A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties...

Area of Science:

• Biochemistry
• Pharmacology
• Cardiovascular Medicine

Background:

• Proprotein convertase subtilisin kexin type 9 (PCSK9) elevates plasma LDL cholesterol by promoting LDL receptor degradation.
• Elevated LDL cholesterol is a major risk factor for cardiovascular disease.
• Current PCSK9 inhibitors are injectable, creating a need for oral alternatives.

Purpose of the Study:

• To discover and characterize NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9.
• To evaluate the efficacy and safety of NYX-PCSK9i in a preclinical model of hyperlipidemia.

Main Methods:

• In vitro assays to assess PCSK9-LDLR interaction inhibition.
• Ex vivo studies on human lymphocytes to evaluate LDLR protection.
• In vivo studies in hyperlipidemic APOE*3-Leiden.CETP mice treated orally with NYX-PCSK9i, alone and with atorvastatin.

Main Results:

• NYX-PCSK9i potently inhibited the PCSK9-LDLR interaction and protected LDLR from degradation.
• Oral administration in mice reduced plasma total cholesterol by up to 57% in a dose-dependent manner.
• NYX-PCSK9i demonstrated additive effects with atorvastatin, increased hepatic LDLR, and promoted fecal cholesterol excretion.
• In vivo safety biomarkers indicated a favorable safety profile.

Conclusions:

• NYX-PCSK9i is a novel, orally bioavailable small-molecule PCSK9 inhibitor with significant cholesterol-lowering activity.
• The compound demonstrates a good safety profile in preclinical studies.
• NYX-PCSK9i represents a potential new oral therapy for hypercholesterolemia, with the ability to augment statin efficacy.