Bempedoic Acid Topic Review

Bempedoic acid (Nexletol, Esperion Therapeutics) is a nonstatin low-density lipoprotein cholesterol (LDL-C)-lowering drug.

It is a first-in-class, small molecule inhibitor of adenosine triphosphate-citrate lyase (ACL), a key enzyme in cholesterol synthesis. Bempedoic acid and a combination bempedoic acid-ezetimibe formulation (Nexlizet, Esperion Therapeutics) received FDA approval in February 2020. [Marrs JC, et al. Drugs Context. 2020;2a,6b; Nexletol (package insert);1a; Nexlizet (package insert);1a]

Bempedoic acid is a prodrug; to exert an inhibitory effect on ACL, it and its active metabolite (ESP15228) must be activated by very long-chain acyl-CoA synthetase I (ACSVL1, an enzyme expressed primarily in the liver) to form ETC-1002-CoA and ESP15228-CoA. The target enzyme, ACL, acts in the cholesterol synthesis pathway upstream of 3-hydroxy-3-methyl-glutaryl-coenzme A (HMG-CoA) reductase, the target enzyme of statins. Inhibition of ACL reduces the conversion of mitochondrial-derived citrate to cytosolic acetyl-CoA, in turn reducing cholesterol synthesis in the liver. [Marrs JC, et al. Drugs Context. 2020;2a; Nexletol (package insert);8a,9a]

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Indications

Bempedoic acid (Nexletol) is currently indicated as an adjunct to diet and statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who have primary hyperlipidemia and require additional LDL-C lowering. [Nexletol (package insert);2a] Bempedoic acid in combination with ezetimibe (Nexlizet) has an identical indication. [Nexlizet (package insert);2a]

The current (2018) multisociety guideline on blood cholesterol management was released before bempedoic acid received FDA approval, and therefore does not contain recommendations specific to bempedoic acid. In general, the guidelines recommend nonstatin agents only under certain conditions and only as an adjunct to maximally tolerated statin therapy. [Grundy SM, et al. Circulation. 2018;1a,10b]

However, in 2022 the American College of Cardiology issued an expert consensus decision pathway to address new lipid-lowering agents and other developments since the 2018 guidelines were issued. That document listed bempedoic acid and bempedoic acid/ezetimibe as nonstatin therapies that may be used to manage atherosclerotic CVD risk via LDL lowering. [Lloyd-Jones DJ, et al. J Am Coll Cardiol. 2022;11a,12a]

Dosage and Administration

The recommended dosage of bempedoic acid (in combination with maximally tolerated statin therapy) is one tablet of 180 mg once per day, taken orally with or without food. [Nexletol (package insert);2a]

The recommended dose for the combination bempedoic acid/ezetimibe regimen (in combination with maximally tolerated statin therapy) is one fixed-dose (180 mg bempedoic acid and 10 mg ezetimibe) tablet per day, taken orally with or without food.  [Nexlizet (package insert);2a]

No dosage adjustment of bempedoic acid monotherapy is necessary in patients with mild to moderate renal impairment (there are limited data for severe renal disease and no data for end-stage renal disease [ESRD]) or with mild to moderate hepatic impairment (there are no data for severe hepatic impairment). [Nexletol (package insert);7a,8a] The bempedoic acid/ezetimibe fixed dose combination likewise does not require dosage adjustment in patients with mild to moderate renal impairment (with limited and no data in severe renal impairment and ESRD, respectively) and in patients with mild hepatic impairment. Because of the unknown effects of increased ezetimibe exposure, the combination formulation is not recommended in patients with moderate or severe hepatic impairment. [Nexlizet (package insert);11a]

Efficacy and Safety

The safety and LDL-C-lowering efficacy of bempedoic acid was assessed in CLEAR Harmony and CLEAR Wisdom, two phase 3, randomized, double-blind trials that compared bempedoic acid to placebo as an adjunct to maximally tolerated statin therapy (in CLEAR Harmony; with or without other lipid-lowering drugs) or lipid-lowering therapy (in CLEAR Wisdom; including patients who did not receive statin therapy). [Goldberg AC, et al. JAMA. 2019;2b; Ray KK, et al. N Engl J Med. 2019;2a]  The two CLEAR trials enrolled patients with ASCVD, HeFH, or both; patients must have had a fasting LDL-C level of 70 mg/dL or higher before randomization. [Goldberg AC, et al. JAMA. 2019;2b; Ray KK, et al. N Engl J Med. 2019;2b] Patients were randomly assigned (2:1) to receive either bempedoic acid (180 mg once daily) or a matching placebo. [Goldberg AC, et al. JAMA. 2019;2b; Ray KK, et al. N Engl J Med. 2019;3a] In CLEAR Harmony, 1,488 patients were randomly assigned to bempedoic acid and 742 to placebo; in CLEAR Wisdom, the numbers were 522 and 257 patients for bempedoic acid and placebo, respectively. [Goldberg AC, et al. JAMA. 2019;4a; Ray KK, et al. N Engl J Med. 2019;3b,4a] In both CLEAR trials, the primary efficacy endpoint was percentage change in LDL-C from baseline at week 12. [Goldberg AC, et al. JAMA. 2019;3a; Ray KK, et al. N Engl J Med. 2019;3a]

