Registered study title and purpose

“A Phase 3, Randomized, Double-Masked, Active-Controlled Trial of a Single Intravitreal Injection of 4D-150 in Adults With Macular Neovascularization Secondary to Age-Related Macular Degeneration” (opens the source at this quote in a new tab)

Main objective in the EU trial record

“The trial objective is to evaluate the efficacy, safety, and durability of a single intravitreal (IVT) injection of 4D-150 (3 ×10^10 vector genomes [vg]) compared with aflibercept (2mg IVT) every 8 weeks (Q8W) in adults with nAMD.” (opens the source at this quote in a new tab)
“The primary efficacy objective is to demonstrate non-inferiority of a single injection of 4D-150 to aflibercept (Q8W) in the mean change in BCVA from baseline to Week 52” (opens the source at this quote in a new tab)

Primary and key secondary endpoints as described by the sponsor

“The primary endpoint is non-inferiority in the mean change from baseline in best corrected visual acuity (BCVA) at 52 weeks. The key secondary endpoint is treatment burden reduction comparing the number of aflibercept injections received in the 4D-150 arm versus the aflibercept comparator arm over 52 weeks.” (opens the source at this quote in a new tab)

Summary: sites and timeline

The ClinicalTrials.gov record for 4FRONT-2 (protocol 4D-150-C004) lists 94 sites in 14 countries: United States (54), Argentina (6), Hungary (6), Japan (5), Australia (4), Germany (3), Latvia (3), Spain (3), United Kingdom (3), Lithuania (2), Singapore (2), Bulgaria (1), Italy (1), and Portugal (1). The EU trial record lists 9 member states (Bulgaria, France, Germany, Hungary, Italy, Latvia, Lithuania, Portugal, and Spain). The study started on 2025-07-22, enrollment was completed in June 2026, and 52-week topline data are expected in the second half of 2027.

Study dates

Milestone	Registry record
Study start (actual)	“2025-07-22”
Primary completion (estimated)	“2028-11”
Study completion (estimated)	“2029-02”

Initiation

“The second Phase 3 trial of 4D-150 in wet AMD, 4FRONT-2, was initiated in June 2025, ahead of schedule.” (opens the source at this quote in a new tab)

Ex-US site activation

“4FRONT-2, Global Clinical Trial: Ex-U.S. site activation and patient screening accelerating across Europe and Asia-Pacific; enrollment remains on track to be completed in H2 2026, with topline data expected in H2 2027” (opens the source at this quote in a new tab)

Enrollment completion and topline timing

“4FRONT-2 global enrollment completed approximately 4 months ahead of initial projections” (opens the source at this quote in a new tab)
“4FRONT-2 over-enrolled (anticipated N>500), with final patient randomization expected in Q3 2026, reflecting strong interest from investigators and patients” (opens the source at this quote in a new tab)
“4FRONT-2 52-week topline data is expected in H2 2027” (opens the source at this quote in a new tab)

Phase 3 randomized, double-masked, aflibercept-controlled design

“4FRONT-2 is a global Phase 3 multicenter, randomized, double-masked, aflibercept 2 mg (Q8W) comparator-controlled study of intravitreal 4D-150 in wet AMD that has enrolled both treatment-naïve and recently diagnosed treatment-experienced patients.” (opens the source at this quote in a new tab)
“Patients in both arms are eligible for supplemental aflibercept injections.” (opens the source at this quote in a new tab)
“4FRONT-1, the first 4D-150 wet AMD Phase 3 trial, is being conducted in North America evaluating treatment-naïve patients with an otherwise identical design to 4FRONT-2.” (opens the source at this quote in a new tab)

Registered design elements

Design element	Registry record
Allocation	“Randomized”
Intervention model	“Parallel”
Masking	“Quadruple”
Primary purpose	“Treatment”

Planned population mix

Population	Quoted presentation text
Region and size	“Global N=480”
Treatment-naive share	“≥60% Treatment naïve”
Previously treated share	“Up to 40% Previously treated*”
Definition of previously treated	“1-4 prior injections, diagnosed within 6 months.”

Aflibercept run-in and response-based randomization

“Enrolling selected population to reduce variability:” (opens the source at this quote in a new tab)
“Randomizing strong aflibercept responders only” (opens the source at this quote in a new tab)
“Durezol® taper (both arms) starting Day -3” (opens the source at this quote in a new tab)

Regulatory alignment for global program

“Study design has been aligned with feedback from U.S. Food and Drug Administration (FDA) under RMAT designation” (opens the source at this quote in a new tab)
“Alignment ongoing with European Medicines Agency (EMA) under PRIME designation” (opens the source at this quote in a new tab)

“The Amendments support the Company’s planned global regulatory submissions for 4D-150, including by the Company’s recently announced partner, Otsuka Pharmaceutical Co., Ltd., in the Asia-Pacific region, and were driven by the Company’s evolving view of the global commercial opportunity for 4D-150.” (opens the source at this quote in a new tab)

