Key Takeaways

  • The phase 3 4SIGHT trial has begun enrolling treatment-naïve patients with DME and will compare intravitreal 4D-150 with aflibercept 2 mg every 8 weeks, with BCVA noninferiority at week 52 as the primary endpoint
  • In the 9-patient SPECTRA phase 3-dose cohort, 4D-150 was associated with a mean 10.8-letter BCVA gain and a mean 176-µm CST reduction at 2 years
  • SPECTRA patients received 61% fewer injections than the company's projected every-8-week aflibercept regimen after loading doses; the small sample size and retrospective nature of the 75% treatment-burden estimate warrant confirmation in Phase 3

4D Molecular Therapeutics (4DMT) has enrolled the first patients at multiple sites in the phase 3 4SIGHT clinical trial evaluating 4D-150 as a potential treatment for diabetic macular edema (DME). The company also reported 2-year results from the phase 1/2 SPECTRA trial, including sustained visual and anatomic improvements and reductions in supplemental anti-VEGF treatment.

The initiation of 4SIGHT expands the late-stage development program for 4D-150 beyond wet age-related macular degeneration (AMD), for which 4DMT has completed enrollment in 2 Phase 3 4FRONT trials.

“The favorable safety profile, durable vision and anatomic improvements and clinically meaningful treatment burden reduction observed through two years in the SPECTRA Part 1 clinical trial in DME strengthen our confidence as we expand 4D-150 into the 4SIGHT Phase 3 trial in DME,” David Kirn, MD, co-founder, president, and CEO of 4D Molecular Therapeutics, said in a company announcement.

The global, multicenter 4SIGHT trial is expected to enroll 514 treatment-naïve patients with DME. The randomized, double-masked study will compare intravitreal 4D-150 with aflibercept 2 mg administered every 8 weeks. All participants will receive 5 loading doses of aflibercept. Randomization requires patients to demonstrate a response to aflibercept following the first 3 loading doses during the run-in period. Responsiveness is defined according to prespecified central subfield thickness (CST) criteria.

The trial's primary endpoint is noninferiority in mean change from baseline in best-corrected visual acuity (BCVA) at week 52.

Key secondary endpoints include the reduction in treatment burden, measured by the number of supplemental aflibercept injections administered in the 4D-150 arm compared with the aflibercept control arm through week 52. Investigators will also evaluate the proportion of patients achieving at least a 2-step improvement from baseline on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale at week 52.

Patients in both treatment groups will be eligible to receive supplemental aflibercept according to trial criteria.

According to 4D Molecular Therapeutics, 4D-150 has received Regenerative Medicine Advanced Therapy designation from the FDA for DME. The company said it has reached alignment with the FDA and European Medicines Agency on potential regulatory submissions based on the single 4SIGHT phase 3 study, together with data from SPECTRA, PRISM, and the 2 Phase 3 4FRONT studies in wet AMD.

SPECTRA results extend to 2 years

The company separately reported 2-year findings from the SPECTRA trial, based on a March 12, 2026, data cutoff.

Among 22 patients included in the safety analysis, investigators reported no intraocular inflammation at any time point and no ocular serious adverse events. No cases of hypotony, endophthalmitis, vasculitis, choroidal effusion, or retinal artery occlusion were reported. The company also reported no progression to proliferative diabetic retinopathy or vitreous hemorrhage.

Clinical activity findings were reported for 9 patients who received the phase 3 dose of 3 × 10^10 vector genomes/eye. At 2 years, patients had a mean BCVA gain of 10.8 letters and a mean CST reduction of 176 µm. Following 3 aflibercept loading doses, patients received a mean of 5.2 supplemental injections, representing a 61% reduction compared with the company's projection of 13 injections under an aflibercept 2-mg every-8-week regimen. Two of the 9 patients, or 22%, remained free of supplemental injections.

4D Molecular Therapeutics also conducted a retrospective analysis applying the supplemental injection criteria being used in 4SIGHT. Under those criteria, patients would have received an estimated mean of 3.2 supplemental injections, corresponding to an estimated 75% reduction from the projected aflibercept regimen. The company cautioned that the analysis is retrospective and that actual results in the phase 3 study may differ.

4D-150 is an investigational intravitreal gene therapy designed to provide sustained retinal expression of aflibercept and inhibition of VEGF-C following a single injection. The therapy uses the company's R100 adeno-associated virus vector and a transgene payload designed to express aflibercept along with an inhibitory RNA targeting VEGF-C.

The program is being developed for both DME and wet AMD, with the goal of maintaining disease control while reducing patients' dependence on repeated anti-VEGF injections.

Arshad M. Khanani, MD, MA, FASRS, director of clinical research at Sierra Eye Associates, clinical professor at the University of Nevada, Reno School of Medicine, and chair of the company's Retina Advisory Board, said the phase 3 trial will further evaluate whether the approach can provide sustained disease control while lowering treatment burden.