In CLEAR Harmony, bempedoic acid treatment resulted in a significantly lower LDL-C levels compared to the placebo at week 12 (treatment difference, 18.1%; P < .001), and the response was maintained through week 52. [Ray KK, et al. N Engl J Med. 2019;6b,8b]

Bempedoic acid also demonstrated efficacy in CLEAR Wisdom; at week 12, LDL-C levels were significantly lower with bempedoic acid than with placebo (treatment difference, –17.4%; P < .001). A significant difference between the two groups was maintained through week 52. [Goldberg AC, et al. JAMA. 2019;4a,6a]

Bempedoic acid demonstrated an acceptable safety profile in the two CLEAR trials. The incidence of adverse events, serious adverse events, and death was similar with bempedoic acid and the placebo. More patients in the bempedoic acid group discontinued treatment because of an adverse event; the difference in discontinuation rate was not driven by adverse events in a particular MedDRA system-organ class or preferred term. [Goldberg AC, et al. JAMA. 2019;6b,7a; Ray KK, et al. N Engl J Med. 2019;5a,8b,10a]

The safety and efficacy of the bempedoic acid-ezetimibe combination treatment was tested in a phase 3, double-blind, randomized trial which enrolled patients with ASCVD, HeFH or multiple cardiovascular risk factors (defined as diabetes in combination with one or more of: age above45 years for men or 55 years for women, family history of coronary heart disease, smoking, hypertension, low high-density lipoprotein [HDL] cholesterol, or coronary calcium score > 95th percentile for the patient’s age, sex and race or ethnicity). Patients were randomly assigned (2:2:2:1) to receive an oral, once daily dose of: 1) bempedoic acid 180 mg and ezetimibe 10 mg (108 patients); 2) bempedoic acid 180 mg (110 patients); 3) ezetimibe 10 mg (109 patients); or 4) placebo (55 patients). Like in the CLEAR trials, the primary efficacy endpoint was percentage change from baseline in LDL-C levels. [Ballantyne CM, et al. Eur J Prev Cardiol. 2020;2b,3a-b]

The combination regimen demonstrated superiority to all comparator groups at week 12, with LDL-C differences of –38%, –19%, and –13.1% compared to the placebo, bempedoic acid and ezetimibe, respectively (P < .001 for all comparisons). [Ballantyne CM, et al. Eur J Prev Cardiol. 2020;4b,7a]

The bempedoic acid-ezetimibe combination treatment had a safety profile similar to that observed in trials of its individual components, and no new safety signals were identified. [Ballantyne CM, et al. Eur J Prev Cardiol. 2020;8a]

The CLEAR Outcomes trial, published in March 2023, showed that bempedoic acid reduced risk for CV events compared with placebo in patients with CVD or at high risk for it who were deemed to be statin intolerant. The incidence of a primary endpoint event (CV death/nonfatal MI/nonfatal stroke/coronary revascularization) was lower with bempedoic acid than with placebo (11.7% vs. 13.3%; HR = 0.87; 95% CI, 0.79-0.96; P = .004). Similarly, incidence of CV death, nonfatal MI and nonfatal stroke was lower with bempedoic acid vs. placebo (HR = 0.85; 95% CI, 0.76-0.96; P = .006), as was fatal or nonfatal MI (HR = 0.77; 95% CI, 0.66-0.91; I = .002) and coronary revascularization (HR = 0.81; 95% CI, 0.72-0.92; P = .001). [Nissen SE, et al. N Engl J Med. 2023;1a].

In a CLEAR Outcomes substudy of patients from the cohort requiring primary prevention published in June 2023, bempedoic acid reduced risk for the primary endpoint by 30% compared with placebo (adjusted HR = 0.7; 95% CI, 0.55-0.89; P = 002). [Nissen SE, et al. JAMA. 2023;1a]

References:

• Ballantyne CM, et al. Eur J Prev Cardiol. 2020;doi:10.1177/2047487319864671.
• Esperion Therapeutics. https://www.esperion.com/news-releases/news-release-details/us-fda-updates-ldl-c-lowering-indication-esperions-nexletolr. Published Dec. 13, 2023. Accessed Dec. 14, 2023.
• Goldberg AC, et al. JAMA. 2019;doi:10.1001/jama.2019.16585.
• Grundy SM, et al. Circulation. 2018;doi:10.1161/CIR.0000000000000625.
• Lloyd-Jones DJ, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.07.006.
• Marrs JC, et al. Drugs Context. 2020;doi:10.7573/dic.2020-6-5.
• Nexletol. Prescribing information. Esperion Therapeutics, Inc. pi.esperion.com/nexletol/nexletol-pi.pdf. Revised June 2022. Accessed December 9, 2022.
• Nexlizet. Prescribing information. Esperion Therapeutics, Inc. pi.esperion.com/nexlizet/nexlizet-pi.pdf. Revised September 2021. Accessed December 9, 2022.
• Nissen SE, et al. JAMA. 2023;doi:10.1001/jama.2023.9696.
• Nissen SE, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215024.
• Ray KK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1803917.