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 (4FRONT-2)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

4d Molecular Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

9 Dec 2025 → ongoing

Decision date (initial)

2025-11-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

4D Molecular Therapeutics, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Others, Efficacy

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.
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.

Secondary objectives 1

1. Not Applicable

Conditions and MedDRA coding

Macular neovascularization secondary to age-related macular degeneration (nAMD)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Data obtained through this study may be provided, after deidentification, to qualified researchers with academic interest in AMD in compliance with ICMJE policy. Data or samples shared will be coded, with no Protected Health Information included. Additionally, descriptions of the study protocol, Statistical Analysis Plan (SAP), informed consent and clinical study report may be shared publicly. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party. Data requests can be submitted starting after final Clinical Study Report and the data will be made accessible indefinitely. Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and SAP and execution of a Data Sharing Agreement (DSA).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Signed informed consent before any protocol-specific assessment is performed
2. Ability to comply with the protocol-specified procedures and visits, in the Investigator’s judgment
3. ≥50 years of age at time of consent
4. 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.
5. MNV secondary to nAMD with IVT anti-VEGF treatment history in the study eye, defined as EITHER: a. Treatment naïve, i.e. no prior IVT anti-VEGF therapy, OR b. 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
6. 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
7. MNV lesion in the study eye of any type (i.e. predominantly classic, minimally classic, or occult [including polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) at the Screening Visit, confirmed by the Reading Center, which exhibits all of the following characteristics: a. Total lesion size of 9 disc areas or less (inclusive of blood, fibrosis, atrophy or neovascularization) on FA b. MNV component area at least 50% of total lesion size on FA c. MNV exudation (i.e. presence of fluid) on SD-OCT
8. CST ≤500μm in the study eye at Screening visit, confirmed by the Reading Center
9. Demonstrated clinical response to aflibercept and functional stability in the study eye: a. 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 b. At Day 1: BCVA measurement must not have decreased by 15 ETDRS letters or more compared to BCVA at the Screening visit
10. BCVA between 25 and 78 ETDRS letters, inclusive (20/320-20/32 Snellen equivalent) in the study eye at the Screening Visit
11. BCVA ≥34 ETDRS letters (~20/200 Snellen equivalent) in the contralateral eye at the Screening Visit
12. Study eye amenable to IVT injection identified by the Investigator prior to Week −5

