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An update on inclisiran for the treatment of elevated LDL cholesterol

Fotios Barkas1,2, Kausik Ray2

  • 1Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.

Expert Opinion on Pharmacotherapy
|March 29, 2024
PubMed

Insights

Inclisiran, a novel small interfering RNA, offers a precise and effective approach to lowering low-density lipoprotein cholesterol for atherosclerotic cardiovascular disease prevention. This therapy targets proprotein convertase subtilisin/kexin type 9 (PCSK9) with potential to reduce global ASCVD burden.

Area of Science:

  • Cardiovascular Medicine
  • Pharmacology
  • RNA Therapeutics

Background:

  • Atherosclerotic cardiovascular disease (ASCVD) remains a leading global health concern.
  • Effective management of low-density lipoprotein cholesterol (LDL-C) is crucial for ASCVD prevention.
  • Novel therapeutic strategies are needed to address the persistent burden of ASCVD.

Purpose of the Study:

  • To provide an expert opinion on the role of LDL-C management in ASCVD prevention.
  • To introduce inclisiran, a novel small interfering RNA (siRNA) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9).
  • To discuss the mechanism, efficacy, and safety of inclisiran based on clinical trial data.

Main Methods:

  • Review of inclisiran's mechanism of action, focusing on hepatic intracellular PCSK9 inhibition.
  • Analysis of pharmacodynamic and pharmacokinetic properties in comparison to PCSK9 monoclonal antibodies.
  • Evaluation of clinical trial data from pivotal Phase III studies (ORION-9, -10, -11) and real-world evidence.

Main Results:

  • Inclisiran demonstrates a unique, precise mechanism with low off-target effects.
  • Clinical trials show inclisiran's efficacy in lowering LDL-C with an extended duration of action.
  • Pooled safety analyses indicate a favorable safety profile for inclisiran.

Conclusions:

  • Inclisiran represents a first-in-class breakthrough in lipid-lowering therapy.
  • It holds significant potential for alleviating the global burden of ASCVD.
  • Further research, including pediatric and cardiovascular outcome trials, is warranted to optimize its use.
Abstract

Keywords:
Cardiovascular diseasePCSK9cholesterolinclisiransmall interfering RNA

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