Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015)

ABSTRACT

Introduction: The identification by Abifadel et al. in 2003 of the first mutations of PCSK9 was the major breakthrough in the cholesterol field that led to a new therapeutic target. This discovery paved the way to new lipid lowering drugs reducing LDL-cholesterol levels through the inhibition of PCSK9. Two anti-PCSK9 monoclonal antibodies have received FDA and EMA approvals: Alirocumab and Evolocumab.

Areas covered: This article reviews the different strategies that are pursued to modulate the functional activity of PCSK9 for lowering LDL-cholesterol levels. It also provides a brief overview of the patents related to PCSK9 from 2011 until the end of 2015. This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9, focusing on anti-PCSK9 monoclonal antibodies and the related clinical trials.

Expert opinion: Anti-PCSK9 antibodies are a new class of lipid lowering drugs with promising results in reducing LDL-cholesterol. Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are eagerly awaited.

KEYWORDS:

• Cholesterol
• PCSK9
• anti-PCSK9 antibodies
• patents
• cholesterol lowering drugs

Article highlights

• Our discovery in 2003 of the first mutations of PCSK9 in autosomal dominant hypercholesterolemia revealed a new protagonist in cholesterol metabolism. This discovery paved the way for other teams around the world to study this protein, which rapidly gained the interest of pharmaceutical companies.

• More than 100 international patents related to PCSK9 have been published since our seminal discovery.

• Several strategies have been developed to inhibit PCSK9. Monoclonal antibodies (mAbs) are the most advanced approach. Two fully human mAbs, Alirocumab (Regeneron/Sanofi) and Evolocumab (Amgen), showed an important reduction of LDL-cholesterol levels and have received FDA and EMA approvals. Other strategies, such as antisense technology or active vaccination are currently being studied in clinical trials.

• Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are keenly awaited.

This box summarizes key points contained in the article.

Declaration of interest

Marianne Abifadel, Catherine Boileau and Jean Pierre Rabès are experts and give lectures for Sanofi-Regeneron and Amgen. 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.

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Additional information

Funding

This work was supported by a grant from Leducq Foundation [FLQ # 13 CVD 03] through the Transatlantic Networks of Excellence in Cardiovascular Research program (‘The function and regulation of PCSK9: a novel modulator of LDLR activity’); Institut National de la Santé et de la Recherche Médicale (INSERM); Conseil de la Recherche de l’Université Saint-Joseph (Beirut, Lebanon), and Lebanese National Council for Scientific Research (CNRS-L).