ABBV-RGX-314 delivers a gene encoding a therapeutic antibody fragment to inhibit vascular endothelial growth factor (VEGF). Early results show it is well-tolerated and leads to improved disease.
A one-time gene therapy has the potential to provide sustained clinical outcomes for wet age-related macular degeneration (AMD), according to two presentations at the American Society of Retinal Specialists in Seattle.
Age-related macular degeneration occurs when the macula, part of the retina at the back of the eye, becomes damaged. About 10% of all cases become wet, which leads to vision loss as a result of excess blood vessel growth between two layers of cells in the retina. It is also called neovascular AMD.
Current treatments for wet AMD focus on vascular endothelial growth factor (VEGF), which is believed to play a significant role in the abnormal formation of blood vessels in the macula. Current anti-VEGF therapies, however, require repeat treatments, with some dosed every month with intravitreal injections, where the therapy is delivered to the back of the eye.
Several anti-VEGF drugs are available, including Regeneron’s Eylea (aflibercept); Genentech’s Lucentis (ranibizumab); Genentech’s Vabysmo (faricimab-svoa); and Novartis’ Beovu (brolucizumab); and Genentech’s Susvimo (ranibizumab), which uses a refillable implant that delivers the medication continuously for up to six months. Additionally, the anti-cancer drug Avastin (bevacizumab) is used off-label to treat wet AMD because it inhibitors the growth of blood vessels to treat patients with colorectal and other cancers.
ABBV-RGX-314 is being developed by RegenXBio as a one-time treatment containing a gene encoding for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF and modify the pathway for the formation of new blood vessels. It uses an adeno-associated viral (AAV) vector for gene transfer.
Two presentations at ASRS looked at results from two different delivery mechanisms for ABBV-RGX-314. In the first presentation, Ashkan Abbey, M.D., director of clinical research at Texas Retina Associates in Dallas, presented results from a study of subretinal delivery, where the therapy is delivery just under the retina. The study compared formulations developed from two different manufacturing processes for ABBV-RGX-314. One is a bioreactor process that would be used to manufacture the commercial product.
Abbey said that the study showed the bioreactor process demonstrated scalability, consistent yield and product purity. This is compared with the initial clinical research manufacturing process, which is a higher dose formulation.
This study is a phase 1/2a trial evaluating the safety and efficacy of ABBV-RGX-314 in patients previously treated with an intravitreal anti-VEGF therapy. It follows 42 patients for two years after single subretinal injection. Patients are then enrolled in a long-term safety follow-up study.
As of Aug. 29, 2022, ABBV-RGX-314 continued to be generally well-tolerated in 37 patients enrolled in the long-term study. Five serious adverse events were reported in four patients, but none was considered drug related. Common adverse events post-operative conjunctival hemorrhage, which resolved within days to weeks; post-operative inflammation, which resolved within days to weeks; and retinal pigmentary changes, which were mild. In cohort 5, there was one drug-related adverse event of significantly decreased best corrected visual acuity (BCVA)
All cohorts in the study demonstrated stable to improved BCVA and retinal thickness, and the majority of patients in all cohorts experienced reductions in anti-VEGF injections, Abbey said.
Initial study results support the dose levels and commercial manufacturing process. “ABBV-RGX-312 manufactured by the bioreactor process demonstrated a similar clinical profile to the HS clinical process,” Abbey said. “Common AEs were similar and protein level expression was similar.”
A phase 2 pharmacodynamic, open-label study is already begun that will evaluate different doses of ABBV-RGX-314 from the two different formulations (clinical versus commercial formulations). In addition, a pivotal phase 3 trial (ASCENT) began recruiting patients last year that compare two doses of ABBV-RGX-314 to Eylea administered via intravitreal injection every eight weeks. The study will recruit 465 patients and the primary outcome is best corrected visual acuity at week 54.
In a separate presentation, results from a phase 2 trial, AAVIATE, were given by David S. Boyer, M.D., adjunct clinical professor of Ophthalmology with the University of Southern California/Keck School of Medicine in Los Angeles. This study assessed the delivery of ABBV-RGX-314 using a suprachoroidal injection. This method uses a microneedle to insert the gene therapy into the space between the sclera (the outer layer of the eye) and the choroid (part of the vascular layer of the eye).
The trial assessed three doses of ABBV-RGX-314. In the first two cohorts, patients were compared with monthly intravitreal injections of Lucentis. All patients in cohorts 3 to 6 received ABBV-RGX-314.
As of Aug. 1, 2022, ABBV-RGX-314 suprachoroidal delivery was reported to be well tolerated across 85 patients dosed in cohorts 1 to 5. Patients treated with ABBV-RGX-314 had stable vision and retinal thickness across all dose levels. Patients in cohort 4 who received the highest dose experienced an 85% reduction in annualized rate of injections with anti-VEGF therapies and 67% of patients were injection free through six months.
Boyer also presented results from cohort 6, which haven’t been present before. These patients received the highest dose and all received a short-course of prophylactic ocular steroids following ABBV-RGX-314. Boyer said the use of the prophylactic steroids reduced the amount of inflammation. “Topical drops seem to control the problem completely,” he said. “Seven weeks of topical therapy seemed to be the magical number.”
Fifteen serious adverse events were reported, but none were considered related to ABBV-RGX-314. Mild intraocular inflammation was reported at similar incidence in the first and second dose levels, with an increase in incidence in mild-to-moderate inflammation seen at the third dose level. All resolved with topical corticosteroids.