Development of a new class of oral and highly potent non-statin LDL-cholesterol lowering therapeutics for patients at high cardiovascular risk

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 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, has been selected for further characterization. The primary objective of this project is to complete preclinical studies to determine efficacy (dose-response, LDLc lowering) and safety of the lead drug candidates, either alone or in combination with statins, in hypercholesterolemic animal models. In parallel, new chemical entities and derivatives of lead molecules will be developed and studied to better understand the structure-activity relationship of those LDLR enhancers in human cells and animal models.

Expected achievements/Impact: This project fulfills an urgent need for cost-effective and oral medications for high risk patients with familial hypercholesterolemia or atherosclerotic cardiovascular diseases. While enlarging MONOGENIC Pharmaceuticals’ patent portfolio, the project will support the filing of applications for first-in-human and human proof-of-concept efficacy and safety clinical trials primarily indicated for patients at high cardiovascular risk on maximally tolerated statin therapy.

Principal Investigator:

Gaétan Mayer
Institut de Cardiologie de Montréal


Steve Poirier
Monogenic Pharmaceuticals

Jean-Claude Tardif 
JCT Biotechnologies


Ongoing Project
$ 4,178,346 / 3 years


Supported by CQDM through:
• MEIAnd by co-funding partners

• Monogenic Pharmaceuticals
• JCT Biotechnologies.