Bempedoic acid

Bempedoic acid (ETC-1002) is a first-in-class, orally administered small-molecule prodrug that inhibits adenosine triphosphate citrate lyase (ACL, also designated ACLY), a cytosolic enzyme positioned upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) in the hepatic cholesterol biosynthesis pathway. The compound is administered as the free acid at a fixed dose of 180 mg in the published literature and undergoes obligate intracellular activation in hepatocytes by very-long-chain acyl-CoA synthetase 1 (ACSVL1, encoded by the SLC27A2 gene), producing the pharmacologically active thioester bempedoic acid-CoA. Because ACSVL1 expression is largely restricted to the liver, bempedoic acid achieves tissue-selective target engagement that spares skeletal muscle, a property that differentiates it mechanistically from statins and that underpins its clinical positioning as a lipid-lowering agent for patients with statin intolerance.

Inhibition of ACL by bempedoic acid-CoA blocks the conversion of mitochondria-derived citrate to acetyl-CoA in the cytosol, thereby reducing the substrate pool for both de novo cholesterol synthesis and de novo fatty acid synthesis. The reduction in intracellular cholesterol activates sterol regulatory element-binding protein 2 (SREBP-2) signaling, upregulates low-density lipoprotein receptor (LDLR) expression on the hepatocyte surface, and increases receptor-mediated clearance of circulating LDL particles. In parallel, bempedoic acid activates AMP-activated protein kinase (AMPK) in hepatocytes and in immune cells, producing a mechanistically distinct anti-inflammatory effect manifest as reductions in high-sensitivity C-reactive protein (hsCRP) that are partially independent of LDL-cholesterol lowering.

The clinical development program, conducted under the CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) trial umbrella, comprises four Phase 3 lipid-lowering efficacy studies (CLEAR Harmony, CLEAR Wisdom, CLEAR Serenity, CLEAR Tranquility) and a large cardiovascular outcomes trial (CLEAR Outcomes). In the Phase 3 lipid-lowering studies, bempedoic acid 180 mg daily produced placebo-corrected reductions in LDL-cholesterol of 17 to 28 percent depending on background statin use, with concurrent reductions in non-HDL-cholesterol, apolipoprotein B, total cholesterol, and hsCRP. The CLEAR Outcomes trial, a randomized, double-blind, placebo-controlled cardiovascular outcomes study enrolling 13,970 statin-intolerant patients with established atherosclerotic cardiovascular disease or at high risk for a first cardiovascular event, demonstrated that bempedoic acid reduced the primary composite endpoint of four-component major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13 percent (hazard ratio 0.87, 95 percent confidence interval 0.79 to 0.96, P = 0.004), with reductions in myocardial infarction of 23 percent and coronary revascularization of 19 percent.

Bempedoic acid was approved by the United States Food and Drug Administration on February 21, 2020 (brand name Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional LDL-cholesterol lowering, and in fixed-dose combination with ezetimibe (brand name Nexlizet) on February 26, 2020. In March 2024, the FDA expanded the indication to include reduction of the risk of cardiovascular events in both primary and secondary prevention populations, making bempedoic acid the first oral non-statin LDL-lowering agent to receive a primary prevention cardiovascular indication. The European Medicines Agency granted marketing authorization for bempedoic acid (Nilemdo) and the bempedoic acid plus ezetimibe combination (Nustendi) in March 2020. The principal adverse events are hyperuricemia and gout (reflecting competition of the bempedoic acid glucuronide metabolite for renal organic anion transporter 2), cholelithiasis, and, rarely, tendon rupture. The compound does not produce the myalgia characteristic of statin therapy, consistent with the absence of ACSVL1 expression in skeletal muscle. This monograph reviews the chemistry, prodrug activation, dual-target pharmacology, pharmacokinetics, preclinical and clinical evidence base, sourcing and quality considerations, drug interaction profile, adverse-event signal, and a comparative assessment of five alternative lipid-lowering agents against bempedoic acid.