Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9-A Narrative Review.

Iveta Merćep,Dominik Strikić,Željko Reiner,Nikolina Friščić,Brian Tomlinson

doi:10.1155/2022/8129513

Abstract

As dyslipidemias remain one of the main risk factors for developing cardiovascular disease, the question of maintaining optimal lipid levels with pharmacotherapy remains a subject of interest worldwide. In contrast to conventional pharmacotherapy, human monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PSCK9) and small interfering RNA- (siRNA-) based drug targeting PCSK9 represent a new strategy for managing lipid disorders and reducing cardiovascular risk. Inclisiran is a long-acting, synthetic siRNA that targets hepatic production of PCSK9 and consequently causes a reduction in LDL-C concentrations by approximately 50% compared to placebo. The structural modification of inclisiran has led to better stability and prolonged biological activity of the drug. The main advantage over conventional pharmacotherapy and anti-PCSK9 monoclonal antibodies is its favorable administration regimen (0–90–180 days), which should lead to much better compliance. Clinical trials conducted so far have confirmed the tolerability and efficacy of inclisiran in long-term PCSK9 and LDL-C level reductions. Moreover, a short-term follow-up on the safety of inclisiran showed a relatively good safety profile of the drug. However, it is still of great importance for ongoing and forthcoming clinical trials to be continued on a larger group of patients in order to assess long-term tolerability, efficacy, and safety of inclisiran.

Highlights

Dyslipidemia is one of the most important risk factors for cardiovascular disease (CVD) [1]
It is important to mention that the spherical structure of the precursor of inclisiran inserted into the lipid nanoparticle, the ALN-PCS molecule, caused a reduction of 70% in both proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and protein concentrations and a 60% reduction in low-density lipoprotein cholesterol (LDL-C) concentrations in animal models with a duration of three weeks [16]
Based on data from all three phase III ORION studies, that is ORION-9, ORION-10, and ORION-11, which have confirmed the robust LDL-C lowering with inclisiran (284 mg) in the long-term with reduced plasma PCSK9 levels by approximately 80%, it seems that inclisiran is the first-inclass small interfering RNA- (siRNA-)based drug, which is efficient in changing the lipoprotein profile into a favorable one in patients with dyslipidemia, in those with elevated LDLC, and has a very good safety profile [23, 29]

Summary

Introduction

Dyslipidemia is one of the most important risk factors for cardiovascular disease (CVD) [1]. The role of low-density lipoprotein cholesterol (LDL-C) in the development of atherosclerosis is well known to be the benefit of lowering elevated LDL-C levels in the reduction of cardiovascular (CV) risk [2]. The current European Society of Cardiology/European Society of Atherosclerosis guidelines for the management of dyslipidemia [3] emphasize on adequate control and treatment of dyslipidemia, on LDL-C lowering. The most recent relevant position papers emphasize the importance of LDL-C lowering, in high, very high, and extremely high-risk patients [4]. Pharmacotherapy with statins is still the gold standard in the treatment of hypercholesterolemia and elevated LDL-C; available data from surveys, prospective studies, and clinical registries provide insight that some patients do not reach their therapeutic goals even with the highest tolerated doses of statins [5–7]. PCSK9 is a protein involved in the regulation of LDL-C metabolism by interfering with LDL receptors, causing a reduction in plasma LDL-C levels

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