Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab

Abstract

This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.

New and Innovative Treatments for Neovascular Age-Related Macular Degeneration (nAMD)

“…Additionally, angiogenesis receives a contribution from alternative pathways, such as the Ang-Tie 2 axis. In this pathway, angiopoietin-1 and angiopoietin-2 are key cytokines that interact with transmembrane receptor tyrosine kinase (Tie-2) [ 33 ]. In healthy states, Tie-2 is bound by angiopoietin-1, which is a protective factor, promoting vascular stability, pericyte recruitment, and the inhibition of vascular permeability factors [ 34 ].…”

“…The current first-line therapy for nAMD exclusively targets VEGF, creating an unmet need for anti-VEGF subresponsive patients. Faricimab aims to fill this void by exploiting the alternative Ang-2/Tie-2 pathway [ 33 ]. Faricimab is the first bispecific monoclonal antibody designed for intraocular use [ 34 ].…”

Faricimab: An Emerging Therapy for the Treatment of Neovascular Age-related Macular Degeneration

“…In conjunction with the upregulation of VEGF in similar disease states, co-expression of these two permeability factors (Ang-2 and VEGF) has been reported to accelerate neovascularization in the developing retina and ischaemic retina models. 12 Recombinant Ang-1, which is analogous to natural Ang-1 with regard to its vascular stability function, was used as a possible injectable treatment for abnormal angiogenesis in mouse models. 13 Findings included decreases in capillary vasoregression, vascular permeability and retinal hypoxia, supporting inhibition of Ang-2 function by its balancing factor.…”

The role of future treatments in the management of neovascular age-related macular degeneration in Europe

“…Faricimab is the first bispecific monoclonal antibody targeting both VEGF-A and angiopoietin-2. 56 Two multicenter prospective, randomized, double-blinded, controlled phase III trials (TENAYA 57 and LUCERNE 58 ) were started in 2019 to evaluate the efficacy and safety of faricimab injected intravitreally every 12 and 16 weeks (with the possibility of reducing treatment interval to every 8 or 12 weeks) compared to aflibercept every 8 weeks in treatment-naïve patients with nAMD (ClinicalTrials.gov identifiers: NCT03823287 and NCT03823300). The first results at one year were reported in a recent press release.…”