Diabetic macular edema (DME) is the leading cause of vision loss in the working age population which, considering the worldwide epidemic of diabetes, represents a growing socioeconomic challenge. DME is characterized by the destabilization of retinal blood vessels resulting in the accumulation of fluid in the macula, the area of the retina responsible for central vision. The current standard of care for DME is anti-VEGF (vascular endothelial growth factor) therapy but many patients do not respond adequately, prompting an intensive effort to discover targets for development of adjunctive therapies. The Tie2 pathway is a widely recognized central regulator of vascular stability, and Tie2 receptor activation has become a prime target for the development of novel therapies for retinal vasculopathies, including DME. With deep knowledge of the Tie2 pathway, Aerpio is developing first-in-class therapies based on activating Tie2 by targeting VE-PTP (vascular endothelial-protein tyrosine phosphatase), a key negative regulator of Tie2 receptor activation. Towards this end, Aerpio's lead small molecule VE-PTP inhibitor (AKB-9778) provided the first clinical proof of concept (PoC) for Tie2 activation in a Phase 2a study in DME, demonstrating improved resolution of macular edema when administered with ranibizumab, an FDA approved anti-VEGF agent. Based on this clinical PoC, Aerpio has advanced a therapeutic antibody program targeting the VE-PTP extracellular domain (ECD) through preclinical PoC and early development of a clinical candidate, ARP-1536. The overall objective of this fast track proposal is to advance ARP-1536 through IND-enabling studies required to support the first clinical trial in patients with DME. The Phase 1 specific aims are directed towards completing key tasks required to enable the GLP toxicology program.
Aim 1 - Assess binding of ARP-1536 in healthy and diseased human tissues. Comparison of binding of the monoclonal antibody ARP-1536 to target epitope (on-target) or at potential cross-reactive sites (off-target) in healthy and diseased human tissue may provide important data regarding regulation of VE-PTP expression in diseased tissue.
Aim 2 - Develop bioanalytical (BA) assays to support nonclinical pharmacokinetic (PK) and Tox studies. BA assays for detection of ARP-1536 in biological matrices and dose formulation are crucial for the Tox studies proposed in Phase 2. Upon meeting the Phase 1 milestones, the Phase 2 specific aims are directed towards production of drug supply for and implementation of the IND-enabling NC-Tox studies.
Aim 1 - Manufacture ARP-1536 to enable the PK and GLP toxicology studies.
Aim 2 - Conduct IND-enabling NC- Tox studies. Upon meeting the Phase 2 milestones, Aerpio will be well positioned to implement the first- in-human clinical trial, putting ARP-1536 another step closer to providing the first highly effective adjunctive therapy for the substantial number of patients with DME and other sight-threatening retinopathies who do not adequately respond to VEGF antagonists.

Public Health Relevance

Diabetic macular edema (DME), the leading cause of vision loss in the working age population, stems from destabilization of blood vessels in the back of the eye leading to leakage of fluid and swelling of the macula (the part of the retina responsible for sharp central vision). While FDA- approved VEGF antagonists can reduce the fluid and have revolutionized the treatment of DME, about 40% of patients fail to respond adequately to these agents leading to an intensive search for new therapies. This proposal will advance the early phase development of ARP-1536, a novel therapeutic agent that targets a pathway critical for stabilizing blood vessels in the back of the eye and has the potential to provide sight saving therapy for a substantial number of patients with DME who fail to respond current therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Wujek, Jerome R
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Aerpio Therapeutics, Inc.
United States
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