4D Molecular Therapeutics (4DMT) has received Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA for 4D-150, a gene therapy candidate, for the treatment of diabetic macular edema (DME).
First things first: Explain RMAT.
Before we do: A regenerative medicine therapy (RMT; such as 4D-150) is defined as a therapy that uses the body’s own cells to promote healing and repair damaged tissues or organs.
As for this designation: RMAT is part of an FDA program exclusively designed for RMTs (and also includes Fast Track and Breakthrough Therapy designations).
- Their purpose: To expedite the development and review process of investigational drug candidates intended to treat, modify, reverse, or cure a serious or life-threatening condition.
And looking at RMAT specifically: This is based on preliminary clinical evidence indicating a specific therapy could potentially address an unmet need for the condition.
Gotcha. Now talk about 4DMT and its science.
The basis for the biotech company's scientific approach revolves around its proprietary vector discovery platform: the Therapeutic Vector Evolution.
The purpose behind this platform: To create novel, targeted, and customized vectors via the use of synthetic aden-associated virus (AAV) capsid-derived sequences.
- And in turn: These vectors are then used to clinically advance 4DMT’s investigational vector delivery-based candidates—including in the ophthalmic space.
Zero in on this DME candidate.
4DMT’s intravitreal (IVT) R100 vector is utilized by the gene therapy 4D-150, which is currently in clinical development for both DME and wet age-related macular degeneration (AMD).
How this utilization works: The R100 vector employs a multi-target transgene payload that expresses both aflibercept and a vascular endothelial growth factor (VEGF)-C inhibitor ribonucleic acid interference (RNAi).
What this payload does: It then suppresses (blocks) four angiogenic factors that are responsible for DME (and wet AMD) to provide a multi-year sustained delivery of anti-VEGF from the retina.
- Its mechanism: A single, low-dose IVT delivery.
Sounds unique! So what is this new designation based on?
That would be the latest positive topline interim data from an ongoing study evaluating 4D-150 for its DME indication, 4DMT reported.
And speaking of clinical data: The company also released positive 52-week phase 2b data earlier this year, in which 4D-150 was well tolerated for wet AMD after 3 years of follow-up.
- Take note: 4D-150 was previously granted RMAT designation for wet AMD.
Tell me about this DME trial.
The prospective, multicenter, randomized, active-controlled, double-masked, dose-ranging phase 2 SPECTRA trial (NCT05930561) was originally divided into two parts with the following details:
- The participants: 72 (estimated) DME patients (aged 18+)
- The design: Dose confirmation (part 1) and dose expansion (part 2)
- The setup:
- Part 1: Patients sequentially assigned to receive one of two open-label dose levels of 4D-150
- Part 2: Patients randomized to receive either one of two 4D-150 dose levels (based on Part 1 findings) or aflibercept control
- Note: Part 1 is not masked
- The outcome measures:
- Primary: annualized number of aflibercept injections in the study eye (measured at 52 weeks)
- Secondary:
- Mean number of aflibercept injections over time (at 52 weeks)
- Change from baseline in best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Scale (ETDRS) visual acuity chart (measured at 104 weeks)
- See here for more, including other outcomes
So what have those interim results found thus far?
Based on just part 1 of the study—which, remember, was to evaluate the 4D-150’s safety and tolerability as well as determine a dose level that could be further evaluated—4DMT reported 32-week data based on 21 DME patients evaluated.
- Note: Each patient received one of three 4D-150 dose levels (low, medium, and high)
The data:
- Safety: 4D-150 was well tolerated with no intraocular inflammation (IOI) at any point
- Notably, all patients completed a 16-week topical corticosteroid taper schedule and remained 100% off steroids
- Efficacy: The lowest 4D-150 dose (3E10 vg/eye) sustained:
- The greatest gain of BCVA (+8.4 letters)
- A central subfield thickness (CST) reduction of -194 µm
- Supplemental injections: For the lowest dose following post-aflibercept loading doses, it achieved "substantially fewer supplemental injections” compared to other doses:
- See here for those numbers.
And the company’s conclusion based on this?
First: 4D-150 has strong potential to treat both wet AMD and DME and to become a “new backbone therapy providing multi-year sustained VEGF inhibition in the retina with a single, safe, [IVT] injection.”
- Note: The company also reported plans to release 52-week interim data from the trial in Q3 2025.
Next: Based on FDA feedback, part 2 of the study is no longer required; instead, 4DMT will conduct a single phase 3 trial that—in combination with data from the gene therapy’s wet AMD program—will be used to support an eventual Biologics License Application (BLA) submission for DME.
So what do we know about this upcoming phase 3 trial?
As the company previously reported, the study will:
- Enroll an estimated 300 to 400 DME patients
- Include a primary endpoint of BCVA noninferiority versus on-label aflibercept 2 mg (with five loading doses administered every 8 weeks (Q8W)
- Feature a revised supplemental injection criteria in accordance with prior successful phase 3 DME studies
And what’s the timeframe for this?
No specific goal dates have been set as yet—stay tuned for those details.
However, if the company is successful in securing its target BLA submission (and acceptance), Carlos Quezada-Ruiz, MD, FASRS, 4DMT’s senior vice president and therapeutic area head of Ophthalmology, previously noted 4D-150’s potential to:
- “Significantly reduce the need for frequent bolus injections and address the current real-world challenge of patient adherence to therapy … leading to better disease management and vision outcomes.”