Evinacumab-dgnb (Evkeeza) Form

Evinacumab-dgnb (Evkeeza®) is a human monoclonal antibody that binds to angiopoietin-like 3 to block its inhibition of lipoprotein lipase. ____
*These criteria do NOT apply to California Commercial Exchange Plans; see CP.PHAR.511 for CA Commercial Exchange. FDA Approved Indication(s) Evkeeza is indicated as an adjunct to other low density lipoprotein-cholesterol (LDL-C) lowering medications for the treatment of adult and pediatric patients, aged 5 years and older, with homozygous familial hypercholesterolemia (HoFH). Limitation(s) of use: • The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). • The effects of Evkeeza on cardiovascular morbidity and mortality have 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 Evkeeza 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, apolipoprotein B [apo B] gene, low density lipoprotein receptor adaptor protein 1 [LDLRAP1] gene); b. Treated LDL-C ≥ 300 mg/dL or non-high-density lipoprotein cholesterol (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); Page 1 of 10

   CLINICAL POLICY Evinacumab-dgnb

2. Prescribed by or in consultation with a cardiologist, endocrinologist, or lipid specialist;
3. Member meets one of the following (a or b): a. Both of the following (i and ii): i. Age ≥ 5 years and < 18 years; ii. LDL-C ≥ 130 mg/dL within the last 60 days despite statin and ezetimibe therapy, unless member has a contraindication (see Appendix F) or history of intolerance to each such therapy; b. Age ≥ 18 years, and recent (within the last 60 days) LDL-C of one of the following (i or ii): i. ≥ 70 mg/dL; ii. ≥ 55 mg/dL if member has ASCVD and is at very high risk (see Appendix H);
4. For members ≥ 18 years old and on statin therapy, both of the following (a and b):
   a. Evkeeza 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;
5. For members ≥ 18 years old and 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, 1 of which must be a hydrophilic statin (pravastatin, fluvastatin, or rosuvastatin); ii. Member meets one of the following (1 or 2): 1) Member has documented statin risk factors (see Appendix F); 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 rechallenge; b) Documentation of re-challenge with titration from lowest possible dose and/or intermittent dosing frequency (e.g., 1 to 3 times weekly);
6. If age ≥ 18 years old, 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 an 8 week trial of Repatha®, unless contraindicated, clinically significant adverse effects are experienced, or member has < 2% LDLR activity; Page 2 of 10

   CLINICAL POLICY Evinacumab-dgnb *Prior authorization may be required for Repatha

8. If request is for coadministration with Juxtapid®, Leqvio®, Praluent®, or Repatha, member has tried the prior therapy for at least 3 consecutive months with inadequate response defined as failure to achieve LDL-C ≤ 250 mg/dL or a 20% reduction in LDL-C from baseline;
9. Documentation of member’s current weight in kg; 10. Dose does not exceed 15 mg/kg every 4 weeks. Approval duration: 6 months 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: HIM.PA.33 for health insurance marketplace; 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: HIM.PA.103 for health insurance marketplace; 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: HIM.PA.154 for health insurance marketplace.
    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 Evkeeza therapy;
15. Documentation of member’s current weight in kg;
    5. If request is for a dose increase, new dose does not exceed 15 mg/kg every 4 weeks. 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): Page 3 of 10

    CLINICAL POLICY Evinacumab-dgnb a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace; 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: HIM.PA.103 for health insurance marketplace; 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 criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace.
    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 – HIM.PA.154 for health insurance marketplace, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALT: alanine transaminase apo B: apolipoprotein B ARH: autosomal recessive hypercholesterolemia ASCVD: atherosclerotic cardiovascular disease eGFR: estimated glomerular filtration rate 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 ULN: upper limit of normal 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 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 ezetimibe/simvastatin (Vytorin®) 10/40 mg PO QD ezetimibe (Zetia®) atorvastatin (Lipitor®) rosuvastatin (Crestor®) 10 mg PO QD 40 mg PO QD 5 - 40 mg PO QD Page 4 of 10

    CLINICAL POLICY Evinacumab-dgnb Drug Name Dosing Regimen pravastatin (Pravachol®) 10 - 80 mg PO QD fluvastatin (Lescol®) 20 - 80 mg PO QD Repatha (evolocumab) 420 mg SC once monthly 420 mg/month 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 80 mg/day 80 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): history of serious hypersensitivity reactions to evinacumab-dgnb or to any of the excipients in Evkeeza • Boxed warning(s): none reported 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 Page 5 of 10

    CLINICAL POLICY Evinacumab-dgnb 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 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 • 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. • According to the Repatha Prescribing Information, patients known to have two LDLR negative alleles (little to no residual function) did not respond to Repatha, with negative defined as < 2% uptake in the TESLA pivotal study. In contrast, patients with < 2% activity did respond to Evkeeza in the ELIPSE HoFH pivotal study. Appendix H: 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) Page 6 of 10

    CLINICAL POLICY Evinacumab-dgnb 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 HoFH Dosing Regimen 15 mg/kg IV every 4 weeks Maximum Dose 15 mg/kg/4 weeks VI. Product Availability Solution for injection in single-dose vials: 345 mg/2.3 mL (150 mg/mL), 1,200 mg/8 mL (150 mg/mL) VII.