Gene therapy 4D-150 enters phase 3 in DME with 4SIGHT trial launch

The first patients have been enrolled in 4SIGHT, a global phase 3 trial comparing a single intravitreal injection of the investigational gene therapy 4D-150 with aflibercept 2 mg every 8 weeks in treatment-naive patients with diabetic macular edema (DME), 4D Molecular Therapeutics (4DMT) recently announced.¹

The company also reported 2-year results from the phase 2 SPECTRA trial. In that trial, 9 patients who received the planned phase 3 dose gained a mean of 10.8 letters of best-corrected visual acuity (BCVA) and received a mean of 5.2 supplemental aflibercept injections.¹

The trial will test whether a one-time, vector-delivered anti-VEGF therapy can maintain visual outcomes comparable to the labeled aflibercept regimen while reducing the injection burden associated with undertreatment in routine DME care. DME is the second indication for 4D-150 to reach phase 3. The first indication was wet age-related macular degeneration (AMD), where both 4FRONT trials have completed enrollment.¹

4SIGHT design and regulatory pathway

4SIGHT is a multicenter, randomized, double-masked, active-controlled trial with a planned enrollment of 514 patients.¹ All participants receive 5 loading doses of aflibercept 2 mg. To be randomized, patients must show a response to aflibercept after the first 3 loading doses. Response is defined as a reduction in central subfield thickness (CST) of at least 10% to 400 µm or less, or a CST below 315 µm.¹ The 4FRONT wet AMD trials use the same enrichment approach.¹

The primary end point is noninferiority in mean BCVA change from baseline at week 52. There are 2 key secondary end points, both at week 52:¹

• the number of aflibercept injections received in the 4D-150 arm vs the comparator arm
• the proportion of patients with at least a 2-step improvement on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS)

Patients in both arms are eligible for supplemental aflibercept. The announcement did not specify the noninferiority margin or follow-up beyond week 52.

4D-150 holds Regenerative Medicine Advanced Therapy (RMAT) designation from the US Food and Drug Administration (FDA) for DME.¹ According to the company, both the FDA and the European Medicines Agency (EMA) have agreed that a single phase 3 DME trial could support marketing applications. That trial would be combined with existing SPECTRA and PRISM data and the 2 phase 3 4FRONT wet AMD trials.¹˒³

SPECTRA 2-year results

SPECTRA (NCT05930561) is a phase 2 dose-ranging trial in adults with DME.² Its first part was open-label and enrolled 22 patients with high disease activity on CST.³˒⁴ Each received a single injection of 4D-150 at 1 of 3 doses:³

• 3 × 10¹⁰ vg/eye (n = 9)
• 1 × 10¹⁰ vg/eye (n = 12)
• 5 × 10⁹ vg/eye (n = 1)

At the March 12, 2026, data cutoff, no intraocular inflammation had been observed at any time point in any of the 22 patients.¹ There were no ocular serious adverse events, and no cases of hypotony, endophthalmitis, vasculitis, choroidal effusion, or retinal artery occlusion. No patient progressed to proliferative diabetic retinopathy or developed vitreous hemorrhage.¹

In the 3 × 10¹⁰ vg/eye group, mean BCVA improved by 10.8 letters and mean CST fell by 176 µm on optical coherence tomography.¹ After 3 aflibercept loading doses, patients received a mean of 5.2 supplemental injections. The company projected 13.0 injections for on-label aflibercept 2 mg every 8 weeks over the same period and describes the difference as a 61% reduction in treatment burden.¹ Two of 9 patients (22%) needed no supplemental injections.

The company also presented a retrospective estimate of a 75% reduction using the 4SIGHT retreatment criteria, which it describes as less stringent than those used in SPECTRA. It notes that actual 4SIGHT results may differ.¹

Clinical context

An analysis of National Health and Nutrition Examination Survey data estimated that about 746,000 US adults aged 40 years or older have DME.⁵ The company cites a figure of approximately 1 million.¹

Intravitreal anti-VEGF therapy is first-line treatment for center-involving DME with vision loss. In VISTA and VIVID, aflibercept 2 mg every 8 weeks after 5 monthly loading doses produced a mean BCVA gain of 10.7 letters at week 52 in each trial.⁶ In the DRCR Retina Network Protocol T, aflibercept, bevacizumab, and ranibizumab all improved vision over 2 years.⁷ Real-world outcomes have lagged behind trial results. A large US analysis found visual acuity at 1 year was roughly 1 line worse than in randomized trials, a gap linked to fewer injections.⁸

About 4D-150

4D-150 uses R100, an adeno-associated virus capsid developed through directed evolution in nonhuman primates to cross vitreoretinal barriers after intravitreal injection.⁹ The vector carries 2 transgenes:⁹

1. a codon-optimized sequence encoding aflibercept, which inhibits VEGF-A, VEGF-B, and placental growth factor
2. a microRNA that suppresses VEGF-C expression

In wet AMD, the phase 1/2 PRISM trial has reported follow-up of up to 3.5 years.¹⁰ At the 3 × 10¹⁰ vg/eye dose, 2 of 71 patients (2.8%) developed transient, mild (1+) intraocular inflammation within the first 28 weeks, with no new cases after that.¹⁰ The phase 3 4FRONT-1 (NCT06864988) and 4FRONT-2 (NCT07064759) trials compare 3 × 10¹⁰ vg/eye of 4D-150 with aflibercept 2 mg.¹¹˒¹²

Interpreting the data

The SPECTRA findings are encouraging on safety, particularly the absence of intraocular inflammation in DME, but the efficacy data come from 9 patients without a concurrent control arm. The 10.8-letter BCVA gain is numerically similar to the aflibercept benchmark from VISTA and VIVID.⁶ However, cross-trial comparisons are limited by differences in populations, loading regimens, and sample size.

