The purpose of this first-in-human study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics of OPT-302 administered as monthly intravitreal injections for 3 months with and without Lucentis™ in patients with wet age related macular degeneration (AMD). This study will be conducted in two parts: Part 1 will comprise an open label, sequential dose escalation and Part 2 a randomized dose expansion.

OPT-302 is a soluble form of VEGFR-3 comprising the extracellular domains 1-3 of human vascular endothelial growth factor receptor (VEGFR)-3 and the Fc fragment of human IgG1. It functions by binding and neutralizing the activity of vascular endothelial growth factor (VEGF)-C and VEGF-D on endogenous VEGFR-2 and VEGFR-3.

VEGF-C and VEGF-D promote blood vessel development (angiogenesis) by binding and activating VEGFR-2 and VEGFR-3. VEGF-C is also a potent inducer of vascular permeability or leakage. Angiogenesis and vascular leakage are key hallmarks of wet AMD. Approved therapies for wet AMD include Eylea™ and Lucentis™ which block the activity of VEGF-A, but not VEGF-C or VEGF-D which are alternate members of the same family of molecules.

VEGF-C and VEGF-D can stimulate blood vessel growth and leakage through the same pathway as VEGF-A (via VEGFR-2), as well as through pathways that are independent of VEGF-A (via VEGFR-3). Published studies have also indicated that VEGF-C and VEGF-D play an important role in mediating resistance to therapies that block VEGF-A such as Lucentis™ and Eylea™.

Combination therapy with OPT-302 an anti-VEGF-A agent provides a more complete blockade of the VEGF family. This strategy targets functional redundancy in the VEGF pathway and mechanisms of 'resistance' or sub-response to VEGF-A inhibition.

Inclusion Criteria:

• Able and willing to provide written informed consent
• Age ≥ 50 years of either gender
• Active CNV lesions secondary to AMD (i.e., subretinal or intraretinal fluid on SD-OCT and / or leakage on fluorescein angiography)
• Either no previous treatment in the study eye with IVT anti-VEGF-A therapy (treatment naïve) or prior IVT anti-VEGF-A therapy (previously treated) with sub-optimal response to treatment and the need for additional treatment
• Best corrected visual acuity in the study eye, using ETDRS testing, of 20/320 or better (Snellen equivalent) in Part 1 (dose escalation) and between 20/40 and 20/320 (Snellen equivalent), inclusive, in Part 2 (dose expansion).
• Women of child bearing potential and male subjects with female partners of child bearing potential must be practicing effective contraception during the trial and for at least 3 months following the last dose of study medication

Exclusion Criteria:

• Previous or concurrent use of systemic anti-VEGF-A agents
• Most recent IVT injection of bevacizumab or ranibizumab <28 days prior to screening or aflibercept <42 days prior to screening
• Previous treatment with photodynamic therapy, thermal laser or external beam radiation in the study eye
• Concurrent treatment in either eye for any ocular condition with an investigational drug or device that has not received regulatory approval
• Anatomic damage to the center of the fovea including fibrosis and scarring making up >50% of total lesion area including the CNV in the study eye
• Geographic atrophy involving the center of the fovea in the study eye
• History or presence of a retinal pigment epithelial tear
• Presence of polypoidal choroidal vasculopathy (if in the opinion of the investigator, anti-VEGF treatment would not be of benefit) or retinal angiomatous proliferation
• Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the study eye
• History of rhegmatogenous retinal detachment or macular hole in the study eye
• History of vitrectomy
• Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye
• History of vitreous hemorrhage within 4 weeks prior to screening in the study eye
• History of major ocular surgery within prior 6 months or anticipated within next 3 months following dosing on day 1
• Uncontrolled glaucoma in the study eye (defined as intraocular pressure of >25 mmHg despite treatment with maximal medical therapy)
• Uncontrolled hypertension ≥180 mmHg systolic or ≥110 mmHg diastolic at baseline
• Uncontrolled diabetes mellitus (Disease must be controlled with hemoglobin A1c (HgbA1c) < 9.0%)
• Clinical evidence of diabetic retinopathies, diabetic macular edema or any other vascular disease affecting the retina, other than AMD, in either eye that, in the opinion of the investigator, would be likely to limit improvement in the macular anatomy and/or function
• Pregnancy or lactation