4D Molecular Therapeutics (4DMT) has announced promising clinical trial results for its genetic medicine candidate, 4D-150, in treating both wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME). The data, presented at the Angiogenesis, Exudation, and Degeneration 2025 conference and in a corporate webcast, highlight 4D-150's potential to reduce the treatment burden for patients while maintaining or improving vision. With positive feedback from the U.S. Food and Drug Administration (FDA), 4DMT is advancing 4D-150 into Phase 3 clinical trials for both indications.
Preclinical Data Highlights Vector Efficacy
Prior to the clinical advancements, preclinical data published in Investigative Ophthalmology & Visual Science (IOVS) showcased the potential of 4DMT's Therapeutic Vector Evolution (TVE) platform and the intravitreal R100 vector. The R100 vector demonstrated superior transduction and transgene expression compared to AAV2, the standard AAV serotype used in retinal gene therapies. In a nonhuman primate wet AMD model, intravitreal administration of the R100-based 4D-150 led to robust retinal expression of dual transgenes (aflibercept and anti-VEGF C) and complete suppression of severe choroidal neovascularization (CNV) lesions.
SPECTRA Trial: Positive Results in DME
Interim data from Part 1 of the SPECTRA clinical trial, which evaluated 4D-150 in DME patients, showed positive safety and clinical activity. The trial enrolled 22 patients across three dose levels. The 3E10 vg/eye dose demonstrated a sustained gain of +8.4 letters in best corrected visual acuity (BCVA) and a reduction of -194 μm in central subfield thickness (CST) through Week 32. Notably, this dose level also achieved an 86% reduction in injection burden compared to projected on-label aflibercept 2mg Q8W, with a mean of 0.6 supplemental injections per patient through Week 32.
Carlos Quezada-Ruiz, M.D., FASRS, SVP, Therapeutic Area Head, Ophthalmology at 4DMT, stated, "4D-150 represents a potentially transformative new therapeutic option for the approximately one million DME patients in the U.S. alone... potentially setting a new backbone therapy providing multi-year sustained VEGF inhibition in the retina with a single, safe, intravitreal injection."
FDA Alignment and Phase 3 Plans for DME
The FDA has aligned with 4DMT on a registrational pathway for 4D-150 in DME, indicating that a single Phase 3 clinical trial, combined with data from the SPECTRA and PRISM (wet AMD) trials, would be acceptable for a Biologics License Application (BLA) submission. The Phase 3 trial is expected to enroll approximately 300-400 patients with a primary endpoint of BCVA noninferiority versus on-label aflibercept 2mg.
PRISM Trial: Promising Data in Wet AMD
4DMT also presented positive interim 52-week data from the Phase 2b Population Extension cohort of the PRISM clinical trial, evaluating 4D-150 in a broad wet AMD patient population. The 3E10 vg/eye dose achieved an 83% reduction in injection burden compared to projected on-label aflibercept 2 mg Q8W. In a recently diagnosed subgroup, 87% required only 0-1 supplemental injection, and 80% were injection-free through 52 weeks.
Dante Pieramici, M.D., a principal investigator of the PRISM study, commented, "The promise of 4D-150 for both patients and clinicians lies in its potential to tackle one of the most pressing unmet needs in vascular retinal diseases—providing a long-lasting, effective treatment option that reduces the frequent burden of bolus anti-VEGF injections."
Safety and Durability
Across both trials, 4D-150 has demonstrated a favorable safety profile, with no significant intraocular inflammation or related adverse events reported. Long-term data from the PRISM trial showed durable and stable aflibercept expression for up to two years, with aqueous humor concentrations consistently within the projected therapeutic range.
Looking Ahead
4DMT anticipates initiating the 4FRONT-1 and 4FRONT-2 Phase 3 trials for wet AMD in Q1 and Q3 2025, respectively. The company plans to present two-year Phase 1/2a and 18-month Phase 2b PRISM data in Q4 2025, with primary endpoint 52-week topline data from both 4FRONT-1 and 4FRONT-2 expected in H2 2027.
With its innovative approach to genetic medicine and promising clinical data, 4DMT's 4D-150 holds the potential to transform the treatment landscape for wet AMD and DME, offering patients a long-lasting, single-injection therapy that reduces the burden of frequent anti-VEGF injections.
