Tyrosine kinase inhibitors for wet age-related macular degeneration: The current developmental landscape

Age-related macular degeneration (AMD) is a leading cause of permanent vision loss in older patients worldwide. The neovascular (wet) AMD is characterized by abnormal choroidal neovascularization driven by vascular endothelial growth factor (VEGF), platelet-derived growth factor, and Tie2 signaling pathways, leading to retinal damage and progressive vision decline. Current standard-of-care anti-VEGF therapies aim to limit choroidal neovascularization through extracellular targeting of cytokines involved in the VEGF signaling pathway implicated in angiogenesis. Although these existing therapies can be effective, many patients face a high treatment burden of multiple intraocular injections, which can negatively impact compliance, safety, and long-term efficacy. Tyrosine kinase inhibitors (TKIs) aim to address these limitations by offering longer durability, broad-spectrum targeting of angiogenic pathways, and a reduction in treatment burden through intracellular targeting of angiogenic pathways. With multiple pharmaceutical TKI candidates advancing through clinical trials and showing promising data, this class of drugs could lead to a shift in future treatment options for patients with wet AMD. Despite the progress TKIs have made, there have yet to be any candidates approved for wet AMD treatment. Much of the existing evidence is from early-phase and short-term studies, and questions remain about long-term efficacy and safety compared to current standard-of-care anti-VEGF therapies. Nevertheless, with multiple candidates advancing through phase III clinical trials, TKIs have the potential to emerge as a next-generation treatment class that may transform the wet AMD therapeutic landscape. SIGNIFICANCE STATEMENT: Given the chronic nature of wet age-related macular degeneration and the limitations of current anti-vascular endothelial growth factor therapies, tyrosine kinase inhibitors have emerged as a promising class of anti-angiogenic agents. This review highlights the recent clinical developments in this evolving therapeutic landscape.