Inclisiran: A Novel Agent for Lowering Apolipoprotein B-Containing Lipoproteins.

ABSTRACT Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B-containing lipoproteins in plasma are the centerpiece of strategies for cardiovascular prevention and treatment in primary and secondary management. Despite the importance of this endeavor, many patients do not achieve appropriate low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) goals, even among those who have experienced atherosclerotic cardiovascular disease (ASCVD). The development of new LDL-C-lowering medications with alternative mechanisms of action will facilitate improved goal achievement in high risk patients. Inclisiran is a novel small interfering ribonucleic acid (siRNA)-based drug that is experimental in the US and approved for clinical use in the EU. It lowers LDL-C and other apolipoprotein B-containing lipoproteins by reducing production of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a protein that normally contributes to LDL-receptor (LDLR) degradation, thereby increasing LDLR density and recycling in hepatocytes. Although the lipid-lowering efficacy of inclisiran is comparable to results achieved with PCSK9-blocking monoclonal antibodies (PCSK9i) (alirocumab and evolocumab), there are several important differences between the two drug classes. First, inclisiran reduces levels of PCSK9 both intracellularly and extracellularly by blocking translation of and degrading PCSK9 messenger RNA. Second, the long biological half-life of inclisiran produces sustained LDL-C-lowering with twice yearly dosing. Third, although PCSK9i drugs are proven to reduce ASCVD events, clinical outcomes trials with inclisiran are still in progress. In this manuscript, we review the clinical development of inclisiran, its mechanism of action, lipid-lowering efficacy, safety and tolerability, and potential clinical role of this promising new agent.