TAKHZYRO, Lanadelumab-flyo Form

Lanadelumab-fylo (Takhzyro™) is a human monoclonal antibody that inhibits the proteolytic activity of kallikrein to reduce the generation of bradykinin. ___ These criteria do NOT apply to California Commercial Exchange Plans. Requests for California Commercial Exchange Plans should be reviewed using HIM.PA.172. FDA Approved Indication(s) Takhzyro is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 2 years and older. 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 Takhzyro is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Hereditary Angioedema (must meet all): *These criteria do NOT apply to California Commercial Exchange Plans. Requests for California Commercial Exchange Plans should be reviewed using HIM.PA.172.

1. Diagnosis of HAE confirmed by a history of recurrent angioedema and one of the following (a or b): a. Low C4 level and low C1-INH antigenic or functional level (see Appendix D); b. Normal C4 level and normal C1-INH level, and at least one of the following (i or ii): i. Presence of a mutation associated with the disease (see Appendix D); ii. Family history of angioedema, and documented failure of high-dose antihistamine therapy (i.e., cetirizine 40 mg/day or equivalent) for at least 1 month or an interval expected to be associated with 3 or more attacks of angioedema, whichever is longer;
   
   2. Prescribed by or in consultation with an allergist, hematologist, or immunologist;
2. Age ≥ 2 years;

3. Prescribed for long-term prophylaxis of HAE attacks and request meets one of the following (a, b, or c): a. Member experiences more than one severe event per month; b. Member is disabled more than five days per month; Page 1 of 8

   CLINICAL POLICY Lanadelumab-fylo c. Member has history of previous airway compromise;

   5. For members age ≥ 6 years: Failure of Haegarda®, unless contraindicated or clinically significant adverse effects are experienced;
   6. Member is not using Takhzyro in combination with another FDA-approved product for long-term prophylaxis of HAE attacks (e.g., Cinryze®, Haegarda®, Orladeyo™);
   7. Dose does not exceed one of the following (a, b, or c): a. For adult and pediatric members ≥ 12 years of age, both (i and ii):
      i. 300 mg every 2 weeks; ii. 1 vial or 1 syringe every 2 weeks; b. For pediatric members 6 to < 12 years of age, both (i and ii): i. 150 mg every 2 weeks; ii. 1 syringe every 2 weeks; c. For pediatric members 2 to < 6 years of age, both (i and ii): i. 150 mg every 4 weeks; ii. 1 syringe every 4 weeks. Approval duration: Medicaid– 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):
   8. 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
   9. 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. Hereditary Angioedema (must meet all):
   10. 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);
   11. Member is responding positively to therapy as evidenced by reduction in attacks from baseline;
   12. Member is not using Takhzyro in combination with another FDA-approved product for long-term prophylaxis of HAE attacks (e.g., Cinryze, Haegarda, Orladeyo);
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   CLINICAL POLICY Lanadelumab-fylo

   4. For age 6 years to < 12 years: Request is for 150 mg every 4 weeks, unless documentation supports member is not well-controlled (e.g., attack(s) within the last 6 months);
   5. For age ≥ 12 years: Request is for 300 mg every 4 weeks, unless documentation supports member is not well-controlled (e.g., attack(s) within the last 6 months);

4. If request is for a dose increase, new dose does not exceed one of the following (a, b, or c): a. For adult and pediatric members ≥ 12 years of age, both (i and ii):
   i. 300 mg every 2 weeks; ii. 1 vial or 1 syringe every 2 weeks; b. For pediatric members 6 to < 12 years of age, both (i and ii):
   i. 150 mg every 2 weeks; ii. 1 syringe every 2 weeks; c. For pediatric members 2 to < 6 years of age, both (i and ii):
   i. 150 mg every 4 weeks; ii. 1 syringe every 4 weeks. Approval duration: Medicaid – 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 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
   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 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 CI-INH: C1 esterase inhibitor
      C4: complement component 4 FDA: Food and Drug Administration HAE: hereditary angioedema HAE-nl-C1INH: hereditary angioedema with normal C1 inhibitor
      Page 3 of 8

   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 cetirizine 40 mg/day (off-label) Typical dosing range (mg/day): 10 mg/day US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema 60 IU/kg body weight SC twice weekly (every 3 or 4 days) C1 esterase inhibitor (Haegarda®) 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. Based on weight, 60 IU/kg/dose Dose Limit/ Maximum Dose 40 mg/day (off- label) Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information
   • Diagnosis of HAE: o There are two classifications of HAE: HAE with C1-INH deficiency (HAE-C1INH, further broken down into Type 1 and Type II) and HAE with normal C1-INH (also known as HAE-nl-C1INH). HAE-nl-C1INH was previously referred to as type III HAE, but this term is obsolete and should not be used. o In both Type I (~85% of cases) and Type II (~15% of cases), C4 levels are low. C1- INH antigenic levels are low in Type I while C1-INH functional levels are low in Type II. Diagnosis of Type I and II can be confirmed with laboratory tests. Reference ranges for C4 and C1-INH levels can vary across laboratories (see below for examples); low values confirming diagnosis are those which are below the lower end of normal. Laboratory Test & Reference Range C4
   Quest Diagnostics 14 – 40 mg/dL Mayo Clinic Lab Corp 13-57 mg/dL (age- and gender-specific ranges) 21 – 39 mg/dL 10-38 mg/dL (age- and gender-specific ranges) 21 – 39 mg/dL 19 – 37 mg/dL C1-INH, antigenic C1-INH, functional Normal: > 67% Equivocal: 41 – 67% Abnormal: < 41% Normal: ≥ 68% Equivocal: 41 – 67% Abnormal: ≤ 40% Normal: > 67% Equivocal: 41 – 67% Abnormal: < 41% Page 4 of 8

   CLINICAL POLICY Lanadelumab-fylo o HAE-nl-C1INH, on the other hand, presents with normal C4 and C1-INH levels. Some patients have a known associated mutation, while others have no identified genetic indicators. HAE-nl-C1INH is very rare, and there are no laboratory tests to confirm the diagnosis; mutations in 6 genes causing HAE-nl-C1INH have been identified: Identified Genes Associated with Mutations in HAE-nl-C1INH F12 ANGPT1 PLG KNG1 MYOF HS3ST6 Maximum Dose See dosing regimen V. Dosage and Administration
   Indication HAE attack prophylaxis
   Dosing Regimen Adult and pediatric patients ≥ 12 years of age
   300 mg SC every 2 weeks A dosing interval of 300 mg every 4 weeks may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months Pediatric patients 6 to < 12 years of age 150 mg SC every 2 weeks A dosing interval of 150 mg every 4 weeks may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months Pediatric patients 2 to < 6 years of age 150 mg SC every 4 weeks VI. Product Availability
   • Single-dose vial: 300 mg/2 mL (150 mg/mL) solution
   • Single-dose prefilled syringes: 300 mg/2 mL (150 mg/mL) solution, 150 mg/1 mL solution
   VII.