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Synonyms: ESP-55016 | ETC-1002 | Nexletol® | Nilemdo®
bempedoic acid is an approved drug (EMA & FDA (2020))
Compound class:
Synthetic organic
Comment: Bempedoic acid (ETC-1002) is an orally delivered non-statin drug for treating dyslipidemia and related cardiovascular disease, which offers an additional pharmaceutical strategy for statin-refractory or statin-intolerant patients [1,4,6]. Its novel mechanism of action makes it the first-in-class ATP citrate lyase (ACLY; P53396) inhibitor to reach the clinic [8]. Bempedoic acid is in fact a prodrug, as it must be converted to its active metabolite bempedoic acid-CoA by endogenous liver acyl-CoA synthetase. Bempedoic acid-CoA is the bona fide ACLY inhibitor. ACLY is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA, which in turn is required for de novo lipogenesis and cholesterogenesis, and its inhibition directly reduces cholesterol synthesis in the liver [3].
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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Summary of Clinical Use  |
| Positive results from Phase 3 trial NCT02666664 were published in early 2019, and showed that bempedoic acid was safe and well tolerated, and that it significantly reduced LDL-cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia (hFH), or both, who were already receiving guideline-recommended statin therapy [5]. The drug was FDA approved in February 2020, indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adult patients with hFH or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. EMA marketing authorisation followed in April 2020. Bempedoic acid is a component of the fixed-dose combination drugs Nexlizet and Nustendi, alongside ezetimibe. These therapies are indicated for the treatment of hFH. |
| Mechanism Of Action and Pharmacodynamic Effects |
| Bempedoic acid acts in the same biosynthetic pathway as the statins, but further upstream, and selectively in the liver. The anti-atherosclerotic, anti-obesity, and glucose-lowering properties exhibited by bempedoic acid are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation, although the underlying mechanisms are still to be fully described. The compound is reported to upregulate the LDL receptor, activate AMP-activated protein kinase (AMPK) and inhibit ATP citrate lyase (ACLY; P53396) [7]. AMPK detects and reacts to changes in the AMP:ATP ratio, regulating glucose uptake, β-oxidation of fatty acids, and glucose transporter 4 (GLUT4) and mitochondria levels, to maintain energy homeostasis. ACLY catalyses an important step in fatty acid biosynthesis [2] generating acetyl-CoA. ACLY links the metabolism of carbohydrates and the production of fatty acids, |
| Clinical Trials | |||||
| Clinical Trial ID | Title | Type | Source | Comment | References |
| NCT02666664 | Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk (CLEAR Harmony) | Phase 3 Interventional | Esperion Therapeutics | ||
