ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials

ABSTRACT

Introduction: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity.

Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.

KEYWORDS:

• ATP-citrate lyase
• bempedoic acid
• ETC-1002
• cardiovascular disease
• hsCRP
• LDL-C
• non-HDL
• statin intolerance

Box 1. Drug Summary Box

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Declaration of interest

M Banach has served on the speaker’s bureau for Abbott/Mylan Abbott Vascular, Actavis, Akcea, Amgen Inc, Biopharm, KRKA, Merck Sharp and Dohme, Sanofi, and Valeant. They also are a consultant for Abbott Vascular, Akcea, Amgen Inc Daichii Sankyo, Esperion, Eli Lilly and Company, Merck Sharp and Dohme, Resverlogix and Sanofi. He has also received grants from Sanofi and Valeant. A Corsini meanwhile has received honoraria for lectures from AstraZeneca, Amgen, Sanofi, Recordati, Novartis, Merck Sharp and Dohme, Mediolanum, Doc Pharma, Mylan and Pfizer. 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

The authors are funded via M Ruscica by the Cariplo Foundation (2015-0552) and intramural Grant Università degli Studi di Milano (PSR2018_MRUSCI) and the Fondazione Carlo Sirtori via C.R. Sirtori.