This is a phase 2 randomized, double -masked study comparing the efficacy of EYP-1901 at 2 dose levels: 2060 microgram (mcg) and 3090 mcg against aflibercept.

This study is evaluating the 2 doses of EYP-1901 against aflibercept in a randomized study.

Inclusion Criteria:

• Documented diagnosis of wAMD in the study eye, with disease onset any time prior to the Screening Visit.
• Documented anatomical response (that is, reduction in fluid on [spectral-domain - optical coherence tomography (SD-OCT)] to previous intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in the study eye prior to the Screening Visit.
• Previously treated with at least 2 anti-VEGF intravitreal injections (that is, bevacizumab, ranibizumab, aflibercept or faricimab) for wAMD per standard of care in the study eye within 6 months prior to the Screening Visit.
• Received previous anti-VEGF therapy 2 to 5 weeks (14 to 35 days) in the study eye prior to Screening Visit, but no more than 42 days prior to randomization to study treatment on Day 1.
• Best corrected visual acuity (BCVA) early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 35 letters (20/200 Snellen equivalent) to 85 letters (20/20 Snellen equivalent) in the study eye at the Screening Visit and on Day 1.
• Able to understand, and willingness to sign, the informed consent and to provide access to personal health information via Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Willingness and ability to comply with all scheduled visits, restrictions, and assessments.
• For women of childbearing potential, or men with female partners of childbearing potential, agreement to the use of an appropriate form of contraception at the Screening Visit and for the duration of the study.

Exclusion Criteria:

• History of pars plana vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in the study eye.
• Prior treatment with Visudyne® (verteporfin), external beam radiation therapy, or transpupillary thermotherapy in the study eye.
• Previous treatment with intravitreal corticosteroid injection or device implantation in the study eye.
• Previous focal laser photocoagulation used for AMD treatment in the study eye.
• Total choroidal neovascularization (CNV) lesion size >12 disc areas [30.5 millimeter square (mm^2)] as assessed by fluorescein angiography (FA) in the study eye at the Screening Visit.
• Central subfield thickness (CST) >350 micrometer (mcm) in the study eye at the Screening Visit or Day 1.
• Intraretinal cystic fluid >25 mcm in diameter involving the central subfield and/or disruption of normal morphology (loss of foveal depression, disruption of external limiting membrane) secondary to cystic intraretinal fluid within the central subfield, in the study eye at the Screening Visit. Diffuse (non-cystic) intraretinal fluid would not be excluded.
• Subretinal hemorrhage in the subfoveal/juxtafoveal location and hemorrhage greater than 1 disc are (1.8 mm^2) if located less than 200 mcm from the foveal center in the study eye at either the Screening Visit or Day 1.
• Subfoveal fibrosis, atrophy, or scarring in the center subfield in the study eye at the Screening Visit.
• Fibrosis >50% of the total lesion, in the study eye at the Screening Visit.
• Retinal pigment epithelium detachment (RPED) thickness >400 mcm at any point within 3 mm of the foveal center in the study eye at either the Screening Visit or Day 1.
• Retinal pigment epithelial tear in the study eye at the Screening Visit or Day 1.
• Any concurrent intraocular condition in the study eye (e.g., cataract or glaucoma) that, in the opinion of the investigator, would have either required surgical intervention during the study to prevent or treat visual loss that might result from that condition or affected interpretation of the study results.
• Historical or active intraocular inflammation (grade trace or above) in the study eye, other than expected findings from routine cataract surgery.
• History of vitreous hemorrhage in the study eye within 12 weeks prior to the Screening Visit.
• History of rhegmatogenous retinal detachment or treatment for retinal detachment or macular hole (stage 3 or 4) in the study eye.
• Aphakia or pseudophakia with the absence of the posterior capsule in the study eye (YAG capsulotomy is permitted).
• Spherical equivalent of the refractive error in the study eye demonstrating >8 diopters of myopia.
• For subjects who have undergone prior refractive or cataract surgery in the study eye, preoperative refractive error in the study eye exceeding 8 diopters of myopia.
• Intraocular surgery (including cataract surgery) in the study eye within 12 weeks prior to the Screening Visit.
• Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular pressure (IOP) >25 mm of mercury (mmHg) or a cup to disc ratio >=0.8, despite treatment with 2 or more classes of antiglaucoma medication) and any such condition which the Investigator feels may require a glaucoma-filtering surgery while in the study.
• History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the study eye.
• History of corneal transplant in the study eye.
• BCVA using ETDRS charts <30 letters (20/250 Snellen equivalent) in the fellow eye.
• Worsening of BCVA ≥10 ETDRS letters in the study eye from the Screening Visit to Day 1.
• Presence of CNV in either eye due to other causes aside from wAMD at the Screening Visit.
• Treatment with Visudyne® in the fellow eye <7 days prior to the Screening Visit.
• Prior participation in a clinical trial involving investigational anti-angiogenic drugs administered in either eye or systemically within 8 weeks prior to the Screening Visit.
• Prior participation in a clinical trial involving investigational ocular gene therapy trial for either eye.
• History of idiopathic or autoimmune-associated uveitis in either eye.
• Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
• Presence of any other systemic or ocular condition which, in the judgment of the investigator, could make the subject inappropriate for entry into this study.
• Uncontrolled blood pressure (defined as systolic >180 mmHg and/or diastolic >100 mmHg), based on the average of three readings taken with the subject in a resting state.
• Myocardial infarction within 6 months prior to screening or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled atrial fibrillation, uncontrolled angina, cardiomyopathy, ventricular arrhythmias or other cardiac conditions which, in the judgment of the investigator, could make the subject inappropriate for entry into this study.
• Serious non-healing wound, ulcer, or bone fracture.
• Glycated hemoglobin (HbA1c) greater than 7% at the Screening Visit.
• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of EYP-1901.
• Current treatment for any active systemic infection.
• Previous use of any systemic anti-VEGF agents or intraocular brolucizumab in the study eye.
• Use of oral corticosteroids (prednisone >10 mg/day or equivalent) within 30 days prior to the Screening Visit.
• History or presence of bleeding disorders, including platelet disorders, hemorrhage, acquired or hereditary coagulation disorders (including deep vein thrombosis and pulmonary embolisms), acquired or hereditary vascular disorders, stroke, or transient ischemic attack.
• Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell carcinoma), any malignancy receiving treatment, or in remission less than 5 years prior to study entry.
• History of allergy to fluorescein, not amenable to treatment.
• Inability to obtain fundus photographs, FA, fundus autofluorescence, or SD-OCT images of sufficient quality to be analyzed and graded by the Central Reading Center.
• Historical or active diagnosis of any medical or psychological condition that could interfere with the ability of the subject to give informed consent, or to comply with study or follow-up procedures.
• Previous participation in any ocular or non-ocular (systemic) disease studies of investigational drugs within 30 days prior to the Screening Visit (excluding vitamins and minerals).
• Use of anti-mitotic or anti-metabolite therapy within 30 days or 5 elimination half-lives of the Screening Visit, whichever is longer.
• Intolerance, contraindication, or hypersensitivity to topical anesthetics, dyes, povidone iodine, mydriatic medications, or any of the ingredients of the EYP-1901 insert.
• Requirement for continuous use of any protocol-prohibited medications or treatments.
• Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of contraception during the study as outlined in this protocol.