4.5 Review

Investigational drugs in clinical trials for macular degeneration

Journal

EXPERT OPINION ON INVESTIGATIONAL DRUGS
Volume 31, Issue 10, Pages 1067-1085

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/13543784.2022.2113375

Keywords

Macular degeneration; geographic atrophy; wet AMD; complement; macrophage; microglia; clinical trials

Funding

  1. Tolentino Eye Research Foundation, University of Central Florida, USA

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This paper reviews the pathogenesis of macular degeneration, current and failed therapeutics, therapies undergoing clinical trials and provides a rationale for why certain AMD therapies may succeed or fail.
Introduction Intravitreal anti-vascular endothelial growth factor (VEGF) injections for exudative age-related macular degeneration (eAMD) are effective and safe but require frequent injections and have nonresponding patients. Geographic atrophy/dry AMD (gaAMD) remains an unmet medical need. New therapies are needed to address this leading cause of blindness in the increasing aged population. Areas covered This paper reviews the pathogenesis of macular degeneration, current and failed therapeutics, therapies undergoing clinical trials and a rationale for why certain AMD therapies may succeed or fail. Expert Opinion VEGF-inhibitors reduce both vascular leakage and neovascularization. Experimental therapies that only address neovascularization or leakage will unlikely supplant anti-VEGF therapies. The most promising future therapies for eAMD, are those that target, more potently inhibit and have a more sustained effect on the VEGF pathway such as KSI-301, RGX-314, CLS-AX, EYEP-1901, OTX-TKI. GaAMD is a phenotype of phagocytic retinal cell loss. Inhibiting phagocytic activity of retinal microglial/macrophages at the border of geographic atrophy and reducing complement derived activators of microglial/macrophage is the most promising strategy. Complement inhibitors (Pegcetacoplan and Avacincaptad pegol) will likely obtain FDA approval but will serve to pave the way for combined complement and direct phagocytic inhibitors such as AVD-104.

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