Key inclusion criteria

Criterion	Quoted registry text
Age	“≥50 years of age at time of consent”
Treatment history, option 1	“Treatment naïve, i.e. no prior IVT anti-VEGF therapy OR”
Treatment history, option 2	“Previously treated with no more than 4 IVT anti-VEGF injections due to nAMD and received diagnosis of nAMD no more than 6 months prior to the Screening Visit AND documented evidence of anatomical improvement and visual stability/improvement in response to previous IVT anti-VEGF treatment, as determined by the Investigator”
Aflibercept response	“Demonstrated clinical response to aflibercept and functional stability in the study eye as confirmed by the Reading Center”
Visual acuity	“BCVA between 25 and 78 ETDRS letters, inclusive (20/320-20/32 Snellen equivalent) in the study eye at the Screening Visit”
Retinal thickness	“CST less than or equal to 500 microns in the study eye at screening visit, confirmed by the central reading center”

Key exclusion criteria

“History of retinal detachment in the study eye” (opens the source at this quote in a new tab)
“History of or presence of active inflammation in either eye” (opens the source at this quote in a new tab)
“Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, other than allowed prior IVT anti-VEGF in the study eye” (opens the source at this quote in a new tab)
“History of autoimmune condition that may predispose to the development of uveitis” (opens the source at this quote in a new tab)

Aflibercept run-in response and functional stability required before randomization

“From Week −5 to Week −1: a ≥ 15% reduction in CST or complete resolution of IRF and/or SRF, determined by SD-OCT and confirmed by the Reading Center” (opens the source at this quote in a new tab)
“At Day 1: BCVA measurement must not have decreased by 15 ETDRS letters or more compared to BCVA at the Screening visit” (opens the source at this quote in a new tab)

Lesion characteristics and fellow-eye visual acuity required at screening

“Active subfoveal MNV or juxtafoveal/ extrafoveal MNV with a subfoveal component (where activity is defined as evidence of SRF, IRF, subretinal hyperreflective material, or leakage) identified by fluorescein angiography (FA) or spectral domain optical coherence tomography (SD-OCT) , in the study eye, at the Screening Visit confirmed by the Reading Center” (opens the source at this quote in a new tab)
“Total lesion size of 9 disc areas or less (inclusive of blood, fibrosis, atrophy or neovascularization) on FA” (opens the source at this quote in a new tab)
“MNV component area at least 50% of total lesion size on FA” (opens the source at this quote in a new tab)
“MNV exudation (i.e. presence of fluid) on SD-OCT” (opens the source at this quote in a new tab)
“BCVA ≥34 ETDRS letters (~20/200 Snellen equivalent) in the contralateral eye at the Screening Visit” (opens the source at this quote in a new tab)

Exclusions for prior gene therapy, complement inhibitors, brolucizumab, and systemic VEGF inhibitors

“Any prior gene therapy (ocular or non-ocular) and/or ocular stem cell therapy” (opens the source at this quote in a new tab)
“Ever received or anticipated to receive IVT complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol) in either eye” (opens the source at this quote in a new tab)
“Any prior exposure to brolucizumab” (opens the source at this quote in a new tab)
“Receiving or anticipated to receive a systemic drug that inhibits VEGF pathways, e.g. bevacizumab, sunitinib, pazopanib” (opens the source at this quote in a new tab)

Ocular surgical history and corticosteroid response exclusions

“History of the following surgeries and procedures: cataract surgery associated with complications, incisional glaucoma surgery (e.g. trabeculectomy), glaucoma tube or shunt placement, pars plana vitrectomy, corneal transplant, sub-macular surgery, retinal detachment surgery, ranibizumab injection implant (Susvimo™), macular laser or extensive panretinal photocoagulation, radiation therapy.” (opens the source at this quote in a new tab)
“History of steroid-induced ocular hypertension or steroid-induced glaucoma in either eye” (opens the source at this quote in a new tab)

Barrier contraception requirement in the three months after dosing

“Agree to use a barrier method (e.g. condom) during intercourse for 3 months after Day 1 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period.” (opens the source at this quote in a new tab)

Summary: dosing schedule

According to the sponsor's trial schedule, which is shared by 4FRONT-1 and 4FRONT-2, 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. 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 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.”

