Bempedoic Acid (Nexletol), Bempedoic Acid/Ezetimibe (Nexlizet) Form

The following are adenosine triphosphate-citrate lyase (ACL) inhibitors requiring prior authorization: bempedoic acid (Nexletol™) and bempedoic acid/ezetimibe (Nexlizet™). Nexlizet contains ezetimibe, which is a cholesterol absorption inhibitor.
FDA Approved Indication(s) Nexletol and Nexlizet are indicated for use as adjuncts to diet and statin therapy for the treatment of primary hyperlipidemia in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Nexletol and Nexlizet are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Heterozygous Familial Hypercholesterolemia and Atherosclerotic Cardiovascular Disease (must meet all):

1. Diagnosis of one of the following (a or b): a. ASCVD as evidenced by a history of any one of the following conditions (i-vii): i. Acute coronary syndromes; ii. Clinically significant coronary heart disease (CHD) diagnosed by invasive or noninvasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography, or nuclear imaging); iii. Coronary or other arterial revascularization;
   iv. Myocardial infarction; v. Peripheral arterial disease presumed to be of atherosclerotic origin; vi. Stable or unstable angina; vii. Stroke or transient ischemic attack (TIA); b. HeFH, and member meets both of the following (i and ii): i. Baseline LDL-C (prior to any lipid-lowering pharmacologic therapy) was one of the following (a or b): a) If age < 20 years: ≥ 160 mg/dL; Page 1 of 11

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   Bempedoic Acid, Bempedoic Acid/Ezetimibe b) If age ≥ 20 years: ≥ 190 mg/dL; ii. HeFH diagnosis is confirmed by one of the following (a or b): a) World Health Organization (WHO)/Dutch Lipid Network familial hypercholesterolemia diagnostic criteria score of > 8 as determined by requesting provider (see Appendix D);
   b) Definite diagnosis per Simon Broome criteria (see Appendix D);

2. Prescribed by or in consultation with a cardiologist, endocrinologist, or lipid specialist;
3. Age ≥ 18 years;

4. For members on statin therapy, both of the following (a and b):
   a. Nexletol or Nexlizet is prescribed in conjunction with a statin at the maximally tolerated dose; b. Member has been adherent for at least the last 4 months to maximally tolerated doses of one of the following statin regimens (i, ii, or iii): i. A high intensity statin (see Appendix E); ii. A moderate intensity statin (see Appendix E), and member has one of the following (a or b): a) Intolerance to two high intensity statins; b) A statin risk factor (see Appendix G); iii. A low intensity statin and member has one of the following (a or b): a) Intolerance to one high and one moderate intensity statins; b) A statin risk factor (see Appendix G) and history of intolerance to two moderate intensity statins;

   5. For members not on statin therapy, member meets one of the following (a or b): a. Statin therapy is contraindicated per Appendix F; b. For members who are statin intolerant, both of the following (i and ii): i. Member has tried at least two statins, one of which must be hydrophilic (pravastatin, fluvastatin, or rosuvastatin);
      ii. Member meets one of the following (a or b): a) Member has documented statin risk factors (see Appendix G); b) Member is statin intolerant due to statin-associated muscle symptoms (SAMS) and meets both of the following (1 and 2): 1) Documentation of intolerable SAMS persisting at least two weeks, which disappeared with discontinuing the statin therapy and recurred with a statin re-challenge; 2) Documentation of re-challenge with titration from lowest possible dose and/or intermittent dosing frequency (e.g., 1 to 3 times weekly);
   6. Member has been adherent to ezetimibe therapy used concomitantly with a statin at the maximally tolerated dose for at least the last 4 months, unless contraindicated per Appendix F or member has a history of ezetimibe intolerance (e.g., associated diarrhea or upper respiratory tract infection);
   7. For Nexletol, documentation that ezetimibe will be prescribed concurrently for as long as Nexletol is prescribed, unless contraindicated per Appendix F or member has a history of ezetimibe intolerance (e.g., associated diarrhea or upper respiratory tract infection); Page 2 of 11

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   Bempedoic Acid, Bempedoic Acid/Ezetimibe

   8. Documentation of recent (within the last 60 days) LDL-C of one of the following (a or b): a. If member has ASCVD (i or ii): i. ≥ 70 mg/dL; ii. ≥ 55 mg/dL, and member is at very high risk (see Appendix I); b. If member has HeFH: ≥ 100 mg/dL;
   9. Treatment plan does not include coadministration with Repatha® or Praluent®;
5. Dose does not exceed either of the following (a or b): a. Nexletol: 180 mg per day; b. Nexlizet: bempedoic acid 180 mg/ezetimibe 10 mg per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      II. Continued Therapy A. All Indications in Section I (must meet all):
   3. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
   4. If statin tolerant, documentation of adherence to a statin at the maximally tolerated dose;
   5. For Nexletol, documentation that ezetimibe is being prescribed concurrently with Nexletol, unless a contraindication or adverse event to ezetimibe has developed;

