Inclisiran (Leqvio) Form

Inclisiran (Leqvio®) is a small interfering ribonucleic acid (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) messenger RNA (mRNA). FDA Approved Indication(s) Leqvio is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce 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 Leqvio is medically necessary when the following criteria are met:
I. Initial Approval Criteria A. Primary Hyperlipidemia (including HeFH) and Atherosclerotic Cardiovascular Disease (must meet all):

1. Diagnosis of one of the following (a, b, or c): a. HeFH, and both of the following (i and ii): i. Baseline LDL-C (prior to any lipid-lowering pharmacologic therapy) was one of the following (1 or 2): 1) If age < 20 years: ≥ 160 mg/dL; 2) If age ≥ 20 years: ≥ 190 mg/dL; ii. HeFH diagnosis is confirmed by one of the following (1 or 2): 1) World Health Organization (WHO)/Dutch Lipid Network familial hypercholesterolemia diagnostic criteria score of > 8 as determined by requesting provider (see Appendix D);
   2) Definite diagnosis per Simon Broome criteria (see Appendix D);
   b. Primary hyperlipidemia that is not HeFH, and both of the following (i and ii):
   i. Documentation of one of the following (1 or 2):
   1) Presence of a genetically mediated form of primary hyperlipidemia as evidenced by confirmatory genetic testing results; 2) A diagnosis of secondary hyperlipidemia has been ruled out with absence of all of the following potential causes of elevated cholesterol (a-f): a) Poor diet;
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   Inclisiran b) Hypothyroidism;
   c) Obstructive liver disease;
   d) Renal liver disease;
   e) Nephrosis;
   f) Medications that have had a clinically relevant contributory effect on the current degree of the member’s elevated lipid levels including, but not limited to: glucocorticoids, sex hormones, antipsychotics, antiretrovirals, immunosuppressive agents, retinoic acid derivatives; ii. Baseline LDL-C (prior to any lipid-lowering pharmacologic therapy) was ≥ 190 mg/dL;
   c. Atherosclerotic cardiovascular disease (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);

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

3. Failure of an 8 week trial of a preferred PCSK9 inhibitor, if applicable, at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for PCSK9 inhibitors

   5. For members on statin therapy, both of the following (a and b): a. Leqvio 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 (1 or 2): 1) Intolerance to two high intensity statins; 2) A statin risk factor (see Appendix G); iii. A low intensity statin and member has one of the following (1 or 2): 1) Intolerance to one high and one moderate intensity statins; 2) A statin risk factor (see Appendix G) 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 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); Page 2 of 13

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   Inclisiran ii. Member meets one of the following (1 or 2): 1) Member has documented statin risk factors (see Appendix G); 2) Member is statin intolerant due to statin-associated muscle symptoms (SAMS) and meets both of the following (a and b): a) Documentation of intolerable SAMS persisting at least two weeks, which disappeared with discontinuing the statin therapy and recurred with a statin re-challenge; b) 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 F or member has a history of ezetimibe intolerance (e.g., associated diarrhea or upper respiratory tract infection);
   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 severe primary hyperlipidemia (including HeFH): ≥ 100 mg/dL;
   9. Treatment plan does not include coadministration with Juxtapid®, Repatha®, or Praluent®;
   10. Dose does not exceed 284 mg initially and at 3 months, then every 6 months thereafter. Approval duration:
       Medicaid/HIM – 9 months Commercial – 6 months or to the member’s renewal date, whichever is longer
       B. Other diagnoses/indications (must meet 1 or 2):
   11. 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
   12. 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.
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   Inclisiran II. Continued Therapy A. Primary Hyperlipidemia (including HeFH) and Atherosclerotic Cardiovascular Disease (must meet all):

4. Currently 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);
   2. If statin tolerant, documentation of adherence to a statin at the maximally tolerated dose;
   3. Member is responding positively to therapy as evidenced by lab results within the last 3 months showing an LDL-C reduction since initiation of Leqvio therapy;
   4. Treatment plan does not include coadministration with Juxtapid, Repatha, or Praluent;

5. If request is for a dose increase, new dose does not exceed 284 mg every 6 months. Approval duration:
   Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer
   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.
      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.
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   Inclisiran IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ASCVD: atherosclerotic cardiovascular disease CHD: coronary heart disease FDA: Food and Drug Administration FH: familial hypercholesterolemia
   HeFH: heterozygous familial hypercholesterolemia LDL-C: low density lipoprotein cholesterol mRNA: messenger RNA PCSK9: proprotein convertase subtilisin–kexin type 9 RNA: ribonucleic acid SAMS: statin-associated muscle symptoms siRNA: small interfering RNA 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 Dosing Regimen ezetimibe/simvastatin (Vytorin®) 10/40 mg PO QD ezetimibe (Zetia®) atorvastatin (Lipitor®) rosuvastatin (Crestor®) 5 - 40 mg PO QD Praluent (alirocumab) 10 mg PO QD 40 mg PO QD 75 mg SC once every 2 weeks or 300 mg SC once every 4 weeks; if response to 75 mg every 2 weeks or 300 mg every 4 weeks is inadequate, dose may be increased to 150 mg once every 2 weeks 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 300 mg/month Repatha (evolocumab) 140 mg SC every 2 weeks or 420 420 mg/month
   mg SC once monthly 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. Appendix C: Contraindications/Boxed Warnings None reported Appendix D: Criteria for Diagnosis of HeFH
   • Dutch Lipid Clinic Network criteria for Familial Hypercholesterolemia (FH) Page 5 of 13

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   Inclisiran FH Criteria Points Member’s Score† 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 Clinical History Patient with premature coronary artery disease Patient with premature cerebral or peripheral vascular disease 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 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.
   • 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 Page 6 of 13

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   Inclisiran • 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 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 Page 7 of 13

   CLINICAL POLICY Inclisiran Statins • 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 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.
   In a final evidence report published March 2021, the Institute for Clinical and Economic Review (ICER) concluded that while uncertainty remains regarding the magnitude of overall benefit and how inclisiran compares to that of PCSK9 inhibitors, the current evidence offers high certainty of at least a small net health benefit for inclisiran when used for patients who have need of significant reduction in LDL-C despite maximally tolerated oral lipid-lowering therapy (B+). Page 8 of 13

   CLINICAL POLICY Inclisiran Appendix I: Criteria for Defining Patients at Very High Risk of Future ASCVD Events3, 16 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 HeFH 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 Primary hyperlipidemia (including HeFH) or hypercholesterolemia with ASCVD Dosing Regimen 284 mg SC on initially and at 3 months, then every 6 months thereafter. If a planned dose is missed by more than 3 months, restart with a new dosing schedule. Leqvio should be administered by a healthcare professional Maximum Dose See regimen VI. Product Availability
   Single-dose prefilled syringe: 284 mg/1.5 mL (189 mg/mL) VII.