Drug Therapy Guidelines Bempedoic Acid (Nexletol [bempedoic acid], Nexlizet [bempedoic acid, ezetimibe]) Applicable Medical Benefit Effective: 5/28/2021 Pharmacy- Formulary 1 x Next Review: 3/23 Pharmacy- Formulary 2 x Date of Origin: 4/23/20 Pharmacy- Formulary 3/Exclusive x Review Dates: 3/20, 3/21 Pharmacy- Formulary 4/AON x I. Medication Description Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) through inhibition of cholesterol synthesis in the liver. Bempedoic acid, an inactive prodrug, and its active metabolite, ESP15228, require coenzyme A (CoA) activation within the liver by very-long-chain acyl CoA synthetase-1 (ACSVL1) to form bempedoic acid-CoA (ETC-1002-CoA) and ESP15228-CoA, respectively. ACSVL1 is primarily expressed in the liver and is absent in adipose tissue and muscles. ACL is an important enzyme that links carbohydrate metabolism to the pathways for cholesterol and fatty synthesis within the liver. Specifically, ACL catalyzes the cleavage of citrate to acetyl-CoA and oxaloacetate within the cholesterol synthesis pathway and is located upstream from HMG-CoA reductase. Both oxaloacetate and acetyl-CoA are important substrates in the synthesis of cholesterol and fatty acids. Thus, inhibition of ACL by bempedoic acid decreases cholesterol and fatty acid synthesis resulting in the upregulation of LDL-C receptors, increased uptake of LDL-C by the liver and reduced blood LDL-C levels. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood. Nexletol (bempedoic acid) and Nexlizet (bempedoic acid; ezetimibe)are indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Limitations of Use: The effect of Nexletol and Nexlizet on cardiovascular morbidity and mortality has not been determined. II. Position Statement Coverage is determined through a prior authorization process for all requests. III. Policy Coverage of Nexletol or Nexlizet is available for members who meet all of the following criteria: • One of the following, dependent upon the diagnosis: Page 1 of 4 Drug Therapy Guidelines Bempedoic Acid (Nexletol [bempedoic Last Review Date: 3/2021 acid], Nexlizet [bempedoic acid, ezetimibe]) o For hyperlipidemia in clinical Atherosclerotic Cardiovascular Disease (ASCVD): ▪ The patient is aged ≥ 18 years AND ▪ The patient has a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL (after treatment with antihyperlipidemic agents but prior to bempedoic acid therapy) AND ▪ The patient has had one of the following conditions or diagnoses: previous myocardial infarction (MI), a history of acute coronary syndrome (ACS), angina (stable or unstable), history of stroke or transient ischemic attack (TIA), peripheral arterial disease (PAD) including aortic aneurysm, or has undergone a coronary or other arterial revascularization procedure in the past (e.g., coronary artery bypass graft [CABG], percutaneous coronary intervention [PCI], angioplasty, coronary stent procedure) o For Primary (familial) Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia [HeFH]): ▪ The patient is aged ≥ 18 years AND ▪ Baseline LDL-C level has been provided AND ▪ One of the following: o WHO/Dutch Lipid Network Criteria score of greater than eight points OR o Definite diagnosis according to Simon-Broome criteria. AND • The medication is prescribed by (or in consultation with) a cardiologist, endocrinologist, or a physician who has obtained additional education/certification in cardiovascular risk management and/or the treatment of lipid disorders AND • The patient meets one of the following: o The patient has tried one high-intensity statin therapy (atorvastatin ≥ 40 mg daily; rosuvastatin ≥ 20 mg daily) AND ezetimibe concomitantly (unless the addition of ezetimibe is contraindicated) for ≥ 8 continuous weeks and the LDL-C level remains ≥ 70 mg/dL OR o The patient has been determined to be statin-intolerant by meeting one of the following criteria: ▪ The patient experienced statin-related rhabdomyolysis (statin-induced muscle breakdown with signs and symptoms such as muscle pain, weakness, tenderness, acute