Challenge: Blood level of cholesterol-rich low-density lipoproteins (LDLc) is directly correlated with the incidence of atherosclerosis and cardiovascular risk. Statins, currently the most prescribed class of lipid-lowering drugs, reduce LDLc by increasing LDL receptor (LDLR) gene expression. However, while being on maximally tolerated lipid-lowering therapy, a majority of high-risk patients still have uncontrolled LDLc and remain at high risk of a major cardiovascular event. Moreover, in a substantial number of patients, statins cause serious side effects. Therefore, there is a large unmet clinical need for affordable, safe and orally available add-on to statin lipid-lowering therapies for patients at high cardiovascular risk.

Solution: The team had previously designed innovative and highly performant screening platforms to enable the discovery of orally available small molecules that robustly enhance LDLR expression on top of statins. Here, a new class of small molecules that strongly decrease LDLc levels in hypercholesterolemic animal models, without any evidence of adverse events, was selected for further characterization. The primary objective of this project was to complete preclinical studies to determine the efficacy and safety of the two lead drug candidates, either alone or in combination with statins, in hypercholesterolemic animal models.  Unfortunately, the dose-response studies  were inconclusive in the animal models, which led to the premature termination of the study.

Expected achievements/Impact: The new expertise gained in the early stages of clinical development for human trial applications will benefit the staff who worked on the various aspects of the project. The project has also led to new collaborations within researchers at McGill. Finally, it enabled the understanding of how LDLR’s 3’UTR could be exploited to treat  hypercholesterolemia, which opens up an avenue for future development.