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SPECTRA Data Suggests 4D-150 Safe for Diabetic Macular Edema, with David Almeida, MD, PhD
An interim report from the ongoing trial shows few adverse events resulting from 60 weeks of treatment with the combined AAV vector/dual-transgene cassette.
New data from the SPECTRA phase 2a clinical trial have revealed the efficacy and safety of 4D-150 in maintaining anatomic and visual improvements in patients with diabetic macular edema (DME) through 60 weeks.
Presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, this data highlights the investigational intravitreal genetic medicine 4D-150. The medication is comprised of an evolved retinotropic AAV vector (R100) and a dual-transgene cassette encoding aflibercept and an miRNA sequence targeting VEGF-C.1
Retinal gene therapy has become a burgeoning industry since the approval of voretigene neparvovec-rzyl (Luxturna) for confirmed biallelic RPE65-mediated inherited retinal disease in December 2017. At the time, it was the first approved gene therapy for inherited disease; since then, the gene therapy landscape in retina has continued to expand into non-hereditary retinal disease as well.2
HCPLive sat down with lead presenter David Almeida, MD, PhD, director of clinical research at Erie Retinal Surgery, to discuss the implications of this new medication and plans for the continuing SPECTRA trial. Almeida described the treatment’s physical makeup in more detail.
“The transgene codes for aflibercept, so that once the promoter activates inside your eye, it will make the aflibercept molecule that we know works well and has good safety,” Almeida told HCPLive. “The other part of the transgene is an RNA inhibitory fragment for VEGF. The idea there is that, because there was the ability to add this additional efficacy and send it to the transgenic construct, this is going to deal with a potential for scarring and fibrosis, or late-stage bad outcomes.”
SPECTRA is a multicenter, open-label phase 2 clinical trial. Investigators included patients with type 1 or 2 diabetes mellitus who exhibited macular thickening secondary to DME. Additionally, patients had to present with a confirmed anti-VEGF response, determined by a central subfield thickness (CST) decrease of ≥40 µm at week -1 versus week -8.1
Participants in the study received loading doses of intravitreal aflibercept 2 mg at weeks -8, -4, and 2. A singular injection of 4D-150 3x1010 vg/eye, 1x1010 vg/eye, or 5x109 vg/eye was then administered on day 1 of the study. Patients were given a 16-week course of tapered topical corticosteroids beginning on day -3.1
SPECTRA’s primary endpoints include adverse events, supplemental anti-VEGF injections, and changes in baseline CST and BCVA.1
So far, 22 participants have received intravitreal 4D-150 3e10 vg/eye (n = 9), 1e10 vg/eye (n = 12), or 5e9 vg/eye (n = 1). Assessed safety outcomes indicated good toleration of 4D-150 through week 60, with no signs of intraocular inflammation or significant changes in intraocular pressure. All patients completed the 16-week corticosteroid program on schedule.1
Mean (standard deviation [SD]) change in BCVA was +9.7 letters in the 3e10 vg/eye group and +8.3 letters in the 1e10 vg/eye group. Mean change in CST was -174 µm in the 3e10 vg/eye group and -140 µm in the 1e10 vg/eye group. Patients saw 58% fewer injections in the 3e10 compared to the 1e10 group.1
The 3e10 vg/eye arm showed a 58% reduction in injection burden compared to the 1e10 vg/eye arm. Additionally, the 3e10 arm saw a 78% reduction compared to a projected regimen of aflibercept 8mg every 8 weeks.1
No intraocular inflammation was recorded at any time point or dose level. All patients completed the topical steroid taper on schedule. No serious ocular treatment-emergent adverse events have been reported, and no events whatsoever have been related to 4D-150.1
Given the sustained vision gains and anatomic control, Almeida expressed excitement regarding the future of 4D-150 and its applications.
“With the excellent safety, I think it’s a first line platform therapy that can really change both the treatment burden aspect of patients with diabetes, but also how well they do with their outcomes,” Almeida said. “That’s where I hope it goes, but I think safety is going to be critical, and I think we’re on our way there.”
With the conclusion of SPECTRA, 4DMT is ready for a phase 3 trial.
Editor's Note: Almeida reports the following disclosures: Regeneron, Alcon, Baush, Bayer, Genentech, Novartis, and others.
References
Almeida D, Emanuelli A, Hu R, Edwards A, et al. Interim Results From the SPECTRA Phase 2a Clinical Trial Evaluating Intravitreal 4D-150 in Adults With Diabetic Macular Edema. Abstract presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, July 30-August 2, 2025.
Rowe LW, Ciulla TA. Gene Therapy for Non-Hereditary Retinal Disease: Age-Related Macular Degeneration, Diabetic Retinopathy, and Beyond. Genes (Basel). 2024;15(6):720. Published 2024 Jun 1. doi:10.3390/genes15060720