Durability is the central question for 4SIGHT. In the 60-week analysis, patients in the phase 3 dose group had received a mean of 1.6 supplemental injections, and 4 of 9 had needed none. The company reported this as a 78% reduction vs projected on-label dosing.³ By 2 years, the cumulative mean had risen to 5.2 injections, only 2 of 9 patients remained injection-free, and the reported reduction had narrowed to 61%.¹˒³ The release does not break down injections by time interval, so it is not possible to tell whether retreatment needs stabilized or kept increasing during the second year.

Arshad M. Khanani, MD, MA, FASRS, of Sierra Eye Associates, enrolled the first patient in 4SIGHT and chairs 4DMT's Retina Advisory Board. In the release, he said that many patients with DME struggle to keep up with frequent anti-VEGF injections, which may contribute to suboptimal outcomes.¹

Limitations and next steps

The SPECTRA data have several limitations:

• a very small phase 3 dose group
• open-label treatment
• comparison with a projected injection count rather than an active control
• retreatment criteria that differ from those of the phase 3 trial

4SIGHT will provide the first randomized, controlled evidence in DME. Because randomization requires a demonstrated aflibercept response, results may not apply to patients with a poor anti-VEGF response. Several questions remain open:

• how long transgene expression lasts
• long-term safety, given that the therapy cannot be withdrawn once delivered
• the effect on retinopathy severity, which the ETDRS-DRSS secondary end point is designed to assess

References

1. 4D Molecular Therapeutics. 4DMT advances 4D-150 into phase 3 for second large market retina indication with initiation of 4SIGHT in DME. News release. GlobeNewswire. September 28, 2026. https://www.globenewswire.com/news-release/2026/09/28/3369825/0/en/4dmt-advances-4d-150-into-phase-3-for-second-large-market-retina-indication-with-initiation-of-4sight-in-dme.html

2. 4D-150 in patients with diabetic macular edema (SPECTRA). ClinicalTrials.gov identifier: NCT05930561. https://clinicaltrials.gov/study/NCT05930561

3. 4D Molecular Therapeutics. 4DMT presents positive 60-week results from 4D-150 SPECTRA clinical trial in DME and regulatory update. News release. July 31, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-60-week-results-4d-150-spectra-clinical

4. Almeida D. Interim results from the SPECTRA phase 2a clinical trial evaluating intravitreal 4D-150 in adults with diabetic macular edema. Presented at: 43rd Annual Scientific Meeting of the American Society of Retina Specialists; July 31, 2025. https://www.asrs.org/content/documents/diabetic-retinopathy-symposium-2.2025.pdf

5. Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132(11):1334-1340. doi:10.1001/jamaophthalmol.2014.2854. https://doi.org/10.1001/jamaophthalmol.2014.2854

6. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254. doi:10.1016/j.ophtha.2014.05.006. https://doi.org/10.1016/j.ophtha.2014.05.006

7. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359. doi:10.1016/j.ophtha.2016.02.022. https://doi.org/10.1016/j.ophtha.2016.02.022

8. Ciulla TA, Bracha P, Pollack J, Williams DF. Real-world outcomes of anti–vascular endothelial growth factor therapy in diabetic macular edema in the United States. Ophthalmol Retina. 2018;2(12):1179-1187. doi:10.1016/j.oret.2018.06.004. https://doi.org/10.1016/j.oret.2018.06.004

9. Calton MA, et al. Design and characterization of a novel intravitreal dual-transgene genetic medicine for neovascular retinopathies. Invest Ophthalmol Vis Sci. 2024;65(14):1. doi:10.1167/iovs.65.14.1. https://doi.org/10.1167/iovs.65.14.1 [full author list to be confirmed]

10. 4D Molecular Therapeutics. 4DMT announces positive long-term data from phase 1/2 PRISM clinical trial in wet AMD. News release. November 6, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-positive-long-term-data-phase-12-prism-clinical/

11. 4D-150 in patients with macular neovascularization secondary to age-related macular degeneration (4FRONT-1). ClinicalTrials.gov identifier: NCT06864988. https://clinicaltrials.gov/study/NCT06864988

12. Single intravitreal injection of 4D-150 in patients with macular neovascularization secondary to age-related macular degeneration (4FRONT-2). ClinicalTrials.gov identifier: NCT07064759. https://clinicaltrials.gov/study/NCT07064759