What is the mechanism of Inclisiran?

Inclisiran is a novel therapeutic agent for the management of hypercholesterolemia, particularly in individuals with a high risk of cardiovascular disease. It is a small interfering RNA (siRNA) molecule that acts by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that plays a crucial role in the regulation of low-density lipoprotein cholesterol (LDL-C) levels.

The mechanism of action of Inclisiran begins with its targeted delivery to hepatocytes, the primary cells in the liver responsible for producing PCSK9. Once administered, usually via subcutaneous injection, Inclisiran utilizes a delivery system based on lipid nanoparticles to ensure efficient uptake by the liver cells. Upon entering the hepatocytes, Inclisiran harnesses the cellular machinery to execute RNA interference (RNAi), a process that selectively degrades the messenger RNA (mRNA) encoding the PCSK9 protein.

The RNAi mechanism is initiated when Inclisiran's siRNA component is incorporated into the RNA-induced silencing complex (RISC). Within the RISC, the siRNA strand guides the complex to the complementary mRNA sequence of PCSK9. The RISC then cleaves the PCSK9 mRNA, leading to its degradation. This degradation prevents the translation of the mRNA into the PCSK9 protein, thereby reducing the overall levels of PCSK9 in the bloodstream.

By lowering PCSK9 levels, Inclisiran indirectly influences the number of LDL receptors present on the surface of hepatocytes. PCSK9 is known to bind to LDL receptors and promote their degradation. With reduced PCSK9 activity, more LDL receptors are spared from degradation and are thus available to remove LDL-C from the bloodstream. This enhancement in LDL receptor availability results in a significant decrease in circulating LDL-C levels, aiding in the reduction of cardiovascular risk.

An important advantage of Inclisiran over other PCSK9 inhibitors, such as monoclonal antibodies, is its long-lasting effect. Inclisiran's mechanism allows for sustained suppression of PCSK9 production, necessitating only two doses per year after an initial phase of two doses given three months apart. This biannual dosing regimen improves patient compliance and convenience, making it a compelling option for long-term cholesterol management.

Clinical trials have demonstrated the efficacy and safety of Inclisiran in reducing LDL-C levels when used in conjunction with statins or other lipid-lowering therapies. The ORION clinical development program, comprising several pivotal trials, has consistently shown that Inclisiran achieves significant and sustained LDL-C reductions in a broad range of patients, including those with familial hypercholesterolemia and atherosclerotic cardiovascular disease.

In summary, Inclisiran represents a groundbreaking approach to cholesterol management through its targeted inhibition of PCSK9 synthesis. Its use of RNA interference to selectively degrade PCSK9 mRNA leads to a cascade of effects that ultimately enhance LDL receptor availability and lower LDL-C levels. With its durable efficacy and convenient dosing schedule, Inclisiran offers a promising therapeutic option for patients at high risk of cardiovascular events due to hypercholesterolemia.