4DMT: First patient enrolled in 4D-150 Phase 2 SPECTRA, PRIS clinical trials

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4D Molecular Therapeutics announced the first patient has been enrolled in the Dose Confirmation stage of the Phase 2 SPECTRA clinical trial (NCT05930561) evaluating intravitreal 4D-150 in patients with diabetic macular edema (DME), and that a Population Extension cohort has been added to the 4D-150 Phase 2 stage of the PRISM clinical trial (NCT05197270) in wet age-related macular degeneration (wet AMD).

Robert Kim, MD, chief medical officer of 4DMT, said in a news release the company is pleased to be advancing 4D-150 in its Phase 2 SPECTRA clinical trial in patients with DME and to further study intravitreal 4D-150 in a broader patient population in wet AMD.

“DME is a major cause of vision loss among people with diabetes and may lead to blindness,” he said in a news release. “Anti-VEGF agents are considered the mainstay of therapy for DME, yet the treatment burden with the current standard of care remains high.”

Based on its unique, multitargeted inhibition of four VEGF family members and the favorable clinical profile observed to date in the Phase 1/2 trial in wet AMD,” Kim said in the release 4D-150 has the potential to provide durable suppression of key pathogenic mediators in DME following a single intravitreal injection that can be administered in-office.

“In wet AMD, we believe that by expanding the patient population treated with 4D-150, we will further characterize 4D-150 in advance of our planned Phase 3 clinical trials, while taking advantage of strong enrollment momentum at clinical sites to date,” Kim said in the release.

David Kirn, MD, co-founder and CEO of 4DMT,noted in the release the continued rapid advancement of 4D-150 in DME and wet AMD demonstrates our commitment to large-market ophthalmology genetic medicines for patients in need, and shows physicians’ and patients’ interest in the transformative potential of single dose intravitreal 4D-150.

“DME is an important opportunity for 4DMT, and we believe 4D-150’s differentiated profile in wet AMD will drive interest and strong enrollment in the SPECTRA trial,” Kirn said in the release. “In wet AMD, 4D-150’s promising clinical profile to date in patients with the highest anti-VEGF need has enabled us to expand the PRISM trial to include a broader patient population in the Population Extension cohort. Importantly, we intend to include a broad wet AMD patient population in pivotal Phase 3 clinical trials with 4D-150. We look forward to sharing multiple clinical and regulatory milestones for 4D-150 in 2024.”

Phase 2 SPECTRA Clinical Trial

The trial is a multicenter, randomized, active-controlled, double-masked dose-ranging trial to evaluate the safety and efficacy of intravitreal 4D-150 in adults with DME and consists of 2 stages:

• Dose Confirmation stage (n=18-24), eligible participants randomized 1:1:1 to receive a single intravitreal injection of 5E9 or 1E10 vg/eye of 4D-150 (initial dose levels) or aflibercept control (n=6 per cohort)
• Dose Expansion stage (n=54), eligible participants randomized 1:1:1 to receive a single intravitreal injection of 4D-150 at one of two dose levels based on results from Dose Confirmation, or aflibercept control (n=18 per cohort)

Key enrollment criteria includes:

• Adult patients with diabetes mellitus with macular thickening secondary to DME involving the center of the fovea and decreased visual acuity attributable primarily to DME
• Study enrolls both treatment-naïve and treatment-experienced DME patients

While the key endpoints are:

• Primary endpoint: annualized number of aflibercept injections in study eye
• Additional endpoints include:
• Incidence and severity of adverse events
• Changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST)
• Percentage of subjects with a ≥2 and ≥3-Step Diabetic Retinopathy Severity (DRS) improvement from baseline on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS)

Phase 2 Stage of PRISM Clinical Trial

The open-label trial is evaluating intravitreal 4D-150 3E10 and 1E10 vg/eye dose levels in patients with wet AMD.

Key enrollment criteria:

• Currently receiving anti-VEGF treatment in the study eye and have demonstrated a clinical response
• 1-6 anti-VEGF injections in last 12 months, in contrast to initial Phase 1/2 cohorts in which patients required ≥6 anti-VEGF injections in last 12 months
• First patient has been enrolled in this cohort

Expected Upcoming Milestones for 4D-150 for Wet AMD and DME

• PRISM Phase 2 Dose Expansion (n=50) initial interim data expected in H1 2024
• Update regarding Phase 3 pivotal trial plans for wet AMD expected in Q1 2024 following initial discussion with FDA in Q4 2023
• Initial interim data from 4D-150 DME Phase 2 Dose Confirmation stage expected in 2024
• Initial interim data from 4D-150 wet AMD Population Extension cohort expected in 2024

About 4D-150

According to the news release, 4D-150 comprises our customized and evolved intravitreal vector, R100, and a transgene cassette that expresses both aflibercept and a VEGF-C inhibitory RNAi. The company. Noted this dual-transgene payload inhibits 4 angiogenic factors that drive wet AMD and DME: VEGF A, B, C and PlGF.

Moreover, the company also noted R100 was invented at 4DMT through our proprietary Therapeutic Vector Evolution platform; we created this platform utilizing principles of directed evolution, a Nobel Prize-winning technology. 4D-150 is designed for single, low-dose intravitreal delivery.