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

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 with inclisiran’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.

KEYWORDS:

• Atherosclerotic cardiovascular disease (ASCVD)
• hypercholesterolemia
• short interfering RNAs (siRNAs)
• inclisiran

Article highlights

• LLTs represent the cornerstone of ASCVD prevention and treatment.

• Poor adherence to LLTs, as well as difficulty of the maximum tolerated SoC therapy to reach recommended goals, constitute obstacles in the effective treatment of ASCVD.

• Inclisiran constitutes a first in class siRNA targeting PCSK9 mRNA and leading to PTGS of PCSK9 gene.

• Phase III clinical trials (ORION trials) revealed a favorable safety profile and a ~ 50% reduction in LDL-C with 300 mg SC inclisiran administration on days 1 and 90, followed by semiannual booster shots.

• The effect of inclisiran on cardiovascular events is currently investigated in a large-scale clinical trial program (VictORION).

• Managing additional healthcare costs and ensuring new agent’s widespread availability is of paramount importance.

Declaration of interest

LS Rallidis has received research grants and honoraria from Amgen Inc, Sanofi, Viatris, Novartis, Vianex and Servier, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.