6. Member is responding positively to therapy as evidenced by lab results within the last 3 months showing an LDL-C reduction since initiation of Nexletol or Nexlizet therapy;

   5. Treatment plan does not include coadministration with Repatha or Praluent; Page 3 of 11

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   6. If request is for a dose increase, new dose does not exceed either of the following (a or b): a. Nexletol: 180 mg per day; b. Nexlizet: bempedoic acid 180 mg/ezetimibe 10 mg per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
   7. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   8. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      III. Diagnoses/Indications for which coverage is NOT authorized:
      A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
      IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ASCVD: atherosclerotic cardiovascular disease CHD: coronary heart disease FDA: Food and Drug Administration HeFH: heterozygous familial hypercholesterolemia LDL-C: low density lipoprotein cholesterol SAMS: statin-associated muscle symptoms TIA: transient ischemic attack WHO: World Health Organization Appendix B: Therapeutic Alternatives
      This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
      Drug Name ezetimibe (Zetia®) atorvastatin (Lipitor®) Dose Limit/Maximum Dose 10 mg/day 80 mg/day Dosing Regimen 10 mg PO QD 40 mg PO QD Page 4 of 11

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   Bempedoic Acid, Bempedoic Acid/Ezetimibe Drug Name rosuvastatin (Crestor®) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Dose Limit/Maximum Dose 40 mg/day Dosing Regimen 5 - 40 mg PO QD Appendix C: Contraindications/Boxed Warnings
   • Contraindication(s):
   o Nexletol: none reported o Nexlizet: known hypersensitivity to ezetimibe tablets • Boxed warning(s): none reported Appendix D: Criteria for Diagnosis of HeFH
   • Dutch Lipid Clinic Network criteria for Familial Hypercholesterolemia (FH) FH Criteria Points Member’s Family History First-degree relative with known premature coronary and vascular disease
   First-degree relative with known LDL-C level above the 95th percentile First-degree relative with tendinous xanthomata and/or arcus cornealis Children aged < 18 years with LDL-C level above the 95th percentile Patient with premature coronary artery disease Patient with premature cerebral or peripheral vascular disease Clinical History Tendinous xanthomata Arcus cornealis prior to age 45 years Physical Examination Cholesterol Levels - mg/dL (mmol/liter) LDL-C ≥ 330 mg/dL (≥ 8.5) LDL-C 250 – 329 mg/dL (6.5 – 8.4) LDL-C 190 – 249 mg/dL (5.0 – 6.4) LDL-C 155 – 189 mg/dL (4.0 – 4.9) Functional mutation in the LDLR, apo B or PCSK9 gene DNA Analysis 1 1 2 2 2 1 6 4 8 5 3 1 8 TOTAL SCORE
   Definite FH: > 8 Score† Place highest score here
   (0, 1 or 2) Place highest score here
   (0, 1 or 2) Place highest score here (0, 4 or 6) Place highest score here (0, 1, 3, 5 or 8) Place score here (0 or 8) Place total score here __ Premature – men < 55 years or women < 60 years †Choose the highest score from each of the five categories and then add together for a total score. The five categories are 1) Family History, 2) Clinical History, 3) Physical Examination, 4) Cholesterol Levels, and 5) DNA Analysis.
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   Bempedoic Acid, Bempedoic Acid/Ezetimibe • Simon Broome Register Group Definition of Definite FH (meets 1 and 2):

   1. One of the following (a or b): a. Total cholesterol level above 7.5 mmol/l (290 mg/dl) in adults or a total cholesterol level above 6.7 mmol/l (260 mg/dl) for children under 16; b. LDL levels above 4.9 mmol/l (190 mg/dl) in adults (4.0 mmol/l in children) (either pre-treatment or highest on treatment);
   2. One of the following (a or b): a. Tendinous xanthomas in patient or relative (parent, child, sibling, grandparent, aunt, uncle); b. DNA-based evidence of an LDL receptor mutation or familial defective apo B- 100; • High and Moderate Risk of ASCVD: o Patients with high risk of ASCVD include the following:  History of clinical atherosclerotic cardiovascular disease (as defined in section II)  Diabetes with an estimated 10-year ASCVD risk ≥ 7.5% for adults 40-75 years of age  Untreated LDL ≥ 190 mg/dL o Patients with moderate risk of ASCVD include the following:  Diabetes with an estimated 10-year ASCVD risk < 7.5% for adults 40-75 years of age  Estimated 10-year ASCVD risk ≥ 5% for adults 40-75 years of age o The calculator for the 10-year ASCVD risk estimator can be found here: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate. Information needed to complete the ASCVD Risk Estimator include: gender, race (white, African American, other), systolic blood pressure, history of diabetes, age, total cholesterol, HDL-cholesterol, treatment for hypertension, smoking history or status, and concurrent statin or aspirin therapy. Appendix E: High, Moderate, and Low Intensity Daily Statin Therapy for Adults High Intensity Statin Therapy
      Daily dose shown to lower LDL-C, on average, by approximately ≥ 50% • Atorvastatin 40-80 mg • Rosuvastatin 20-40 mg Moderate Intensity Statin Therapy Daily dose shown to lower LDL-C, on average, by approximately 30% to 50% • Atorvastatin 10-20 mg • Fluvastatin XL 80 mg • Fluvastatin 40 mg BID • Lovastatin 40 mg • Pitavastatin 1-4 mg • Pravastatin 40-80 mg • Rosuvastatin 5-10 mg • Simvastatin 20-40 mg Page 6 of 11

