Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis

Jul 7, 2026

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Inclisiran offers a low-density lipoprotein cholesterol–lowering approach designed for atherosclerotic cardiovascular disease prevention and treatment. The article addresses the remaining clinical need in lipid-lowering therapy, where many patients fail to reach goals due to poor adherence or limitations of standard of care. As the first available small interfering RNA therapy, inclisiran targets PCSK9 mRNA, enabling post-transcriptional gene silencing. Phase III results report ~50% LDL-C reduction with dosing on days 1 and 90 and semiannual boosters.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

Abstract

Introduction

Areas covered

Expert opinion

Article history

Keywords

Introduction

Burden and risk factors of CVD/ASCVD

LDL-C as primary therapeutic target

Standard lipid-lowering therapies (statins, ezetimibe, PCSK9 inhibitors)

Expert Opinion on Drug Discovery ISSN: (Print) (Online) Journal [homepage: ](homepage: www.tandfonline.com/journals/iedc20)[www.tandfonline.com/journals/iedc20](homepage: www.tandfonline.com/journals/iedc20) Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis Donatos Tsamoulis, Loukianos S. Rallidis & Constantine E. Kosmas To cite this article: Donatos Tsamoulis, Loukianos S. Rallidis & Constantine E. Kosmas (28 May 2024): Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis, Expert Opinion on Drug Discovery, DOI: 10. 1080/17460441 .2024.2360415 To link to this article: [https://doi.org/10.1080/17460441.2024.2360415](https://doi.org/10.1080/17460441.2024.2360415) Published online: 28 May 2024. | Submit your article to this journal | | --- | | View related articles | | View Crossmark data | Full Terms & Conditions of access and use can be found at [https://www.tandfonline.com/action/journalInformation?journalCode=iedc20](https://www.tandfonline.com/action/journalInformation?journalCode=iedc20) DRUG DISCOVERY CASE HISTORY Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis Donatos Tsamoulis, Loukianos S. Rallidis and Constantine E. Kosmas Second Department of Cardiology, National & Kapodistrian University of Athens, Athens, Greece ABSTRACT Introduction: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality. Lipid lowering therapy (LLT) constitutes the cornerstone of ASCVD prevention and treatment. However, several patients fail to achieve therapeutic goals due to low treatment adherence or limitations of standard-of-care (SoC) LLTs. Inclisiran represents a pivotal low-density lipoprotein cholesterol (LDL-C) lowering agent aiming to address current unmet needs in LLT. It is the first available small interfering RNA (siRNA) LLT, specifically targeting PCSK9 mRNA and leading to post-transcriptional gene silencing (PTGS) of the PCSK9 gene. Areas covered: Promising phase III trials revealed an ~ 50% reduction in LDL-C levels with subcutaneous inclisiran administration on days 1 and 90, followed by semiannual booster shots. Coupled withinclisiran’s favorable safety profile, these findings led to its approval by both the EMA and FDA. Herein, the authors highlight the preclinical discovery and development of this agent and provide the reader with their expert perspectives. Expert opinion: The evolution of gene-silencing treatments offers new perspectives in therapeutics. Inclisiran appears to have the potential to revolutionize ASCVD prevention and treatment, benefiting millions of patients. Ensuring widespread availability of Inclisiran, as well as managing additional healthcare costs that may arise, should be of paramount importance. ARTICLE HISTORY Received 5 April 2024 Accepted 23 May 2024 KEYWORDS Atherosclerotic cardiovascular disease (ASCVD); hypercholesterolemia; short interfering RNAs (siRNAs); inclisiran 1. Introduction Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. According to the World Health Organization (W.H.O.), almost one in three deaths in 2019 occurred due to CVD with the majority of them being the result of a heart attack or a stroke. Socioeconomic status, behavioral factors, such as the use of tobacco, genetics and metabolic features, such as diabetes mellitus (DM) and hypercholesterolemia, constitute the risk factors for the development of CVD, as well as the main therapeutic targets for its prevention and treatment [1] . Atherosclerotic cardiovascular disease (ASCVD) constitutes the principal pathophysiological process of CVD with LDL playing the key role in the pathogenesis of atherosclerosis. Strong data suggest that LDL-C lowering, regardless of the way this is achieved, is proportionally as

FAQs

Why is inclisiran considered important in atherosclerotic cardiovascular disease (ASCVD) management?

ASCVD remains a major cause of morbidity and mortality, and current lipid-lowering therapy often fails due to inadequate adherence or limitations of standard-of-care options. Inclisiran is presented as a means to address these unmet needs through LDL-C lowering.

How does inclisiran work at the molecular level?

Inclisiran is a small interfering RNA that specifically targets PCSK9 mRNA, leading to post-transcriptional gene silencing of the PCSK9 gene.

What LDL-C reduction and dosing schedule are reported from later-stage evidence?

Promising phase III trials showed an approximately 50% reduction in LDL-C after subcutaneous dosing on days 1 and 90, followed by semiannual booster shots, alongside a favorable safety profile.

Jul 7, 2026

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