4DMT receives FDA Regenerative Medicine Advanced Therapy designation for 4D-150 genetic medicine for intravitreal treatment of Wet AMD

(Image Credit: AdobeStock/Giovanni Cancemi)

4D Molecular Therapeutics this week announced that the FDA has granted the RMAT designation for the investigational genetic medicine candidate 4D-150 for intravitreal treatment of wet age-related macular degeneration (wet AMD).

According to the company’s news release, the FDA granted RMAT designation based on the potential of 4D-150 to address the unmet medical need within this population.

RMAT designation is part of the 21st Century Cures Act, and the program was created to expedite the development and review of regenerative medicine therapies intended to treat, modify, reverse or cure a serious condition. Receiving RMAT designation offers sponsor companies all the benefits of the fast track and breakthrough therapy designation programs, allowing for early, close and frequent interactions with the FDA with the goal of expediting drug development.¹

The company noted the designation comes on the heels of interim Phase 1 PRISM clinical data for 4D-150 that demonstrated an encouraging safety, tolerability and clinical activity profile. The company also noted 4D-150 ultimately could fulfill an unmet medical need to safely maintain long-term visual acuity outcomes while avoiding the need for repeated intravitreal injections. 4DMT is now working with the FDA and EMA on preliminary Phase 3 clinical trial plans and expects to provide an update in February 2024 along with 4D-150 interim randomized Phase 2 PRISM trial data.¹

David Kirn, MD, co-founder and CEO of 4DMT, pointed out in the news release the company was pleased to receive the first-ever RMAT designation for an investigational treatment for wet AMD with our intravitreal 4D-150 genetic medicine.

“This designation validates our belief in 4D-150’s potential to address the high unmet need of wet AMD patients, to maintain their visual acuity outcomes, and to reduce their treatment burden,” Kirn said in the news release. “We continue to work closely with the FDA and EMA on efficiently advancing 4D-150 development for both wet AMD and diabetic macular edema, and having both RMAT and PRIME designations enables us to further collaborate expeditiously in our efforts to advance development in both geographies.”

Robert Kim, MD, chief medical officer of 4DMT, pointed out that wet AMD patients are waiting for a durable therapy with the potential to significantly reduce treatment burden and preserve vision long term.

“We are grateful that the two largest pharmaceutical regulatory agencies in the world recognize 4D-150’s potential by awarding the unprecedented combination of both RMAT and PRIME designations in wet AMD,” Kim said in the news release. “I am incredibly proud of the team at 4DMT for this accomplishment and we look forward to sharing initial interim data from our randomized Phase 2 Dose Expansion clinical trial in the highest anti-VEGF need patients in February at the 2024 Angiogenesis Conference.”

In July 2023, 4DMT announced that a dose response was demonstrated in favor of the highest tested dose of 3E10 vg/eye, including a promising reduction in supplemental anti-VEGF injections (4 of 4 evaluable patients injection-free) and a clinically meaningful reduction in mean central subfield thickness (CST) at 36 weeks in a patient population with high anti-VEGF need.

As of July 2023, intravitreal 4D-150 remained well tolerated at all doses in all patients, with no Grade ≥1 inflammatory cells, hypotony, dose-limiting toxicities or treatment-related serious adverse events (SAE) during follow-up through 36 weeks in all 15 patients.

Moreover, according to a news release, 4DMT announced the 3E10 vg/eye dose cohort showed a durable reduction in supplemental anti-VEGF injections beyond 36 weeks, with 3 of 4 evaluable participants remaining injection-free beyond one year and one patient remaining injection-free during a maximum follow-up of 80 weeks with no change in safety profile observed.¹

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:²

• 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 include:

• 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.¹

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.²

All of our product candidates are in clinical or preclinical development and have not yet been approved for marketing by the FDA or any other regulatory authority. No representation is made as to the safety or effectiveness of our product candidates for the therapeutic uses for which they are being studied.

References:

1. 4D Molecular Therapeutics, Inc. 4DMT receives FDA Regenerative Medicine Advanced Therapy (RMAT) designation for 4D-150 genetic medicine for intravitreal treatment of wet AMD, the first RMAT designation in WET AMD. GlobeNewswire News Room. December 21, 2023. Accessed December 21, 2023. https://www.globenewswire.com/news-release/2023/12/21/2799961/0/en/4DMT-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-for-4D-150-Genetic-Medicine-for-Intravitreal-Treatment-of-Wet-AMD-the-First-RMAT-Designation-in-Wet-AMD.html.

2. Hutton D. 4DMT: First patient enrolled in 4D-150 phase 2 spectra, Pris Clinical Trials. Ophthalmology Times. September 7, 2023. Accessed December 21, 2023. https://www.ophthalmologytimes.com/view/4dmt-first-patient-enrolled-in-4d-150-phase-2-spectra-pris-clinical-trials.