👤 Kevin Chemello

Elevated concentrations of both low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) [Lp(a)] is probably the most detrimental lipid profile in terms of cardiovascular health. Our primary objective was to review the reports published before January 2026 pertaining to the metabolism of lipoprotein(a) and associated cardiovascular disease (CVD) risk specifically in familial hypercholesterolemia. Lp(a) has consistently been found elevated in familial hypercholesterolemia (FH) cohorts. To a large extent, this results from the fact that elevated Lp(a) increases the likelihood for a patient to be clinically diagnosed as FH. For long, increases in Lp(a) concentrations observed in FH patients have been regarded as the consequence of impaired Lp(a) plasma clearance by the LDL receptor. However, recent studies strongly advocate against a significant role for the LDL receptor in mediating Lp(a) hepatic uptake. The molecular mechanisms by which Lp(a) is cleared from blood still remain elusive. Finally, mounting clinical evidence indicates that lowering LDL-C pharmacologically will not offset the specific cardiovascular risk stemming from elevated Lp(a) in FH. It is highly recommended to systematically measure Lp(a) in FH patients. These patients should be treated with high-dose statins, when necessary, in combination with a proprotein convertase subtilisin/kexin type 9 inhibitor to reach LDL-C therapeutic goals. Hopefully, the Lp(a) lowering therapies currently under development will prove instrumental for adequate treatment of FH patients with concomitantly elevated Lp(a) in coming years. Show less

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins. Show less