PF-04523655 Dose Escalation Study, and Evaluation of PF-04523655 With/Without Ranibizumab in Diabetic Macular Edema (DME)

Patients will be enrolled concurrently according to one of two sets of criteria designated as Stratum I and Stratum II.

• Stratum I will enroll up to 24 subjects with low vision, inclusive of possible intermediate doses, in up to 4 cohorts of 3-6 evaluable subjects.
• Stratum II will enroll approximately 240 subjects with DME 1:1:1:1 in up to 4 cohorts of 60 evaluable subjects.

Key Stratum I Inclusion Criteria:

• Visual acuity in the study eye ≤ 20/200.
• Low visual acuity is the result of an irreversible condition affecting the posterior segment of the study eye.

Key Stratum I Exclusion Criteria:

• History of vitrectomy.
• History of IVT injection in study eye within last 6 months.
• History of vitreous hemorrhage, retinal detachment, or invasive trauma in study eye.
• History of uveitis or endophthalmitis in either eye.
• Any active inflammatory condition in study eye.
• Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
• Any medical condition, concomitant therapy or previous incisional or laser surgery that, in the opinion of the Investigator, would preclude IVT injection in the study eye.
• Intraocular pressure in either eye ≥25 mmHg on maximal medication.
• Cataract surgery and laser corneal surgery within 3 months prior to dosing in the study eye and all other intraocular surgeries at any time.
• Participation in a concurrent interventional study within 30 days prior to dosing.

Key Stratum II Inclusion Criteria:

• History of diabetes mellitus (Type 1 or Type 2).
• Retinal thickening secondary to the edema caused by diabetes mellitus.
• Best corrected visual acuity (BCVA) of 20/40 or worse and up to 20/320 or better in the study eye at Screening.
• Standard of care treatment for DME can be withheld for at least 90 days after the subject has enrolled in the study (study eye only).

Key Stratum II Exclusion Criteria:

• History of panretinal photocoagulation within 6 months or macular laser photocoagulation within 3 months of prior to dosing in the study eye.
• Any IVT injection therapy performed in the study eye within 3 months prior to dosing.
• Iris neovascularization, vitreous hemorrhage, tractional retinal detachment, vitreomacular traction, clinically significant epiretinal membrane or clinically significant preretinal fibrosis involving the macula in the study eye.
• History of vitreoretinal surgery or incisional glaucoma surgery in the study eye.
• Prior intraocular surgery or corneal laser surgery, performed within 3 months prior to dosing in the study eye.
• Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
• High risk (in the opinion of the Investigator) proliferative diabetic retinopathy (PDR) in the study eye.
• Current infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
• Monocular subjects.
• History of idiopathic or autoimmune uveitis in either eye.
• Aphakia or absence of the posterior capsule in the study eye.
• Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema.
• Uncontrolled glaucoma in either eye.
• Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.
• Use of corticosteroids that, in the Investigator's opinion, may change the status of the subject's diabetic retinopathy in the study eye.