4D Molecular Therapeutics (4DMT) announced that the first patients have been enrolled across multiple sites in the 4SIGHT phase 3 clinical trial evaluating 4D-150 for the treatment of diabetic macular edema (DME).
This update also comes with a 2-year data readout from the phase 2 SPECTRA trial.
First up: 4DMT.
It helps to know about 4DMT’s Therapeutic Vector Evolution.
- What it is: a proprietary platform that uses synthetic adeno-associated virus (AAV) capsid–derived sequences to create customized vectors (such as R100, below) for advancing vector delivery–based product candidates, including 4D-150.
And there’s also the customized R100 intravitreal (IVT) vector.
- What it does: utilizes a dual transgene payload—aflibercept and a vascular endothelial growth factor (VEGF)-C–inhibitory RNAi—to block four angiogenic factors driving wet AMD in order to deliver 4D-150.
How, exactly?
4D-150 is formulated to offer a multi-year, sustained, and low-dose intravitreal (IVT) delivery of anti-VEGF from the retina.
Its clinical performance thus far:
- Check out this 52-week wet age-related macular degeneration (AMD) data from the phase 2b PRISM trial
- See here findings from a 60-week phase 2 analysis on its second proposed indication: diabetic macular edema (DME)
The gene therapy has also received FDA Regenerative Medicine Advanced Therapy (RMAT) designation for DME
Before we get into this new data, wasn’t 4DMT recently in the news?
Indeed. In August the company reported positive 2-year data from the phase 2b PRISM clinical trial (NCT05197270) evaluating 4D-150 in the treatment of wet AMD.
Moving on to the 4SIGHT trial.
The global phase 3 multicenter, randomized, double-masked trial will compare 4D-150 to aflibercept 2 mg (Q8W) comparator-controlled trial in treatment-naïve patients with DME (n=514).
Patients in both arms will be eligible for supplemental aflibercept injections, and all patients will receive five aflibercept loading doses.
Note: Similar to the 4FRONT phase 3 wet AMD trials (NCT06864988 and
NCT07064759), randomization requires on-trial demonstration of aflibercept responsiveness following the first three of five loading doses during the run-in period (central subfield thickness [CST] ≥10% reduction and ≤400 µm or CST <315 µm).
And the main outcome measures?
The primary endpoint is non-inferiority in the mean change from baseline in BCVA at Week 52.
The key secondary endpoints include:
- Treatment burden reduction
- Comparing the number of aflibercept injections received in the 4D-150 arm vs. the aflibercept comparator arm through Week 52
- The proportion of participants with a ≥2-step improvement from baseline in Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at Week 52
With that out of the way, let’s get to the SPECTRA trial findings.
As a reminder: Last year we covered 60-week data from the phase 2 trial (NCT05930561), wherein the gene therapy was well tolerated and there was a 78% reduction in supplemental injections (from Week 8 to 60) for the 3E10 vg/eye dose.
Note: For the data below, the phase 3 dose (3E10 vg/eye, n=9), was utilized and the data cutoff was March 12, 2026.
Clinical efficacy of 4D-150 for the treatment of DME:
- Mean gain in BCVA of +10.8 letters
- Mean reduction in CST of -176 µm, as measured by OCT
- Post-aflibercept loading doses, patients required substantially fewer injections compared to on-label aflibercept 2mg Q8W:
- 61% overall treatment burden reduction (5.2 mean supplemental injections per patient vs. 13.0 injections projected with on-label aflibercept 2 mg Q8W)
- 75% estimated overall treatment burden reduction utilizing 4SIGHT phase 3 supplemental injection criteria, which are more in line with contemporary phase 3 trials (3.2 estimated mean supplemental injections per patient vs. 13.0 injections projected with on-label aflibercept 2 mg Q8W; retrospective estimate, actual results in 4SIGHT may differ)
- 2 of 9 (22%) participants remained injection-free
What about the safety data?
The safety results (n=22) demonstrated that:
- 4D-150 was well tolerated, with no intraocular inflammation (IOI) at any timepoint
- No ocular serious adverse events (SAEs)
- No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions
- No progression to proliferative diabetic retinopathy or vitreous hemorrhage
Any comments from the company?
“In real-world practice, many patients with DME struggle to adhere to the frequent anti-VEGF injection schedule because of the substantial treatment burden and the need for numerous other physician visits, which may contribute to suboptimal visual outcomes,” stated 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 4DMT Retina Advisory Board.
He added: “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.”
So! When can we expect an update?
4DMT reported that it has alignment with the FDA and the European Medicines Agency on potential Biologics License Application (BLA) and marketing authorization application filings with the single 4SIGHT phase 3 DME trial.
- The basis for these filings : Data generated to date for 4D-150 in both the SPECTRA and PRISM clinical trials combined with data from the two phase 3 clinical trials in the 4FRONT wet AMD program.
And for the wet AMD indication: The company noted that it expects topline data from the phase 3 trials 4FRONT-1 and 4FRONT-2 in Q2 2027 and H2 2027, respectively.