4083674

AZD0780 - an oral PCSK9 inhibitor with a novel mode of action for the treatment of cardiovascular disease

Date
August 21, 2024

PCSK9 is a circulating protein that increases circulating LDL-cholesterol (LDL-C) by binding to and degrading LDL receptors (LDLR). PCSK9 inhibitors are therefore of interest for the reduction of LDL-C and prevention of cardiovascular disease. Currently approved and in development PCSK9 inhibitors either inhibit the classical PCSK9-LDLR protein-protein interaction (PPI) interface or protein expression and are either injectables (antibodies or siRNA) or have food interactions. Improved oral PCSK9 inhibitors are sought in order to decrease cost and increase patient convenience.
We report a novel, functional binding pocket on the PCSK9 C-terminal domain (CTD) that is druggable by small molecules with attractive developability properties. This led to the development of a new class of small molecule PCSK9 inhibitors that includes our clinical candidate AZD0780. Unlike the peptidic or mAb-based PCSK9 inhibitors, AZD0780 does not inhibit the PCSK9-LDLR PPI but instead inhibits PCSK9 via a novel mode of action.
In a Phase I clinical study, AZD0780 was generally safe and well-tolerated and has recently progressed to Phase 2 clinical studies.
We will describe the hit finding and lead optimisation program, the preclinical profile of AZD0780 and details of its mode of action as well as a summary of the Phase I clinical trial results.

Presenter


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DIVISION/COMMITTEE: [MEDI] Division of Medicinal Chemistry