4D Molecular Therapeutics (4DMT) released interim 52-week results from an extension cohort of the phase 2b PRISM clinical trial evaluating 4D-150, an investigational gene therapy, for the treatment of wet age-related macular degeneration (AMD).
The findings were presented during the virtual Angiogenesis, Exudation, and Degeneration 2025 annual meeting.
First up: the science behind 4DMT.
This rare disease-focused, clinical-stage biotechnology company has developed a proprietary vector discovery platform, dubbed the Therapeutic Vector Evolution.
Its purpose: Using synthetic adeno-associated virus (AAV) capsid-derived sequences to create customized vectors for the clinical advancement of 4DMT’s vector delivery-based product candidates.
- In the ophthalmic space: The R100 intravitreal vector (developed and customized by 4DMT) is utilized by 4D-150 (our topic of discussion) for wet AMD and diabetic macular edema (DME).
Talk more about this gene therapy.
Referred to as a potential “backbone therapy,” 4D-150 uses the R100 vector, which leverages a multi-target transgene payload expressing both aflibercept and a vascular endothelial growth factor (VEGF)-C inhibitory RNA interference (RNAi).
- In turn: This dual payload is designed to block four angiogenic factors responsible for wet AMD and diabetic macular edema (DME).
The intended effect: To provide multi-year sustained delivery of anti-VEGF from the retina via a single, low-dose intravitreal (IVT) delivery.
Next: Let’s get into this clinical study.
We’ll start with the original PRISM trial details.
- The design: A prospective, multicenter, randomized, controlled, and masked phase 1/2 trial (NCT05197270)
- The participants: 150 patients (ages ≥50 years) diagnosed with wet AMD who:
- Were actively receiving anti-VEGF treatment
- Previously demonstrated a clinical response consistent with anti-VEGF activity within the last 12 months before the start of the trial
- The setup: The study was split into two parts:
- Dose exploration (escalation)
- Patients randomized into three cohorts to receive a single IVT injection of 4D-150
- Dose expansion
- Patients randomized 2:2:1 to receive one of two 4D-150 doses or aflibercept via IVT every 8 weeks (Q8W)
- Dose exploration (escalation)
And what were the findings from parts 1 and 2?
Part 1: Positive 24-week interim data showed all three 4D-150 doses were well tolerated, with the highest dose (3 E10 vg/eye) exhibiting the greatest level of activity—including a superior reduction in supplemental anti-VEGF injections and mean central subfield thickness (CST).
- See our May 2023 coverage on this.
Part 2: Interim 24-week data found a single IVT dose of 4D-150 demonstrated favorable safety results, with an 89% (high dose) and 85% (low dose; 1E10 vg/eye) reduction in anti-VEGF injection rates—plus 84% (high dose) and 90% (low dose) of patients received 0 or 1 supplemental injections of aflibercept.
- See our February 2024 coverage on this.
Got it. Now get into this 52-week data.
The population extension cohort of the PRISM study evaluated the highest dose of 4D-150 (3E10 vg/eye) as well as the number of supplemental aflibercept injections that followed among two participant groups:
- Group 1: 30 patients with broad wet AMD disease activity
- Group 2: 15 patients in a recently diagnosed subgroup
Start with the supplemental injections.
We’ll take it group-by-group over the 52 weeks.
In Group 1, investigators observed an 83% overall reduction, with 0.97 mean supplemental injections per patient over the duration versus 6.0 injections projected for aflibercept 2 mg (Q8W).
- Plus: 70% of patients required 0 to 1 injections while 57% were injection-free
As for Group 2, investigators noted a 94% reduction in supplemental injections, with 0.33 mean supplemental injections per patient over the 52-week period (versus 6.0 injections with aflibercept Q8W.
- Plus: 87% of patients required 0 to 1 injections while 80% were injection-free
And visual outcomes?
For Group 1: Best-corrected visual acuity (BCVA) improved and maintained by +2.2 letters.
For Group 2: BCVA improved and maintained by +3.1 letters.
For both groups: A durable CST improvement resulted in fewer fluctuations, with 11 µm; -13 µm (Group 1) and -10 µm; -20 µm (Group 2) in supplemental injection-free patients.
Now to the safety update on 4D-150.
As of Jan. 15 (the data cut-off date), 4DMT reported that 4D-150 “continues to be well tolerated during up to 3 years of follow-up in all patients” treated with the high dose.
The numbers (for both groups, encompassing 71 patients):
- 2.8% of patients had 4D-150-related 1+ intraocular inflammation (IOI)
- 99% completed steroid prophylaxis taper on schedule
- 99% remained completely off steroids
There were also no reports of 4D-150-related:
- Hypotony
- Endophthalmitis
- Vasculitis
- Occlusive/non-occlusive retinal vasculitis
- Choroidal effusions
Noted. So this latest data sounds pretty promising …
Indeed it does—and remember that this is only for 4D-150’s high dosage (3E10 vg/eye).
As PRISM principal investigator Dante Pieramici, MD, noted, the promise of 4D-150 lies in its “potential to tackle one of the most pressing unmet needs in vascular retinal diseases—providing a long-lasting, effective treatment option that reduces the frequent burden of bolus anti-VEGF injections.”
Lastly, what’s next for this gene therapy?
Sticking with the PRISM trial: 2-year phase 1/2a and 18-month phase 2b data are anticipated in Q4 2025.
And beyond that: 4DMT is gearing up to initiate two studies as part of a global registrational program on 4D-150 (4FRONT-1 and 4FRONT-2) in Q1 and Q3 2025, respectively.
- The plan: To report primary endpoint (52-week) topline data from both trials in H2 2027.
As always, stay tuned for updates!