Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9

Hypercholesterolemia is a leading cause of cardiovascular disease and mortality in men and women throughout the USA and abroad. The development of statins (HMG-CoA reductase inhibitors) to lower plasma atherogenic cholesterol levels and improve cardiovascular outcomes represents one of the greatest contributions to clinical science in the twentieth century, although residual risk remains even among statin-treated patients. Our understanding of lipid metabolism took a giant leap forward in 2003 with the discovery of proprotein convertase subtilsin/kexin type 9 (PCSK9), a low abundance circulating protein with an outsized effect on the regulation of plasma cholesterol levels. Evolocumab and alirocumab represent the first two US Food and Drug Administration-approved fully human monoclonal antibodies that target PCSK9, which not only lower low-density lipoprotein (LDL) cholesterol to unprecedented levels, but also further improve important cardiovascular outcomes. Small interfering RNA (siRNA) molecules now represent the next generation of drugs designed to antagonize PCSK9. Inclisiran is a siRNA specific for PCSK9 that prevents translation of PCSK9 messenger RNA, leading to decreased concentrations of the protein and lower concentrations of LDL cholesterol. The ORION clinical development program includes several completed and ongoing clinical trials designed to evaluate the safety and efficacy of inclisiran and test its ability to improve hard cardiovascular outcomes. This review discusses the mechanisms of action of inclisiran, examines the current evidence, and provides a comparison of similarities and differences relative to the PCSK9 inhibitors.