4DMT Enrolls First Patients in 4SIGHT Phase 3 Trial of 4D-150 for Diabetic Macular Edema
核心洞察
4D Molecular Therapeutics has enrolled the first patients in the global 4SIGHT Phase 3 trial of intravitreal 4D-150 in treatment-naive diabetic macular edema (搜索), with a planned enrollment of 514 patients.
The trial's primary endpoint is non-inferiority in mean change from baseline in best corrected visual acuity at Week 52 versus aflibercept 2 mg every eight weeks.
Two-year SPECTRA Part 1 data showed no intraocular inflammation or ocular serious adverse events, with a mean BCVA gain of 10.8 letters at the Phase 3 dose.
4D Molecular Therapeutics has enrolled the first patients across multiple sites in 4SIGHT, a global Phase 3 trial of intravitreal 4D-150 in treatment-naive diabetic macular edema (搜索) (DME). The company announced the start of the study alongside updated two-year data from the SPECTRA Part 1 trial in DME, with a data cutoff of March 12, 2026.
The initiation makes DME the second Phase 3 indication for 4D-150, following the two 4FRONT Phase 3 trials in wet age-related macular degeneration (搜索), for which enrollment has been completed.
"The initiation of 4SIGHT marks an important step in advancing 4D-150 toward becoming a continuous backbone therapy for sustained control of major VEGF (搜索)-driven retinal diseases," said David Kirn, M.D., co-founder, president and chief executive officer of 4DMT. He said the two-year SPECTRA data strengthened the company's confidence as it expands 4D-150 into the DME Phase 3 program.
4SIGHT Trial Design
4SIGHT is a multicenter, randomized, double-masked, aflibercept 2 mg every eight weeks (Q8W) comparator-controlled trial enrolling 514 treatment-naive patients with DME. All participants receive five aflibercept loading doses.
The primary endpoint is non-inferiority in the mean change from baseline in best corrected visual acuity (BCVA) at Week 52. Key secondary endpoints are treatment burden reduction, measured as the number of aflibercept injections received in the 4D-150 arm versus the comparator arm through Week 52, and the proportion of participants with at least a 2-step improvement from baseline on the Early Treatment Diabetic Retinopathy (搜索) Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52. Patients in both arms are eligible for supplemental aflibercept injections.
As in the 4FRONT wet AMD trials, randomization requires on-trial demonstration of aflibercept responsiveness after the first three of five loading doses during the run-in period, defined as a central subfield thickness (CST) reduction of at least 10% and CST of at least 400 µm, or CST below 315 µm.
Regulatory Alignment
4D-150 holds FDA Regenerative Medicine Advanced Therapy designation for DME. According to 4DMT, the company has alignment with the FDA and the European Medicines Agency (搜索) on potential Biologics License Application and marketing authorization application filings based on the single 4SIGHT Phase 3 DME trial, supported by data generated to date in the SPECTRA and PRISM trials combined with data from the two 4FRONT Phase 3 trials in wet AMD.
Two-Year SPECTRA Results
In the SPECTRA Part 1 trial, 4D-150 was well tolerated across 22 patients, with no intraocular inflammation at any timepoint, no ocular serious adverse events, and no cases of hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions. No patients progressed to proliferative diabetic retinopathy (搜索) or vitreous hemorrhage.
At the Phase 3 dose of 3E10 vg/eye (n=9), patients gained a mean of 10.8 letters in BCVA and showed a mean CST reduction of 176 µm as measured by optical coherence tomography.
On supplemental injections, SPECTRA used stringent criteria intended to maximize patient safety while assessing initial clinical activity. After three aflibercept loading doses, patients required substantially fewer injections than on-label aflibercept 2 mg Q8W, corresponding to a 61% overall treatment burden reduction (5.2 mean supplemental injections per patient versus 13.0 injections projected with on-label aflibercept 2 mg Q8W). Applying the 4SIGHT Phase 3 supplemental injection criteria, which the company said are more in line with contemporary Phase 3 trials, yielded an estimated 75% overall treatment burden reduction (3.2 estimated mean supplemental injections per patient versus 13.0 projected). That figure is a retrospective estimate and actual results in 4SIGHT may differ. Two of nine patients (22%) remained injection-free.
"Based on the 2-year data from the SPECTRA trial, I believe a single in-office injection of 4D-150 has the potential to transform the treatment paradigm for DME by providing sustained disease control while reducing treatment burden," said Arshad M. Khanani, M.D., M.A., FASRS, director of clinical research at Sierra Eye Associates, clinical professor at the University of Nevada, Reno School of Medicine, and chair of the 4DMT Retina Advisory Board. He noted that many patients with DME struggle to adhere to frequent anti-VEGF (搜索) injection schedules because of treatment burden and the need for numerous other physician visits, which may contribute to suboptimal visual outcomes.
Mechanism and Disease Context
4D-150 is designed as a continuous backbone therapy delivering anti-VEGF (搜索) biologics (aflibercept and anti-VEGF-C (搜索)) within the retina for multiple years, and potentially lifelong, after a single intravitreal injection. It uses 4DMT's primate-evolved intravitreal AAV vector, R100, developed through the company's Therapeutic Vector Evolution platform, together with a transgene payload designed for robust aflibercept expression plus an anti-VEGF-C inhibitory RNA.
DME is a complication of diabetic retinopathy (搜索) characterized by inflammation and swelling in the macula from blood vessel leakage, which can lead to vision loss. Published data cited by the company estimate approximately one million individuals with DME in the United States. The condition is typically treated with intravitreal anti-VEGF (搜索) agents administered roughly every 4 to 12 weeks, and patient compliance with therapy is poor, leaving significant unmet need.
4DMT's second product candidate, 4D-710, is described as the first known genetic medicine to demonstrate successful delivery and expression of the CFTR (搜索) transgene in the lungs of people with cystic fibrosis (搜索) after aerosol delivery. All of the company's product candidates remain in clinical or preclinical development and have not been approved for marketing by the FDA or any other regulatory authority.