Exclusion criteria 5

1. Ocular Conditions: a. MNV due to causes other than nAMD in either eye b. Fibrosis, atrophy, or subretinal hemorrhage in the foveal central subfield (1 mm diameter), retinal pigment epithelial tear, macular hole, vitreomacular traction, Stargardt disease, drug induced maculopathies, macular edema not due to nAMD, or retinal neovascular occlusion, in the study eye as determined by the Reading Center at the Screening Visit c. History of retinal detachment in the study eye d. Any active ocular inflammation or active ocular or periocular infection in either eye (e.g. infectious blepharoconjunctivitis) at any time between the Screening Visit and Randomization. e. History of intraocular inflammation (e.g. endophthalmitis), or uveitis in either eye, or presence of any cells or flare in the anterior chamber or any cells or haze in the vitreous in the study eye at any time prior to Randomization. f. History of latent ocular or periocular infection (e.g. ocular syphilis, herpetic eye disease) g. History of steroid-induced ocular hypertension or steroid-induced glaucoma in either eye h. Intraocular pressure (IOP) <6 mmHg (by Goldmann tonometry) in the study eye i. Any history of ocular hypotony or ciliary body dysfunction/pathology in either eye as determined by the Investigator j. Glaucoma or intraocular hypertension requiring more than 2 topical medications for control (defined as IOP <22 mm Hg) in the study eye k. Any other pre-existing eye conditions or surgical complications that in the opinion of the Investigator would preclude participation in an interventional clinical trial or interfere with the interpretation of study endpoints.
2. Ocular Treatments/Interventions in the Study Eye: a. Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, other than allowed prior IVT anti-VEGF, including, but not restricted to IVT therapy (e.g. steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention b. Aphakia, pseudophakia with anterior chamber intraocular lens, or significant violation of the posterior capsule with the exception of yttrium-aluminum garnet (YAG) with posterior chamber lens implantation c. 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. d. Uncomplicated cataract surgery, YAG laser posterior capsulotomy, or glaucoma laser treatment in the 3 months prior to the Screening Visit e. Any concurrent intraocular condition (e.g. amblyopia, aphakia, retinal detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the opinion of the Investigator, could either reduce the potential for visual improvement or require medical or surgical intervention during the study f. Any prior exposure to brolucizumab
3. Prior/Concomitant Medications (Systemic or in Either Eye): a. Receiving or anticipated to receive a systemic drug that inhibits VEGF pathways, e.g. bevacizumab, sunitinib, pazopanib b. Ever received or anticipated to receive IVT complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol) in either eye c. History of serious allergy, hypersensitivity, or contraindications to fluorescein and/or trial-specified interventions (e.g. 4D-150 excipients, aflibercept, povidone-iodine)
4. Prior Interventional Trial Participation: a. Received an investigational drug, agent, device, or therapy (ocular or non-ocular) in the 3 months or at least 5 half-lives (whichever is longer) prior to Screening b. Any prior gene therapy (ocular or non-ocular) and/or ocular stem cell therapy
5. Systemic Conditions and Considerations: a. Major illness or major surgical procedure in the 28 days prior to the Screening Visit b. Uncontrolled blood pressure, defined as resting average systolic value ≥160 mmHg and/or average diastolic value ≥100 mmHg, based on triplicate measurements at 1-minute intervals at Screening. If blood pressure exceeds these values, measurements can be repeated up to 3 times within the Screening Visit window. Blood pressure medications should be at stable dose/regimen for at least 28 days prior to Screening. c. Acute coronary syndrome, myocardial infarction or coronary artery revascularization, cerebrovascular accident, transient ischemic attack within 6 months of the Screening Visit d. Any history of syphilis (whether or not treated) e. History of autoimmune condition that may predispose to the development of uveitis, including, but not limited to Behcet disease, spondyloarthropathies, multiple sclerosis, HLA-B27 syndrome, Crohn’s disease, sarcoidosis, lupus, or rheumatoid arthritis f. Any documented active or suspected malignancy, or history of malignancy within 12 months prior to Screening, except appropriately treated/resected localized tumor with low risk for recurrence (e.g. treated local basal cell or squamous cell carcinoma of the skin, noninvasive bladder cancer, prostate cancer stage 1 or 2 with stable prostate-specific antigen for 6 months, or any cancer considered surgically cured) g. Intercurrent illness or condition that, in the opinion of the Investigator, may place the subject at an unacceptable risk, prevent the subject from completing the trial, or confound interpretation of trial results h. Female of child-bearing potential, per (CTFG, 2020).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean change from baseline in BCVA ETDRS letter score at Week 52

Secondary endpoints 6

1. Mean annualized number of aflibercept injections after Week 4 through Weeks 52 and 104
2. Incidence and timing of aflibercept injections after Week 4 through Weeks 52 and 104
3. Proportion of subjects not requiring aflibercept injections after Week 4 through Weeks 52 and 104 in the 4D-150 arm
4. Time to first aflibercept injection after Week 4 in the 4D-150 arm
5. Mean change from baseline in CST over time through Weeks 52 and 104
6. Mean change from baseline in BCVA ETDRS letter score over time through Weeks 52 and 104

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

4d Molecular Therapeutics Inc.

Sponsor organisation

4d Molecular Therapeutics Inc.

Address

5858 Horton Street

City

Emeryville

Postcode

94608-2006

Country

United States

Scientific contact point

Organisation

4d Molecular Therapeutics Inc.

Contact name

Melina Cavichini

Public contact point

Organisation

4d Molecular Therapeutics Inc.

Contact name

Melina Cavichini

Third parties 14

Locations

9 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 170 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications