4D Molecular Therapeutics announced positive interim clinical data from the phase 1 dose exploration stage of its phase 1/2 trial for 4D-150 to treat wet age-related macular degeneration (AMD).
Tell me about this company first.
Based in Emeryville, California, 4D Molecular Therapeutics (4MDT) is a clinical-stage biotherapeutics company focused on the development of genetic medicines for rare diseases in ophthalmology, pulmonology, and cardiology.
The company’s proprietary vectory discovery platform—the Therapeutic Vector Evolution—utilizes synthetic adeno-associated virus (AAV) capsid-derived sequences to create customized vectors for the clinical advancement of its product candidates.
And this specific product candidate?
4D-150 is a novel genetic medicine using the R100 vector (developed and customized by 4DMT), which leverages a multi-target transgene payload expressing both aflibercept and a vascular endothelial growth factor (VEGF)-C inhibitory RNA interference (RNAi).
The dual payload is designed to block four angiogenic factors responsible for wet AMD and diabetic macular edema (DME).
To note, 4D-150 is intended for single, low-dose intravitreal delivery.
Now talk about this trial.
The prospective, multicenter, randomized, controlled, and masked phase 1/2 PRISM clinical trial (NCT05197270) is assessing 65 patients (ages ≥50 years) diagnosed with wet AMD who were actively receiving anti-VEGF treatment and previously demonstrated a clinical response consistent with anti-VEGF activity within the last 12 months before the start of the trial.
The trial is split into two parts: dose exploration (technically escalation) and dose expansion.
And the first part?
The phase 1 dose exploration stage of the study included 15 patients in three cohorts (n = 5 per cohort) receiving a single intravitreal injection of 3E10 vg, 1E10 vg, and 6E9 vg/eye, respectively.
Topical steroids were administered at tapering doses over the course of 20 weeks.
What was being measured?
The primary outcome measures included the development and severity of treatment-emergent adverse events (TAEs) as well as serious adverse events (SAEs).
Findings?
All three doses were well-tolerated through 24 weeks in all 15 patients.
The highest dose (3E10 vg/eye) exhibited the greatest level of activity at 24 weeks, including a superior reduction in supplemental anti-VEGF injections and mean central subfield thickness (CST) reduction.
And the primary endpoints?
No inflammation was observed in 93% of patients as well as no SAEs, hypotony, or dose-limiting toxicities were noted across all three cohorts—including at 24-to-64-week follow-up.
Further, supplemental anti-VEGF injections weren’t needed in 75% of patients in the 3E10 vg/eye group at 36 weeks follow-up.
Any other data from that high-dose group?
Yes … at 36 weeks, a clinically-meaningful improvement in mean CST (-74 µm) and stable best-corrected visual acuity (BCVA) were noted.
So what’s next?
Next up is the phase 2 dose expansion stage of the trial, which will be randomized 2:2:1 to 3E10 vg/eye or 1E10 vg/eye of 4D-150 or aflibercept.
According to the company, enrollment (n = 50) is over 50% completed; 4DMT expects to conclude enrollment by Q3 2023.
Per Clinical Trials, the study’s estimated completion date is September 30, 2026.
And the significance?
In the words of 4DMT’s CMO Robert Kirn, MD, ““4D-150 is the first retinal genetic medicine that is designed to inhibit all four VEGF-related molecules that drive disease in wet AMD.”Stay tuned for further updates in the meantime!