renal failure and/or elevated creatine kinase [CK] levels [e.g., greater or equal to 10 times the upper limit of normal]) OR ▪ The patient experienced skeletal-related muscle symptoms (e.g., myopathy [muscle weakness] or myalgia [muscle aches, soreness, stiffness, or tenderness]) and meets both of the following criteria: • The skeletal-related muscle symptoms (e.g., myopathy or myalgia) occurred while receiving separate trials of both atorvastatin and rosuvastatin AND • When receiving separate trials of both atorvastatin and rosuvastatin the skeletal- related muscle symptoms (e.g., myopathy, myalgia) resolved upon discontinuation of each respective statin therapy. AND Page 2 of 4 Drug Therapy Guidelines Bempedoic Acid (Nexletol [bempedoic Last Review Date: 3/2021 acid], Nexlizet [bempedoic acid, ezetimibe]) • If able to tolerate statins, the patient continues to receive the maximum-tolerated dose of a statin while receiving bempedoic acid therapy. IV. Quantity Limitations Coverage is provided as follows: • Nexletol: up to 30 tablets per each 30 days. • Nexlizet: up to 30 tablets per each 30 days. V. Coverage Duration Coverage is available for 12 months and may be renewed. VI. Coverage Renewal Criteria Coverage can be renewed in 12-month increments based upon the following criteria: • Clinically significant LDL-C reduction has been shown with treatment AND • Stabilization of disease or absence of disease progression AND • Absence of unacceptable toxicity from the drug. VII. Billing/Coding Information • Nexletol is available as 180 mg bempedoic acid tablets. • Nexlizet is available as 180 mg bempedoic acid/10 mg ezetimibe tablets. IX. Summary of Policy Changes 4/23/20: new policy 5/28/21: no policy changes X. References 1. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013 Jan 31;1:CD004816. 2. Cholesterol Treatment Trialists’ (CCT) Collaborators, Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol lowering therapy in 18,686 people with diabetes in 14 randomized trials: a meta-analysis. Lancet. 2008;371(9607)117-125. 3. Baigent C, Keech A, Kearney PM, et al, for the Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366(9493):1267-1278. 4. Cuchel M, Bruckert E, Ginsberg HN, et al, for the European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolemia. Homozygous familial hypercholesterolaemia: new insights and guidance for Page 3 of 4 Drug Therapy Guidelines Bempedoic Acid (Nexletol [bempedoic Last Review Date: 3/2021 acid], Nexlizet [bempedoic acid, ezetimibe]) clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholestolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146-2157. 5. Marina Cuchel, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society, European Heart Journal, Volume 35, Issue 32, 21 August 2014, Pages 2146–2157, https://doi.org/10.1093/eurheartj/ehu274. Accessed 2/2019. 6. Nexletol (bempedoic acid) package insert. Ann Arbor, MI: Esperion Therapeutics, Inc.; 2020 Feb. 7. Nexlizet (bempedoic acid and ezetimibe) package insert. Ann Arbor, MI: Esperion Therapeutics, Inc.; 2020 Feb. 8. Micromedex Solutions. Truven Health Analytics, Inc. Ann Arbor, MI. Accessed 1/2021. The Plan fully expects that only appropriate and medically necessary services will be rendered. The Plan reserves the right to conduct pre-payment and post-payment reviews to assess the medical appropriateness of the above-referenced therapies. Drug therapy initiated with samples will not be considered as meeting medical necessity for coverage for non-preferred or prior authorized medications. The preceding policy applies only to members for whom the above named pharmacy benefit medications are included on their covered formulary. Members with closed formulary benefits are subject to trying all appropriate formulary alternatives before a coverage exception for a non-formulary agent will be considered. The preceding policy is a guideline to allow for coverage of the pertinent medication/product, and is not meant to serve as a clinical practice guideline. Page 4 of 4 .