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   Bempedoic Acid, Bempedoic Acid/Ezetimibe Low Intensity Statin Therapy Daily dose shown to lower LDL-C, on average, by < 30% • Simvastatin 10 mg • Pravastatin 10-20 mg • Lovastatin 20 mg • Fluvastatin 20-40 mg Appendix F: Statin and Ezetimibe Contraindications Statins • Decompensated liver disease (development of jaundice, ascites, variceal bleeding, encephalopathy) • Laboratory-confirmed acute liver injury or rhabdomyolysis resulting from statin treatment • Pregnancy, actively trying to become pregnant, or nursing • Immune-mediated hypersensitivity to the HMG-CoA reductase inhibitor drug class (statins) as evidenced by an allergic reaction occurring with at least TWO different statins Ezetimibe • Moderate or severe hepatic impairment [Child-Pugh classes B and C] • Hypersensitivity to ezetimibe (e.g., anaphylaxis, angioedema, rash, urticaria) In July 2021, the FDA requested removal of the contraindication against use of statins in pregnant women. Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.
   https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda- requests-removal-strongest-warning-against-using-cholesterol Appendix G: Statin Risk Factors Statin Risk Factors • Multiple or serious comorbidities, including impaired renal or hepatic function • Unexplained alanine transaminase (ALT) elevations > 3 times upper limit of normal, or active liver disease • Concomitant use of drugs adversely affecting statin metabolism
   • Age > 75 years, or history of hemorrhagic stroke • Asian ancestry Appendix H: General Information • Patients should remain on concomitant therapy with a statin if tolerated due to the established long term cardiovascular benefits. • The diagnosis of SAMS is often on the basis of clinical criteria. Typical SAMS include muscle pain and aching (myalgia), cramps, and weakness. Symptoms are usually bilateral and involve large muscle groups, including the thigh, buttock, back, and shoulder girdle musculature. In contrast, cramping is usually unilateral and may involve small muscles of the hands and feet. Symptoms may be more frequent in physically active patients. Symptoms often appear early after starting stain therapy or after an increase in dose and usually resolve or start to dissipate within weeks after cessation of therapy, although it may take several months for symptoms to totally resolve. Persistence of symptoms for Page 7 of 11

   CLINICAL POLICY Bempedoic Acid, Bempedoic Acid/Ezetimibe more than 2 months after drug cessation should prompt a search for other causes or for underlying muscle disease possibly provoked by statin therapy. The reappearance of symptoms with statin rechallenge and their disappearance with drug cessation offers the best evidence that the symptoms are truly SAMS. • Pravastatin, fluvastatin, and rosuvastatin are hydrophilic statins which have been reported to confer fewer adverse drug reactions than lipophilic statins.
   Appendix I: Criteria for Defining Patients at Very High Risk of Future ASCVD Events3, 10, 12 Very high risk is defined as having either a history of multiple major ASCVD events OR 1 major ASCVD event and multiple high-risk conditions: • Major ASCVD events: o Recent acute coronary syndrome (within the past 12 months) o History of myocardial infarction (other than recent acute coronary syndrome event listed above) o History of ischemic stroke o Symptomatic peripheral artery disease (history of claudication with ankle-brachial index < 0.85 or previous revascularization or amputation) • High-risk conditions: o Age ≥ 65 years o FH o History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s) o Diabetes o Hypertension o Chronic kidney disease (estimated glomerular filtration rate [eGFR] 15-59 mL/min/1.73 m2) o Current tobacco smoking o Persistently elevated LDL-C (LDL-C ≥ 100 mg/dL [≥ 2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe o History of congestive heart failure V. Dosage and Administration
   Indication ASCVD, HeFH Dosing Regimen One tablet PO QD Maximum Dose One tablet/day VI. Product Availability
   Drug Name Bempedoic acid (Nexletol) Bempedoic acid/ezetimibe (Nexlizet) Tablet: bempedoic acid 180 mg/ezetimibe 10 mg Availability Tablet: 180 mg VII.