4D Molecular Therapeutics Announces 4SIGHT Phase 3 DME Enrollment, SPECTRA 2‑Year Data

What Happened

• On September 28, 2026, 4D Molecular Therapeutics (4D) reported that the first patients have been enrolled across multiple sites in 4SIGHT, a global Phase 3 randomized, double‑masked trial (N=514) of intravitreal 4D‑150 versus aflibercept 2 mg (Q8W) in treatment‑naïve diabetic macular edema (DME) patients. The primary endpoint is non‑inferiority in mean change from baseline in best corrected visual acuity (BCVA) at Week 52; all patients receive five aflibercept loading doses and both arms are eligible for supplemental aflibercept injections. Randomization requires on‑trial demonstration of aflibercept responsiveness during the run‑in (after 3 of 5 loading doses).
• The company also reported 2‑year data from the SPECTRA trial (data cutoff March 12, 2026). Safety (N=22) showed 4D‑150 was well tolerated with no intraocular inflammation or ocular serious adverse events. For the Phase 3 dose cohort (3E10 vg/eye, n=9), mean BCVA gain was +10.8 letters and mean central subfield thickness (CST) reduction was −176 µm. Supplemental injection use was substantially lower versus projected on‑label aflibercept: observed 61% reduction (5.2 mean supplemental injections vs. 13.0 projected) and a 75% estimated reduction using 4SIGHT supplemental criteria (3.2 estimated vs. 13.0 projected); 2 of 9 patients remained injection‑free.

Key Details

• Filing date: September 28, 2026; 4SIGHT enrollment started the same day.
• 4SIGHT design: global Phase 3, N=514, primary endpoint = non‑inferiority in BCVA change at Week 52; comparator = aflibercept 2 mg Q8W.
• SPECTRA 2‑year safety population N=22; Phase 3 dose activity cohort n=9: mean BCVA +10.8 letters; mean CST −176 µm.
• Treatment burden: 61% observed reduction vs. projected aflibercept Q8W; 75% estimated reduction under 4SIGHT criteria (retrospective estimate).

Why It Matters

• A Phase 3 start is a major clinical milestone: successful 4SIGHT enrollment and a single pivotal trial pathway (company says it has alignment with FDA and EMA) are key steps toward potential regulatory filings for 4D‑150 in DME. The product has FDA Regenerative Medicine Advanced Therapy (RMAT) designation.
• The SPECTRA 2‑year data provide early evidence of vision improvement (+10.8 letters) and meaningful retinal thickness reduction with a favorable safety profile in a small sample, and suggest lower treatment burden versus current aflibercept dosing—an important potential commercial advantage if confirmed in Phase 3.
• Investors should note limitations stated in the filing: small sample sizes for the activity cohort (n=9), retrospective estimates of treatment‑burden reduction, and forward‑looking statements subject to risks (see the company’s 10‑Q and other SEC filings).