Update on PCSK9 Inhibitors and New Therapies

US Endocrinology 2016;12(1):18–21 DOI: http://doi.org/10.17925/USE.2016.12.01.18


Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.
Keywords: PCSK9, low-density lipoprotein (LDL) cholesterol, LDL receptor, cardiovascular disease, familial hypercholesterolemia
Disclosure: Evan A Stein has received consulting fees from Amgen, Regeneron, Sanofi, Genentech, Roche, The Medicines Co, ISIS, Catabasis, AstraZeneca, CymaBay, CVS/ Caremark and BMS related to PCSK9 inhibitors and other lipid lowering drugs. Frederick J Raal has received honoraria and/or consulting fees from AstraZeneca, Pfizer, Merck, Amgen, Sanofi and his institution grants/research support from Amgen and Sanofi. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received for the publication of this article.
Acknowledgments: The authors were solely responsible for the writing and submission of the manuscript.
Received: March 10, 2016 Accepted April 15, 2016
Correspondence: Evan A Stein, Director Emeritus, Metabolic and Atherosclerosis Research Center, 5355 Medpace Way, Cincinnati, OH, US. E: esteinmrl@aol.com
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Statins, first approved for general use in 1987 based on their low-density lipoprotein cholesterol (LDL-C) lowering ability, took another decade to demonstrate cardiovascular disease (CVD) benefit.1–4 Since 1990 there have been more efficacious statins but only one other modestly effective LDL-C-reducing drug, ezetimibe, has been shown to significantly reduce CVD events compared to statin alone.5–8

There remains an unmet need for patients, many at high CVD risk, who are unable to achieve ‘optimal’ LDL-C targets with statin therapy, or are intolerant to statins. Two new drugs were approved in 2013–2014 both of which inhibit production of LDL, or its precursor very (V)LDL; mipomersen, an apolipoprotein B antisense agent, and lomitapide, an inhibitor of microsomal triglyceride transport protein.9 However their use is strictly limited to the rare orphan population with homozygous familial hypercholesterolemia (HoFH) with prescribing controlled by a Risk Evaluation and Monitoring Strategy in the USA and a ‘named patient’ program in other countries.9 Thus the proprotein convertase subtilisin/ kexin type 9 (PCSK9) monoclonal antibodies (mAbs), alirocumab and evolocumab, approved in late 2015, now provide a new class of drugs which substantially and safely decrease LDL-C.10–13

Proprotein convertase subtilisin/kexin 9 inhibitors
PCSK9 plays a key role in regulating LDL-C clearance by binding to the LDL receptor (LDLR) resulting in its degradation.14 Loss-of-function (LOF) mutations resulting in small lifelong LDL-C reductions are associated with a ~40% reduction in CVD risk.15,16 In 2006, Legace discovered that circulating PCSK9 interacted with the LDLR providing a rationale for development of mAbs to inhibit PCSK9.17 The first two PCSK9 mAbs, alirocumab and evolocumab, entered clinical trials in 2009 and have since demonstrated dramatic, rapid and persistent reductions in LDL-C in patients with a wide variety of lipid pheno- and genotypes, comorbidities and on a variety of background therapies.18–39 This resulted in both compounds receiving US Food and Drug Administration (FDA) and European Medicine’s Agency (EMA) approval in late 2015. evolocumab received approval in Japan in early 2016.10–13,40 A third mAb, bococizumab, is still in phase III clinical development.41

Pharmacokinetic and pharmacodynamics
Following subcutaneous (SC) injection mAbs are rapidly absorbed into the circulation, bind to PCSK9, reducing free PCSK9 and reduce LDL-C within days. At a dose of ~150 mg LDL-C plateaus at roughly 60%, which is maintained for two weeks.18,19 A three-fold increase to 420 mg provides no additional LDL-C reduction but does suppress PCSK9 and LDL-C for four weeks.19

Low-desity lipoprotein cholesterol in nonFH
patients and influence of background therapy As statins cause an increase in synthesis and circulating PCSK9, it was suggested that inhibition of PCSK9 would be synergistic when added to

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Keywords: PCSK9, low-density lipoprotein (LDL) cholesterol, LDL receptor, cardiovascular disease, familial hypercholesterolemia