) and December (ASCENT).
Now talk about this new trial.
The multicenter, open-label, randomized, active-controlled, dose-escalation phase 2 AAVIATE trial (NCT04514653) is assessing the safety and efficacy of ABBV-RGX-314 in 115 participants (aged 50-89) diagnosed with wet AMD.
See here for the full inclusion and exclusion participant criteria.
And the doses?
Three doses/dose combinations of ABBV-RGX-314 are divided among six cohorts:
- Cohort 1
- Dose 1 (2.5x1011 GC/eye)
- Cohorts 2 & 3
- Dose 2 (5x1011 GC/eye)
- Cohorts 4-6
- Dose 3 (1x1012 GC/eye)
Cohort 5 is evaluating ABBV-RGX-214 in (n = 20) patients who are neutralizing antibodies (NAb) positive, while Cohort 6 includes a short course of prophylactic steroids post-injection. Of note, “GC/eye" is defined as genome copies per eye.
What’s being measured?
Per the company, the primary endpoint is the mean change in vision for patients dosed with ABBV-RGX-314, measured via BCVA at Week 40 from baseline—vs patients receiving monthly injections of ranibizumab.
Secondary objectives included:
- ABBV-RGX-314 safety and tolerability
- Change in central retinal thickness (CRT), measured via spectral-domain optical coherence tomography (SD-OCT)
- Additional anti-VEGF injection following ABBV-RGX-314
The complete list of secondary endpoints can be found here (seven in total).
And this interim data?
RegenxBio reported that, as of Nov. 6, 2023, ABBV-RGX-314 was well-tolerated among all patients from the three dose levels.
No drug-related serious adverse events (SAEs) were observed, while all treatment-emergent AEs (TEAEs) through 6 months were mild or moderate in the study eye. These included:
- Conjunctival hemorrhage
- Increased intraocular pressure (IOP)
- Episcleritis
- Conjunctival hyperemia
Break it down by dose levels.
Patients in dose levels 1 and 2 experienced mild intraocular inflammation (IOI) at a similar incidence rate, while mild to moderate IOI was noted at dose level 3 in Cohort 4 and 5.
Note: all IOI cases were resolved following use of topical corticosteroids.
Go on…
Interestingly, dose level 3 (Cohort 6) reported no cases of IOI. Participants in this cohort received a “short-course of prophylactic topical corticosteroids” following an injection of ABBV-RGX-314.
What about the primary/secondary endpoints?
Per RegenxBio, those treated with ABBV-RGX-314 demonstrated stable BCVA and CRT at 6 months.
Further, “a clinically meaningful reduction in anti-VEGF treatment burden was observed following administration of ABBV-RGX-314,” the company stated.
Which dose level had the highest reduction?
Dose level 3, where participants demonstrated an 80% reduction in annualized injection rate, “with 50% of patients remaining injection-free.”
Expert input?
RegenxBio’s CMO Steve Pakola, MD, expressed the company’s positivity regarding the latest ABBV-RGX-314 data: “The potential of ABB-RGX-314 to transform the way chronic retinal conditions are treated has been demonstrated in multiple trials using both subretinal and suprachoroidal delivery, and these latest interim results … continue to support this outlook,” he stated.
And the significance?
ABBV-RGX-314 has the potential to sustain constant anti-VEGF therapy and stabilize or improve vision for the long term in wet AMD patients.
So what’s next?
Since the trial was slated to conclude in January 2024 (per Clinical Trials), stay tuned for a full data readout later this year!