Novel targets beyond vascular endothelial growth factor-A inhibition: improving vision with neovascular age-related macular degeneration treatment.

The primary goal in the management of neovascular age-related macular degeneration (nAMD) is to optimise visual acuity outcomes for patients. Landmark clinical trials have demonstrated improved visual outcomes with standard-of-care vascular endothelial growth factor (VEGF) inhibitors, principally targeting a single ligand (VEGF-A). However, in the real-world setting, not all patients attain optimal visual outcomes with these monotherapies. The role of the VEGF-A and VEGF receptor (VEGFR)-2 axis in angiogenesis and vascular permeability is well characterised, but other VEGF family members, including VEGF-C and VEGF-D, which activate VEGFR-2 and VEGFR-3, have also been implicated in nAMD pathogenesis. This may explain the heterogeneous responses observed with current therapies that primarily inhibit VEGF-A signalling, and in patients who continue to lose vision despite treatment, the consequences can be profound. Vision loss affects daily living and can lead to increased cost of care and susceptibility to falls and injuries. This review will explore the VEGF family of ligands and receptors and their role in nAMD, as well as novel therapeutics in development that target mediators beyond VEGF-A with the potential to provide improved vision benefits to patients. In particular, sozinibercept, an investigational trap biologic inhibitor of VEGF-C and VEGF-D ligands, has shown promising efficacy with superior vision gains when used in combination with ranibizumab dosed monthly (standard-of-care therapy) vs. standard-of-care alone (i.e. monthly ranibizumab). This adds to the increasing evidence that multifaceted approaches that target the VEGF family beyond VEGF-A have the potential to provide better vision outcomes for patients with nAMD.