Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the 
treatment of neovascular age-related macular degeneration (nAMD) and diabetic 
macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular 
stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and 
VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 
axis, resulting in vascular leakage. Areas covered: Faricimab, a bispecific 
antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. 
Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed 
to show benefit over aflibercept monotherapy in achieving visual gains in phase 
2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP 
inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously 
administered VE-PTP inhibitor that, when combined with monthly ranibizumab, 
reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. 
AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared 
to placebo. AXT107, currently in the preclinical phase, promotes conversion of 
Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other 
receptor tyrosine-kinases. Expert opinion: Tie-2/Angiopoietin pathway modulators 
show promise to reduce treatment burden and improve visual outcomes in nAMD and 
DME, with potential to treat cases refractory to current treatment modalities.