Gene Therapy Restores Aflibercept Expression in Wet AMD
4D Molecular Therapeutics plans to initiate enrollment in the phase 2 randomized portion of the study in the first quarter of 2023.
The gene therapy 4D-150(4D Molecular Therapeutics) has demonstrated efficacy in updated data from participants with wet age-related macular degeneration (AMD) in cohort 1 of the phase 1/2 PRISM trial (NCT05197270).
“This clinical data on 4D-150 marks an important milestone for 4DMT,” David Kirn, MD, cofounder and chief executive officer, 4DMT, said in a statement. “We are developing 4D-150 for the treatment of large and sustainable markets in ophthalmology, including wet AMD and diabetic macular edema. We believe these results further validate the potential for both our intravitreal R100 vector for other large market eye diseases, and our Therapeutic Vector Evolution platform as an engine to grow our product pipeline.”
The 5 participants in cohort 1 received a single intravitreal injection of 3E10 vg/eye of 4D-150. These participants had a mean annualized anti-VEGF injection rate of around 11 in the 12 months prior to trial enrollment, which was reduced by 96.7% after treatment. Most of these participants (80%) had not received any supplemental aflibercept injections for around 40, 36, 32, or 16 weeks after treatment. Investigators also evaluated aflibercept transgene protein expression and found that all participants had therapeutic levels of expression in the aqueous humor of the eye at 12 weeks after injection.
4D-150 has been safe and well-tolerated to date, with no serious adverse events (AEs) or dose-limiting toxicities reported, including intraocular inflammation, hypotony, endophthalmitis, retinal vasculitis, retinal artery occlusion, or choroidal effusions.
READ MORE: Wet AMD Gene Therapy Demonstrates Promising Safety and Efficacy in Phase 1 Trial
“In the ongoing phase 1/2 PRISM trial, I’m encouraged by the excellent safety and tolerability of intravitreal 4D-150 in patients with wet AMD. At the low dose of 3E10 vg/eye, we have seen a clinically significant reduction in annualized anti-VEGF injection rate in high need patients who previously required very frequent anti-VEGF injections,” principal investigator Arshad M Khanani, MD, MA, FASRS, managing partner and director, clinical research, Sierra Eye Associates, and clinical associate professor, University of Nevada, added. “Utilizing a novel R100 vector and a dual transgene payload, 4D-150 is the first retinal gene therapy that is designed to inhibit all four VEGF-related molecules that drive angiogenesis. I am looking forward to enrolling patients in the randomized Phase 2 expansion stage of this clinical trial.”
4D-150 is comprised of the vector R100, which allows for low doseintravitreal delivery,and expresses aflibercept and a VEGF-C RNAi to inhibit VEGF as well as the angiogenic factors A, B, C, and PIGF. 4D plans to initiate enrollment of the phase 2 randomized portion of the study in the first quarter of 2023 to evaluate doses of 4D-150 ranging from 3E10 to 1E10 vg/eye. Further data from all dose exploration cohorts in the phase 1 portion of the study will be announced in the second quarter of 2023. The company is also exploring other preclinical candidates developed with the R100 vector.
