Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia

ABSTRACT

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds and promotes the lysosomal degradation of the low-density lipoprotein receptors (LDLR). Upon its discovery in 2002, PCSK9 inhibition has subsequently emerged as a novel target for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease. Evolocumab, a monoclonal antibody directed against human PCSK9, was approved in 2015 as an adjunct to lipid-lowering therapy for treating patients with familial hypercholesterolemia (FH) or patients with high cardiovascular risk, who are treated with maximally tolerated lipid-lowering agents and have not reached the recommended LDL-C levels.

Areas covered: The authors illustrate the rapid pace of the drug development process that monoclonal antibodies, including evolocumab, have demonstrated during the last decade. In less than 15 years from its discovery, this lipid-lowering target has successfully progressed from bench-side to clinical practice and has been recently approved to reduce cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD).

Expert opinion: Evolocumab has demonstrated a good safety profile and robust efficacy in terms of its lipid-lowering effect and ASCVD risk reduction, yet affordability, accessibility, and cost-effectiveness of PCSK9 monoclonal antibodies remain a hurdle in the ‘real-world’ setting. These challenges facing the upcoming generation of precision medicine therapies must be addressed upfront.

KEYWORDS:

• Proprotein convertase subtilisin/kexin type 9
• familial hypercholesterolemia
• evolocumab
• drug development
• precision medicine

Article highlights

• The fascinating timeline of the PCSK9 inhibitors path: from the preclinical discovery to the clinical development and marketing approval in less than 15 years.

• Several novel therapies for severe dyslipidemia originate from the identification of naturally occurring rare gene variants. The case histories of PCSK9, ApoC-III and ANGPTL-3 inhibitors represent good examples of the contribution of omics sciences to drug development [116].

• Evolocumab is approved as an adjunct to lipid-lowering therapy for treating patients with familial hypercholesterolemia (HeFH and HoFH) or patients with high cardiovascular risk who have not reached the recommended LDL-C levels.

• Evolocumab and other PCSK9 inhibitors still face access and cost-effectiveness challenges and the pricing should significantly drop in order to reach an acceptable and affordable threshold of quality-adjusted life-year (QALY).

• Emerging therapies targeting PCSK9 inhibition are being developed, particularly siRNA therapies, including Inclisiran [19] and others [120]. PCSK9 inhibition remains a highly valuable target for the management of hypercholesterolemia and associated risk.

This box summarizes key aspects of this article.

Declaration of interest

D Gaudet has been involved as a principal investigator or consultant in pivotal trials in FH for Aegerion, Amgen, Cerenis, Cymabay, Gemphire, HDL Therapeutics, Regeneron and Sanofi. 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.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.