4DMT enrols first patients in 4SIGHT Phase 3 DME gene therapy trial
4D Molecular Therapeutics (Nasdaq: FDMT) has begun enrolling patients in 4SIGHT, its global Phase 3 trial evaluating the intravitreal gene therapy candidate 4D-150 in treatment-naïve diabetic macular edema (DME). The Emeryville, California company said first patients have been enrolled across multiple sites, marking a significant step in its ambition to establish 4D-150 as a continuous anti-VEGF backbone therapy for major retinal vascular diseases.
The 4SIGHT trial is a randomised, double-masked, comparator-controlled study targeting 514 patients, using aflibercept 2 mg administered every eight weeks as the active comparator. All participants receive five aflibercept loading doses. The primary endpoint is non-inferiority in mean change from baseline in best corrected visual acuity at week 52. Key secondary endpoints include treatment burden reduction, measured as the number of supplemental aflibercept injections received in the 4D-150 arm versus the comparator arm, and the proportion of patients achieving at least a two-step improvement in diabetic retinopathy severity at week 52.
Supporting data from SPECTRA
Alongside the trial launch, 4DMT disclosed two-year data from the SPECTRA Part 1 trial (data cutoff March 2026, N=22). At the Phase 3 dose of 3E10 vg/eye in the nine evaluable patients, the therapy produced a mean gain of 10.8 letters in best corrected visual acuity and a mean reduction in central subfield thickness of 176 µm. The safety read was clean: no intraocular inflammation was recorded at any timepoint, and no ocular serious adverse events, hypotony, endophthalmitis, vasculitis, or choroidal effusions were observed over the two-year window.
On treatment burden, SPECTRA patients required substantially fewer injections post-loading than would be expected with standard-of-care aflibercept. Using the 4SIGHT supplemental injection criteria, the company estimated a 75% overall treatment burden reduction, equivalent to approximately 3.2 mean supplemental injections per patient versus 13.0 projected with on-label aflibercept. Two of the nine patients at the Phase 3 dose remained injection-free. 4DMT acknowledged that this estimate is a retrospective calculation and that actual 4SIGHT outcomes may differ.
4D-150 carries FDA Regenerative Medicine Advanced Therapy designation for DME, and 4DMT said it has regulatory alignment with both the FDA and the European Medicines Agency on potential Biologics Licence Application and marketing authorisation application filings based on data from the single 4SIGHT trial combined with earlier SPECTRA and PRISM datasets, as well as the two parallel 4FRONT Phase 3 trials in wet age-related macular degeneration.
Market and competitive context
DME affects an estimated one million people in the United States and represents a multi-billion-dollar market currently dominated by repeated intravitreal injections of anti-VEGF agents including aflibercept (Eylea) and ranibizumab. Poor patient adherence to frequent dosing schedules is a well-documented clinical problem that translates into suboptimal visual outcomes in real-world practice.
4DMT is not alone in pursuing durable gene-based approaches to retinal disease. Several programmes from academic spinouts and established ophthalmology-focused biotechs are at earlier stages using adeno-associated virus vectors to deliver sustained anti-VEGF expression, though 4D-150's dual payload targeting both VEGF-A and VEGF-C, via aflibercept expression and an inhibitory RNA respectively, is positioned by the company as differentiated. The RMAT designation and regulatory alignment on a single pivotal trial are meaningful advantages if the efficacy and safety data remain robust at scale; the non-inferiority design against a well-validated standard of care keeps the regulatory bar legible, though it means the trial will not generate a superiority claim on vision gain.
Near-term milestones include full enrolment of 4SIGHT and continued readouts from the two 4FRONT wet AMD Phase 3 trials. Together, the three pivotal studies could position 4D-150 for a simultaneous dual-indication filing, a commercially significant outcome in a retinal disease market where treatment burden reduction is increasingly recognised as a key payer and patient priority.