4FRONT-1
32 evidence topics · 16 sources
Objective
Primary objective as described by the sponsor
Location and study date
Summary: sites and timeline
The ClinicalTrials.gov record for 4FRONT-1 (protocol 4D-150-C003) lists 95 sites: 91 in the United States and 4 in Canada. The study started on 2025-03-03; enrollment was completed in February 2026 and randomization in March 2026. Primary completion is estimated for June 2027 and study completion for June 2028, and the sponsor expects 52-week topline data in the second quarter of 2027.
Study dates
| Milestone | Registry record |
|---|---|
| Study start (actual) | “2025-03-03” |
| Primary completion (estimated) | “2027-06” |
| Study completion (estimated) | “2028-06” |
Region and first enrollment
Enrollment completion and topline timing
Study design
Phase 3 randomized, double-masked, aflibercept-controlled design
Registered design elements
| Design element | Registry record |
|---|---|
| Allocation | “Randomized” |
| Intervention model | “Parallel” |
| Masking | “Quadruple” |
| Primary purpose | “Treatment” |
Aflibercept run-in and response-based randomization
Design as first disclosed in 2024, including masking and FDA alignment
Eligibility criteria
Key inclusion criteria
Treatment
Summary: dosing schedule
According to the sponsor's trial schedule, participants in both arms receive aflibercept 2 mg at Weeks -5 and -1 and are randomized on Day 1, when the 4D-150 arm receives a single intravitreal injection of 4D-150 3E10 vg/eye and the aflibercept arm receives a sham injection. Both arms receive aflibercept at Week 4 (the third loading dose). From Week 12 through Week 52 the aflibercept arm receives aflibercept every 8 weeks and the 4D-150 arm receives sham injections at the same visits. Both arms receive a Durezol (difluprednate) taper starting on Day -3, and both arms are eligible for supplemental aflibercept when protocol-defined disease activity criteria are met.
Treatment arms
| Arm | Quoted registry description |
|---|---|
| 4D-150 IVT (3E10 vg/eye), experimental | “If randomized to the 4D-150 treatment arm, 4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1” |
| Aflibercept (AFLB) 2 mg IVT, active comparator | “Eylea (aflibercept) will be administered at applicable visits” |
Supplemental aflibercept criteria
| Criterion | Quoted presentation text |
|---|---|
| Arms eligible | “Supplemental Aflibercept Criteria (Both arms)” |
| BCVA reference value | “BCVA: Average of Week 4 & 8” |
| CST reference value | “CST: Week 8” |
| Vision and anatomy | “Vision & Anatomy: ≥5 letter loss in BCVA AND ≥50 µm increase in CST” |
| Vision | “Vision: ≥10 letter loss in BCVA” |
| Anatomy | “Anatomy: ≥100 µm increase in CST” |
| Hemorrhage | “New vision-threatening hemorrhage” |
| Investigator discretion | “PI discretion not allowed.” |
Study outcomes
Rationale for using best corrected visual acuity as the primary endpoint
Registered primary and secondary outcomes
Noninferiority margins: FDA and ex-US regulators
Supplemental criteria designed to protect the BCVA endpoint
FDA guidance on selecting a noninferiority margin
Derivation of a 4-letter margin from historical anti-VEGF trials
A 4.5-letter margin in a prior nAMD phase 3 trial versus aflibercept
Margins used in recent nAMD registration trials
Shift to noninferiority designs in nAMD after MARINA and ANCHOR
Statistical analysis description
Number of participants (Planned and analyzed)
Planned enrollment: registry record
| Enrollment type | Participants |
|---|---|
| Estimated | “480” |
Protocol amendment increasing target enrollment
Randomized participants
Analyzed population
No evidence found.
Description of analysis sets
No evidence found.
Results
Participant disposition
No evidence found.
Baseline characteristics
No evidence found.
Efficacy results
No evidence found.
Health-related quality of life and patient-reported outcomes
No evidence found.
Safety results
No evidence found.
Study limitations
Summary
No results have been reported as of September 2026; 523 participants were randomized and 52-week topline data are expected in the second quarter of 2027. The trial tests noninferiority rather than superiority for BCVA, with a margin of 4.5 letters for the FDA and approximately 4 letters for EMA and PMDA; a 4.5-letter margin is wider than the 4-letter margin prespecified in the faricimab (TENAYA and LUCERNE) and aflibercept 8 mg (PULSAR) registration trials. Participants in both arms can receive supplemental aflibercept, so the 52-week BCVA comparison measures 4D-150 plus as-needed aflibercept against fixed aflibercept every 8 weeks, and the key secondary endpoint (number of aflibercept injections) depends on the supplemental criteria, which exclude investigator discretion. The sponsor's 2024 design stated that no supplemental injections would be allowed in the control arm, whereas 2025 and 2026 disclosures state that both arms are eligible. Enrollment is restricted to treatment-naive participants in the United States and Canada with BCVA of 25 to 78 letters, CST of 500 µm or less, and a documented anatomic response to aflibercept during a run-in (15% or greater CST reduction or fluid resolution), which the sponsor describes as selecting strong aflibercept responders to reduce variability; results may therefore not apply to aflibercept non-responders, participants with thicker retinas, or previously treated populations. The primary endpoint is at 52 weeks, while 4D-150 is a one-time gene therapy intended for multi-year effect; durability beyond 104 weeks and long-term safety are not addressed by the registered outcomes. The statistical analysis sets, handling of intercurrent events, and multiplicity strategy have not been published.