Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis

Abstract

The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%–20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

“…Inclisiran is a small interfering RNA (siRNA) directed to PCSK9 mRNA. Inhibiting PCSK9 synthesis mediates upregulation of LDL receptors on the hepatocytes, thereby lowering plasma LDL-C concentration (Rogula et al 2021 ). It is a next-in-class therapy indicated for the treatment of heterozygous familial hypercholesterolemia as add-on or replacement for treatment with statins.…”

“…Another continuing trend is that neurology/psychiatry and infectious disease remain strong areas of innovation (Mullard 2021a ). While still not being approved in large numbers, the antisense oligonucleotide casimersen (Shirley 2021 ) and siRNA inclisiran (Rogula et al 2021 ) continue a trend for nucleic acid-related treatments as seen in the 2020 approvals of the antisense oligonucleotid viltolarsen (Iftikhar et al 2021 ) and the siRNA lumasiran (Scott and Keam 2021 ). In a more general vein, these data testify to the ongoing innovation in medical treatment and the role of pharmacology for human wellbeing.…”

Using RNAi in the treatment of cardiovascular diseases - therapeutics based on siRNA overview

“…The EU approval of the drug was based on the results of the ORION clinical trials, which confirmed the efficacy and safety of Inclisiran in lowering LDL levels in patients with hypercholesterolaemia at the maximum doses of statins. Inclisiran lowers LDL levels by more than 50% with one dose every 6 months, which is a great innovation in the treatment of hyperlipidemia, where statins alone reduce LDL by 10-20%, and inclisiran is well tolerated by patients [21].…”

Emerging Anti-Atherosclerotic Therapies

“…The mechanism of action is based on RNA interference, a process during which double-stranded RNA silences the PCSK9 gene by triggering the complementary mRNA degradation and thus preventing PCSK9 protein production. The inhibition of hepatic synthesis of PCSK-9 is associated with the upregulation of many LDL receptors on the hepatocytes, resulting in the reduction in plasma LDL-C concentration [48][49][50]. Inclisiran markedly reduces LDL-C levels with an acceptable side-effect profile and an infrequent dosing regimen; it is administered subcutaneously with an initial dose, repeated at 3 months and then every 6 months [51].…”