An update on inclisiran for the treatment of elevated LDL cholesterol

ABSTRACT

Introduction

The burden of atherosclerotic cardiovascular disease (ASCVD) persists globally, demanding innovative therapeutic strategies. This manuscript provides an expert opinion on the significance of managing low-density lipoprotein cholesterol in ASCVD prevention and introduces inclisiran, a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9).

Areas Covered

This work delves into the intricate mechanism of inclisiran, highlighting its unique approach of hepatic intracellular PCSK9 inhibition, its precision and low off-target effects risk. Pharmacodynamic and pharmacokinetic distinctions from PCSK9 monoclonal antibodies are explored, underlining inclisiran’s efficiency, extended duration, and clearance. Clinical trials, including pivotal phase-III placebo-controlled studies (ORION-9, −10, −11), the open-label ORION-3 and pooled safety analysis of these trails including the open-label phase of ORION-8, as well as real-word data are discussed to provide a comprehensive evaluation of inclisiran’s efficacy and safety.

Expert Opinion

Inclisiran stands as a first-in-class breakthrough in lipid-lowering therapies, showing potential in alleviating the global burden of ASCVD and is supported by multiple global regulatory approvals. To optimize inclisiran’s utilization and comprehend its long-term effects, future directions include pediatric studies, cardiovascular outcome trials, and extended-duration investigations. Overall, inclisiran emerges as a precise and effective therapeutic option, offering significant promise for preserving cardiovascular health.

GRAPHICAL ABSTRACT

KEYWORDS:

• Cardiovascular disease
• cholesterol
• inclisiran
• PCSK9
• small interfering RNA

Article highlights

• Inclisiran aims to address the challenges of long-term adherence and tolerability of current lipid-lowering therapies.

• Inclisiran, belonging to the siRNA drug class, utilizes double-stranded RNA molecules to precisely intervene in LDL metabolism, targeting liver-specific PCSK9 mRNA degradation and thereby enhancing LDL clearance.

• The advantages of inclisiran include its rapid absorption, efficient liver uptake, and minimal accumulation over time, ensuring sustained efficacy with less frequent dosing.

• Clinical trials and real-world data support the efficacy of inclisiran in diverse populations, demonstrating sustained reductions in LDL-cholesterol levels.

• According to the latest evidence from both trials and recent observational studies, the safety profile of inclisiran continues to be favorable and consistent.

Disclosure of interest

F Barkas reports grants and personal fees from Amgen, Novartis, Novo Nordisk, and Sanofi, outside the submitted work.

K K Ray reports grants from Amgen, grants from Daiichi Sankyo, grants from Regeneron, grants from Sanofi, grants from pfizer, grants from MSD, during the conduct of the study; personal fees from Amgen, grants and personal fees from Sanofi, personal fees from Regeneron, personal fees from Pfizer, personal fees from Viatris, personal fees from Abbott, personal fees from Astra Zeneca, personal fees from Lilly, personal fees from Kowa, personal fees from Novo Nordisk, personal fees from Boehringer Ingelheim, personal fees from Esperion, personal fees from Cargene, personal fees from Resverlogix, personal fees from Novartis, personal fees from Silence Therapeutics, personal fees from New Amsterdam, personal fees from SCRIBE Therapeutics, personal fees from CRISPR, personal fees from VAXXINITY, personal fees from AMARIN, personal fees from CSL Behring, personal fees from Bayer, personal fees from Beren Therapeutics, personal fees from Biologix Pharma, 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

Novartis provided a scientific accuracy review at the request of the journal editor. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.