A new review examined vascular endothelial growth factor-C and -D as alternatives to vascular endothelial growth factor-A treatments and signaling pathways in neovascular macular degeneration and other retinal diseases.

Originally investigated in oncology to combat aggressive cancer cell metastasis, vascular endothelial growth factor-A (VEGF-A) has also been indicated in angiogenesis-driven retinal diseases, including neovascular macular degeneration (nAMD) and diabetic macular edema (DME).

“Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis,” explain the investigators in the review in Ophthalmology and Therapy. “Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases.”

VEGF-C and VEGF-D are upregulated after VEGF-A “inhibition with aflibercept and bevacizumab or in conditions of experimentally induced underexpression of VEGF-A, which may in part contribute to the clinical sub-responsiveness reported in many patients treated with anti-VEGF-A monotherapy in both oncology and ocular diseases.”

The researchers further described how VEGF-C and VEGF-D can bind and activate additional VEGF receptors that induce growth of both blood vessels and lymphatics. Most research around the VEGF family has been focused on VEGF-A because it was the first ligand member to be identified as a key regulator of angiogenesis both during homeostasis and in disease. However, research on the functions of VEGF-C and -D is ongoing to understand the dual-blocking approach of the receptors they target. The review points to several oncological advances with VEGF drugs that may have lessons for physicians treating nAMD, DME, retinal vein occlusion, and retinopathy of prematurity.

Specifically in nAMD, immune cells secrete high levels of VEGF-A, VEGF-C, and VEGF-D, among other proangiogenic and proinflammatory cytokines, which ultimately lead to “leakage of blood vessel fluid that damages the photoreceptor layer and impairs vision.”

The current standard of care—inhibition of VEGF-A with biologic protein-based therapeutics—requires frequent intravitreal injections with limited durability. Research aims to reduce patients’ injection burden and find agents that help maintain visual acuity or reduce further vision loss. The most common treatments currently available are bevacizumab, ranibizumab, and aflibercept, though bevacizumab is often used off-label for nAMD. Additionally, recently approved treatments are brolucizumab and faricimab, formulated to require fewer injections and biosimilars. Research includes approaches with extended dosing regimens and gene therapies, but they are still in trials and have faced limitations. Despite extensive efforts, there are still unmet needs to further improve visual gains and durability of treatment responses for patients. The compensatory mechanisms of upregulation of other VEGF family ligands, such as VEGF-C and -D after VEGF-A suppression, beg the question of whether broader parallel inhibition of other members may improve efficacy, the researchers note.

A “trap” inhibitor of VEGF-C and VEGF-D is in clinical development. This soluble fusion protein binds and sequesters VEGF-C and VEGF-D, preventing the receptor signaling that promotes angiogenesis, further inflammatory response, and vascular leakage. Broader blockage of signaling pathways has been achieved when this inhibitor is used in combination with anti-VEGF-A therapies. It is currently in phase 3 trials with treatment-naïve nAMD patients.

Other therapies in development include:

• Tyrosine kinase inhibitors, which “act intracellularly to prevent downstream signaling cascade pathways” of VEGF and possibly other receptors
• A dual-transgene vector that expresses aflibercept and an inhibitory RNA to target inhibition of VEGF-A, VEGF-B, VEGF-C, as well as additional growth factors
• An integrin-regulating peptide, which inhibits a VEGF receptor and activates TIE-2 to suppress vascular leakage
• A VEGF-A/VEGF-C bispecific fusion protein that binds and neutralizes VEGF-A and VEGF-C to inhibit VEGF-C upregulation after VEGF-A neutralization

“A growing body of research is providing compelling evidence that, in retinal diseases such as nAMD, the pathophysiology is broader than simply dysregulation or overproduction of VEGF-A,” the researchers add. Combination inhibition of extracellular ligands VEGF-A, VEGF-C, and VEGF-D, and/or intracellular blockade of VEGF receptor signaling—which has been successfully applied in oncology—also may hold promise for addressing some current challenges of nAMD management, which could lead to better outcomes for patients.

"Considering the role of angiogenesis and vascular permeability in the pathogenesis of retinopathy, these processes are important targets for ophthalmic therapies, and evidence presented in this review suggests targeting VEGF-C and VEGF-D can inhibit them," the researchers conclude.

A full list of author disclosures can be found in the published review.