The purpose of the study is to determine the safety and efficacy of 4 monthly injections of iSONEP given alone or in combination with Lucentis, Avastin or Eylea in subjects with wet Age-related Macular Degeneration (AMD). iSONEP not only has an anti-permeability effect, but also has anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. The drug may therefore have the ability to achieve better visual outcomes than Lucentis, Avastin or Eylea, particularly in those subjects who do not demonstrate a robust response to Lucentis, Avastin or Eylea after several monthly injections. Further, the combination of Lucentis, Avastin or Eylea and iSONEP may be additive or synergistic. By inhibiting the multiple mechanisms that contribute to exudative-AMD-related vision loss, better visual outcomes may be possible than with Lucentis, Avastin or Eylea alone.

The study will be conducted in subjects who qualify as "sub-responders" to Lucentis, Avastin or Eylea meaning that each subject has (i) residual subretinal or intra-retinal fluid observed on Cirrus or Spectralis Spectral Domain Optical Coherence Tomography (SD-OCT), (ii) leakage on fluorescein angiogram (FA), and (iii) an average central subfield thickness of ≥250 μm. Additionally, each subject will have previously received a minimum of 3 intravitreous (IVT) injections of Lucentis, Avastin or Eylea within the 12-month period prior to screening. Screening must occur between 28 and 65 days from the subject's last Lucentis or Avastin treatment or between 42 and 79 days from the subject's last Eylea treatment. Subjects must be dosed within 14 days of screening, and as of the day of initial study treatment (Day 0), meet the following criteria: (i) Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected visual acuity (BCVA) of ≥25 and ≤73 letters (approximately 20/320 and 20/40 on the Snellen scale), (ii) residual subretinal or intra-retinal fluid observed on Cirrus or Spectralis SDOCT, and (iii) leakage on FA.

Inclusion Criteria:

• ≥50 years of age with a diagnosis of wet AMD
• Subjects who have received 3 injections of Lucentis or Avastin or Eylea within 12 months prior to screening
• Active subfoveal CNV secondary to AMD (leakage on FA)
• Presence of residual subretinal or intraretinal fluid on Cirrus or Spectralis SDOCT
• SDOCT in the 1 mm central macular subfield on the retinal map analysis of ≥250 μm at screening
• ETDRS BCVA of ≥25 and ≤73 letters (approximately 20/320 and 20/40 on the Snellen scale) at screening and on Day 0
• In the fellow eye, ETDRS BCVA of 20/400 or better
• Subject with serous pigment epithelial detachment (PED) (any part of which may be subfoveal) with intraretinal and/or subretinal fluid may be included

Exclusion Criteria:

• Most recent IVT injection of Lucentis or Avastin fewer than 28 days and more than 65 days prior to screening
• Most recent IVT injection of Eylea fewer than 42 days and more than 79 days prior to screening
• Previous photodynamic therapy (PDT) or Macugen® at any time point
• Focal thermal laser or grid laser within 3 months prior to Day 0
• Use of IVT, subtenon or subconjunctival steroids within 3 months prior to Day 0
• Use of topical ophthalmic corticosteroids 2 weeks prior to Day 0
• Intraocular surgery, including cataract surgery, and / or laser of any type within 3 months prior to Day 0 or anticipated need for ocular surgery or ophthalmic laser treatment during the study period
• Subjects previously treated with, or are currently receiving treatment with another investigational agent or device for neovascular AMD in the study eye
• Retinal total lesion size >12 disc areas (30.5 mm2), including blood, scars and neovascularization as assessed by FA in the study eye
• Presence of a fibrovascular PED extending underneath the center of the fovea
• Presence of retinal angiomatous proliferation (RAP) lesions
• Presence of polypoidal choroidal vasculopathy (PCV) (if suspected, Indocyanine Green Angiography (ICG) should be performed at the discretion of the Investigator)
• Subretinal hemorrhage in the study eye if any of the following is true: (i) the subretinal hemorrhage represents 50% or more of the total lesion area; (ii) subfoveal blood is 1 or more disc areas in size (iii) subfoveal blood where the fovea is surrounded by less than 270 degrees of visible CNV on FA
• Scar or fibrosis making up >50% of total lesion area in the study eye
• Anatomic damage to the center of the fovea including fibrosis, scarring or atrophy
• History of a retinal pigment epithelial tear
• History of vitreous hemorrhage within 4 weeks prior to screening in the study eye
• Clinical evidence of diabetic retinopathy, diabetic macular edema or any other vascular disease affecting the retina, other than AMD, in either eye
• Uncontrolled glaucoma defined as: (i) as intraocular pressure ≥25 mmHg despite treatment with anti glaucoma medication in the study eye or (ii) by the Investigator
• Prior trabeculectomy or other filtration surgery in the study eye (prior laser trabeculoplasty is allowed)