An In-Depth Pharmacological and Clinical Review of Inclisiran: A First-in-Class siRNA Therapeutic for Hypercholesterolemia

Executive Summary

Inclisiran, marketed under the brand name Leqvio®, represents a significant advancement in the management of hypercholesterolemia, establishing a new class of lipid-lowering therapies based on small interfering RNA (siRNA) technology. It is the first and only approved siRNA therapeutic designed to lower low-density lipoprotein cholesterol (LDL-C), a primary causal factor in the development of atherosclerotic cardiovascular disease (ASCVD). This report provides a comprehensive analysis of inclisiran, covering its molecular characteristics, novel mechanism of action, pharmacological profile, pivotal clinical trial evidence, safety and tolerability, global regulatory status, and its comparative positioning within the current therapeutic landscape.

The core innovation of inclisiran lies in its unique mechanism of action, which harnesses the natural cellular process of RNA interference (RNAi). It is specifically engineered to inhibit the hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that promotes the degradation of LDL receptors (LDLR). By preventing the translation of PCSK9 messenger RNA (mRNA), inclisiran effectively "turns off the tap" of PCSK9 production within the liver. This leads to an increased density of LDLRs on the hepatocyte surface, enhancing the clearance of LDL-C from the circulation. This intracellular mechanism of synthesis inhibition fundamentally distinguishes inclisiran from the existing class of PCSK9 monoclonal antibodies (mAbs), which act extracellularly by binding to and sequestering the already-secreted PCSK9 protein.