Dose selection

“The Phase 2b trial enrolled 45 patients at two dose levels of a single intravitreal dose of 4D-150 (3E10 and 1E10 vg/eye); 3E10 vg/eye was chosen as the dose for the 4FRONT Phase 3 clinical trials” (opens the source at this quote in a new tab)

Registered primary and secondary outcomes

Outcome	Registry record	Time frame
Primary	“Mean change from baseline in Best Corrected Visual Accuity (BCVA) Early Treatment for Diabetic Retinopathy (ETDRS) letter score at Week 52”	“52 Weeks”
Secondary	“Mean annualized number of aflibercept injections after Week 4 through Weeks 52 and 104”	“104 Weeks”
Secondary	“Incidence and timing of aflibercept injections after Week 4 through Weeks 52 and 104”	“104 Weeks”
Secondary	“Proportion of subjects not requiring aflibercept injections after Week 4 through Weeks 52 and 104 in the 4D-150 arm”	“104 Weeks”
Secondary	“Mean change from baseline in Central Subfield Thickness (CST) over time through Weeks 52 and 104”	“104 Weeks”
Secondary	“Mean change from baseline in BCVA ETDRS letter score over time through Weeks 52 and 104”	“104 Weeks”

Noninferiority margins: FDA and ex-US regulators

“As previously disclosed, the 4FRONT Trials were initiated to provide >90% power for a primary endpoint of BCVA noninferiority of 4D-150 versus aflibercept 2mg Q8 weeks with a margin of 4.5 letters (in accordance with U.S. Food and Drug Administration guidance).” (opens the source at this quote in a new tab)
“The increase in target enrollment in the 4FRONT Trials is designed to provide approximately 90% power with a noninferiority margin of approximately 4 letters outside of FDA jurisdiction such as Japan Pharmaceuticals and Medical Devices Agency and European Medicines Agency.” (opens the source at this quote in a new tab)

“Robustly powered for global approval standards (~4 letter noninferiority margin)” (opens the source at this quote in a new tab)

FDA guidance on selecting a noninferiority margin

“It is therefore usual in NI studies to choose a smaller margin (M2) that reflects the largest loss of effect that would be clinically acceptable.” (opens the source at this quote in a new tab)

Derivation of a 4-letter margin from historical anti-VEGF trials

“The 4-letter non-inferiority margin preserves approximately 70% of the least estimated benefit of ranibizumab over sham control in the MARINA study.” (opens the source at this quote in a new tab)
“From a clinical perspective, the non-inferiority margin should be fewer than 5 letters, given that a loss of 5 letters (one ETDRS line) between treatments would be considered clinically relevant.” (opens the source at this quote in a new tab)

A 4.5-letter margin in a prior nAMD phase 3 trial versus aflibercept

“The maximum clinically acceptable true difference between KSI-301 and aflibercept among wAMD patients to be considered non-inferior is 4.5 ETDRS letters, i.e. the non-inferiority margin (NI) is 4.5 letters.” (opens the source at this quote in a new tab)

Primary endpoint and time to first aflibercept injection as recorded in the EU register

Outcome	EU trial record
Primary endpoint	“Mean change from baseline in BCVA ETDRS letter score at Week 52”
Secondary endpoint not listed on ClinicalTrials.gov	“Time to first aflibercept injection after Week 4 in the 4D-150 arm”

Certification of visual acuity measurement for the primary endpoint

“Best corrected visual acuity (BCVA) certification, Low Luminance visual acuity, manifest refraction, and lane certifications” (opens the source at this quote in a new tab)

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“480”

Sample size and power

“Target enrollment per study is 480 patients randomized 1:1 to 4D-150 or the aflibercept comparator arm, providing approximately 90% power with a noninferiority margin of 4 letters as aligned with the Japan Pharmaceuticals and Medical Devices Agency and EMA and over 90% power with a noninferiority margin of 4.5 letters per FDA guidance.” (opens the source at this quote in a new tab)

Protocol amendment increasing target enrollment

“On December 10, 2025, 4D Molecular Therapeutics, Inc. (the “Company”) announced its intention to implement protocol amendments (the “Amendments”) to the 4FRONT-1 and 4FRONT-2 Phase 3 clinical trials of 4D-150 in wet AMD (the “4FRONT Trials”) to increase target enrollment from 400 to 480 patients per trial.” (opens the source at this quote in a new tab)

Expected randomized participants

“We completed enrollment for 4FRONT-2 in June 2026 ahead of schedule with >500 patients expected to be randomized.” (opens the source at this quote in a new tab)

Analyzed population

No evidence found.

Summary

No results have been reported as of September 2026; enrollment was completed in June 2026 with more than 500 participants expected to be randomized, final randomization was expected in the third quarter of 2026, and 52-week topline data are expected in the second half of 2027 (registry primary completion estimated November 2028). The design matches 4FRONT-1 apart from population and geography, so the limitations of 4FRONT-1 apply: noninferiority testing with a 4.5-letter FDA margin and an approximately 4-letter margin for EMA and PMDA, supplemental aflibercept allowed in both arms under criteria that exclude investigator discretion, randomization restricted to participants with a documented anatomic response to aflibercept during the run-in, and a 52-week primary endpoint for a one-time gene therapy. Up to 40% of participants may be previously treated (1 to 4 prior anti-VEGF injections and diagnosis within 6 months), so results will not apply to patients with longer disease duration or extensive prior treatment. Because 4FRONT-2 enrolled across 14 countries, including sites in Europe, Latin America, Japan, Singapore, and Australia, regional differences in practice may add variability, and the EU trial record excludes women of child-bearing potential. The statistical analysis sets, handling of intercurrent events, and multiplicity strategy have not been published.