Abstract 710: Specific Removal Of Oxidized Cholesterol With A Cyclodextrin Dimer Drug Candidate Towards Reversing Atherosclerosis

Abstract

Cardiovascular disease (CVD) is the world’s biggest killer. Current treatments for CVD are failing to deliver on promises to beat this deadly and complex family of diseases. New approaches that go beyond targeting LDL are needed. Cyclarity Therapeutics has developed a novel class of specifically engineered, dimerized cyclodextrin (CD) molecules for the encapsulation of toxic oxidized cholesterol. Oxidized cholesterol accumulates over time and causes dysfunction in many cell types, linking it to several age-related diseases including atherosclerosis. Presently, treatments for atherosclerosis are invasive, expensive, and/or show limited benefits. Here, a combination of in silico, in vitro, and ex vivo methods are used to implement a synergistic rational drug design strategy for developing CDs to remove atherogenic oxidized cholesterol (primarily 7-ketocholesterol (7KC)) from cells and tissues. Our results thus far indicate that our lead compound, UDP-003, can both prevent and reverse the formation of atherogenic foam cells in-vitro. UDP-003 binds and clears 7KC from in-vivo and ex-vivo systems selectivity. IND enabling studies, including pivotal GLP studies in rodent and non-rodent species, are complete and show that UDP-003 has an excellent safety profile with no significant clinical liabilities. UDP-003 has been awarded the Innovative Licensing and Access Pathway (ILAP) Innovation Passport by the MHRA, which is accelerating Cyclarity’s path to clinic and will facilitate rapid and innovative clinical trials. In totality, our data suggest that targeted removal of 7KC from foam cells with our proprietary class of cyclodextrin compounds has the potential to prevent and reverse the formation of atherosclerotic plaques. This innovation represents the first disease-modifying therapeutic approach to treating atherosclerotic disease.