Lomitapide (Juxtapid) Form

Lomitapide (Juxtapid®) is a microsomal triglyceride transfer protein inhibitor. FDA Approved Indication(s) Juxtapid is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein (LDL) apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Limitation(s) of use: • The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH). • The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined. 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 Juxtapid is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Homozygous Familial Hypercholesterolemia (must meet all):

1. Diagnosis of HoFH defined as one of the following (a, b, or c): a. Genetic mutation indicating HoFH (e.g., mutations in low density lipoprotein receptor [LDLR] gene, proprotein convertase subtilisin kexin 9 [PCSK9] gene, apo B gene, low density lipoprotein receptor adaptor protein 1[LDLRAP1] gene); b. Treated LDL-C ≥ 300 mg/dL or non-HDL-C ≥ 330 mg/dL; c. Untreated LDL-C ≥ 500 mg/dL, and one of the following (i or ii): i. Tendinous or cutaneous xanthoma prior to age 10 years; ii. Evidence of HeFH in both parents (e.g., documented history of elevated LDL- C ≥ 190 mg/dL prior to lipid-lowering therapy);
2. Prescribed by or in consultation with a cardiologist, endocrinologist, or lipid specialist;

3. Age ≥ 18 years;
   Page 1 of 10

   CLINICAL POLICY Lomitapide

4. Documentation of recent (within the last 60 days) LDL-C of one of the following (a or b): a. ≥ 70 mg/dL; b. ≥ 55 mg/dL if member has ASCVD and is at very high risk (see Appendix H);
5. For members on statin therapy, both of the following (a and b):
   a. Juxtapid 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 D); ii. A moderate intensity statin (see Appendix D), and member has one of the following (a or b): a) Intolerance to two high intensity statins; b) A statin risk factor (see Appendix F); 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 F) and history of intolerance to two moderate intensity statins;
6. For members not on statin therapy, member meets one of the following (a or b): a. Statin therapy is contraindicated per Appendix E; 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 F); 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);
   7. 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 E or member has a history of ezetimibe intolerance (e.g., associated diarrhea or upper respiratory tract infection);
7. Failure of a preferred PCSK9 inhibitor, if applicable, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for PCSK9 inhibitors
8. Treatment plan does not include coadministration with Leqvio®, Repatha®, or Praluent®;

9. Dose not exceed (a and b): a. 60 mg per day; b. 2 capsules per day. Approval duration: 6 months
   Page 2 of 10

   CLINICAL POLICY Lomitapide B. Other diagnoses/indications (must meet 1 or 2):

10. 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 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 and CP.PMN.16 for Medicaid; or
11. 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 and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. Homozygous Familial Hypercholesterolemia (must meet all):
12. 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);
13. If statin tolerant, documentation of adherence to a statin at the maximally tolerated dose;
14. Member is responding positively to therapy as evidenced by lab results within the last 3 months showing an LDL-C reduction since initiation of Juxtapid therapy;
15. Treatment plan does not include coadministration with Leqvio, Repatha, or Praluent;
    5. If request is for a dose increase, new dose does not exceed (a and b):
       a. 60 mg per day; b. 2 capsules per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
16. 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 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 and CP.PMN.16 for Medicaid; or

17. 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 Page 3 of 10

    CLINICAL POLICY Lomitapide criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial 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 and CP.PMN.53 for Medicaid or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALT: alanine aminotransferase apoB: apolipoprotein B ASCVD: atherosclerotic cardiovascular disease FDA: Food and Drug Administration HDL-C: high-density lipoprotein cholesterol HeFH: heterozygous familial hypercholesterolemia HoFH: homozygous familial hypercholesterolemia LDL-C: low density lipoprotein cholesterol LDLR: low density lipoprotein receptor LDLRAP1: low density lipoprotein receptor adaptor protein 1 PCSK9: proprotein convertase subtilisin kexin 9
    SAMS: statin-associated muscle symptoms TC: total cholesterol ULN: upper limit of normal Dosing Regimen 10/40 mg PO QD ezetimibe/simvastatin (Vytorin®) 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 Dose Limit/ Maximum Dose 10 mg-40 mg/day (use of the 10/80 mg dose is restricted to patients who have been taking simvastatin 80 mg for 12 months or more without evidence of muscle toxicity) 10 mg/day 80 mg/day 40 mg/day 420 mg/month 150 mg SC every 2 weeks 300 mg/month ezetimibe (Zetia®) atorvastatin (Lipitor®) rosuvastatin (Crestor®) Repatha (evolocumab) 420 mg SC once monthly Praluent (alirocumab) 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. 10 mg PO QD 40 mg PO QD 5 - 40 mg PO QD Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o Pregnancy Page 4 of 10

    CLINICAL POLICY Lomitapide o Concomitant use with strong or moderate CYP3A4 inhibitors o Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases • Boxed warning(s): risk of hepatotoxicity Appendix D: High and Moderate 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 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 E: 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 Page 5 of 10

    CLINICAL POLICY Lomitapide Appendix F: 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 G: General Information • Because of the risk of hepatotoxicity, Juxtapid is available only through a Risk Evaluation and Mitigation Strategy (REMS) program called the Juxtapid REMS Program. • Low density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene is also known as autosomal recessive hypercholesterolemia (ARH) adaptor protein 1 gene. • 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
    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 H: Criteria for Defining Patients at Very High Risk of Future ASCVD Events3, 16, 13 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 Page 6 of 10

    CLINICAL POLICY Lomitapide 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 Dosing Regimen HoFH 5 mg PO QD up to maximum dose following a specific titration schedule as follows: Maximum Dose 60 mg/day Dosage – duration of administration before considering increase to next dosage: 5 mg QD – at least 2 weeks 10 mg, 20 mg, 40 mg QD – at least 4 weeks for each dose • Doses should be escalated gradually based on acceptable safety and tolerability. • Modify dosing for patients taking concomitant cytochrome P450 (CYP) 3A4 inhibitors, renal impairment, or baseline hepatic impairment. • Dose adjustments are also required for patients who develop transaminase values at least 3x ULN during Juxtapid treatment. VI. Product Availability
    Capsules: 5 mg, 10 mg, 20 mg, 30 mg VII.