4D-150 Reduces Injection Burden in DME, Paving Way for FDA-Backed Phase 3

Carlos Quezada-Ruiz, MD

Credit: LinkedIn

Topline interim data from Part 1 of the SPECTRA clinical trial revealed the positive safety and clinical activity of 4D-150 in patients with diabetic macular edema (DME), with feedback from the US Food and Drug Administration (FDA) supporting the drug’s progression to Phase 3.¹

Announced by 4DMT on January 10, 2025, 4D-150 sustained gains in best-corrected visual acuity (BCVA) and a reduction in central subfield thickness (CST), while remaining tolerable without signs of intraocular inflammation (IOI) across the SPECTRA trial.

“The promising initial safety and clinical activity data of 4D-150 in DME patients, together with the promising results in wet AMD, reinforces the potential applicability of 4D-150 across multiple VEGF-driven retinal diseases,” Carlos Quezada-Ruiz, MD, senior vice president, therapeutic area head in ophthalmology at 4DMT, said in a statement. “4D-150 represents a potentially transformative new therapeutic option for the approximately 1 million DME patients in the US alone.”

4D-150 is under investigation as a potential backbone therapy targeting multi-year sustained delivery of anti-vascular endothelial growth factor (VEGF) to the retina with a single intravitreal injection in DME and wet age-related macular degeneration (AMD). The SPECTRA trial evaluated the safety and tolerability of 4D-150, using stringent supplemental aflibercept criteria and enrolling patients with high CST.

To identify the dose level for further evaluation, a total of 22 patients were enrolled across 3 dose levels: 3E10 vg/eye (n = 9), 1E10 vg/eye (n = 12), and 5E9 vg/eye (n = 1). A single patient in the 1E10 vg/eye terminated the study before completion of a post-baseline assessment after death determined unrelated to 4D-150.

In the safety assessment (n = 21), 4D-150 remained well-tolerated, without reports of IOI at any time point. Each patient completed the 16-week topical corticosteroid taper and remained off steroids. There were additionally no signs of hypotony, endophthalmitis, vasculitis, choroidal effusions, or retinal artery occlusions.

Efficacy analysis at 32 weeks found the 3E10 vg/eye arm sustained BCVA gains of +8.4 letters and CST reductions of –194 µm. Further analysis revealed that, post-aflibercept loading doses, the 3E10 vg/eye dose achieved notably fewer supplemental injections, compared with the 1E10 vg/eye and projected on-label aflibercept 2 mg every 8 weeks (Q8W) treatment arms.

Mean injection rates per patient included 0.6 for the 3E10 vg/eye arm, 1.4 for the 1E10 vg/eye arm, and 4.0 for the projected aflibercept 2 mg Q8W arm. Notably, the 3E10 vg/eye arm achieved a reduction of 61% versus the 1E10 vg/eye arm, and a reduction of 86% vs. the projected on-label aflibercept 2 mg Q8W. Full 52-week interim data is expected at a scientific conference in mid-2025.

Based on these data, 4DMT announced its alignment with the FDA on a single Phase 3 clinical trial as the basis for the 4D-150 Biologics License Application (BLA) submission in DME. The alignment was confirmed based on a review of both SPECTRA and PRISM (wet AMD) combined with 2 planned clinical trials in the 4FRONT wet AMD program.

This feedback allows 4DMT to proceed to Phase 3 without conducting SPECTRA Part 2, with both parties aligned on the trial population (~300-400 patients), the primary endpoint (BCVA noninferiority vs. on-label aflibercept 2 mg Q8W), and revised supplemental injection criteria. 4DMT has selected the 3E10 vg/eye dose of 4D-150 for the Phase 3 trial.

In a separate news release on January 10, 2025, 4DMT shared its strategically focused pipeline plan, announcing it will focus most of its research and development operations on global development and pre-commercial planning for 4D-150 in wet AMD.²

“The alignment with the FDA on the design and path forward for a single Phase 3 trial in DME is a positive step forward in our ability to realize 4D-150’s potential as a pipeline-in-a-product, which may unlock DME as a second large market indication shortly after wet AMD,” David Kirn, MD, co-founder and chief executive officer of 4DMT, added in a statement.

References

1. _{4DMT announces positive interim data from 4D-150 spectra clinical trial in DME and alignment with FDA on registrational path. 4D Molecular Therapeutics. January 10, 2025. Accessed January 10, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-positive-interim-data-4d-150-spectra-clinical#top.}
2. _{4DMT focuses pipeline to prioritize 4D-150 in wet AMD & DME and 4D-710 in CF and extends cash runway. 4D Molecular Therapeutics. January 10, 2025. Accessed January 10, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-focuses-pipeline-prioritize-4d-150-wet-amd-dme-and-4d-710.}