4D Molecular Therapeutics (4DMT) has announced positive interim data from its Phase 1/2 PRISM clinical trial of 4D-150, an investigational gene therapy for wet age-related macular degeneration (wet AMD). The data, presented at the company's 4D-150 Wet AMD Development Day, highlight the potential for durable clinical benefit and a reduced treatment burden compared to current standard-of-care anti-VEGF injections.
The PRISM study evaluated 4D-150 in patients with wet AMD. Results from a cohort of 30 patients showed an 89% overall reduction in annualized injections through 52 weeks of follow-up. Notably, 70% of these patients were injection-free during this period. In a subgroup of 15 recently diagnosed patients (diagnosed ≤6 months), the reduction in annualized injections was even more pronounced at 98%, with 87% achieving injection-free status.
Clinical Activity and Safety Profile
The study also demonstrated sustained anatomic control, as measured by central subfield thickness (CST), with fewer fluctuations. Mean best-corrected visual acuity (BCVA) remained stable in the Phase 1/2a group and improved in the Phase 2b group. Safety data indicated that 4D-150 was well-tolerated, with an intraocular inflammation (IOI) rate of 2.8% (2 out of 71 patients), comparable to approved anti-VEGF agents. No 4D-150-related hypotony, endophthalmitis, vasculitis, choroidal effusions, or retinal artery occlusions were observed.
4FRONT Phase 3 Program
Based on these promising results, 4DMT is planning a global 4FRONT Phase 3 development program. The program will consist of two double-masked, randomized, controlled non-inferiority trials comparing a single dose of 4D-150 (3E10 vg/eye) to on-label aflibercept (2mg every 8 weeks). The primary endpoint will be non-inferiority in BCVA. The first study, 4FRONT-1, is expected to enroll 500 treatment-naïve wet AMD patients and is slated to begin in Q1 2025. The study design incorporates feedback from the FDA under its Regenerative Medicine Advanced Therapy (RMAT) designation and alignment is ongoing with the European Medicines Agency (EMA) under PRIME designation.
Mechanism of Action
4D-150 is designed to address the limitations of current wet AMD treatments, which typically require frequent intravitreal injections. The gene therapy utilizes an intravitreal vector to deliver a transgene encoding for aflibercept and an RNAi molecule that blocks the VEGF-C protein. This dual mechanism allows 4D-150 to suppress four different VEGF proteins, disrupting a key disease pathway in wet AMD.
Expert Commentary
"Our patients with wet AMD require frequent life-long treatment with intravitreal injections, leading to a high treatment burden and suboptimal outcomes in the real world compared to clinical trials," said Arshad M. Khanani, MD, MA, FASRS, Director of Clinical Research at Sierra Eye Associates and Clinical Professor at the University of Nevada, Reno. "Based on the data to date, 4D-150 has the potential to decrease treatment burden and control wet AMD with a safe, single routine intravitreal injection while maintaining vision and anatomy."
