GAMIFANT, Emapalumab-lzsg Form

Emapalumab-lzsg (Gamifant™) is an interferon gamma (IFNγ) blocking antibody. FDA Approved Indication(s) Gamifant is indicated for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.
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 Gamifant is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Primary Hemophagocytic Lymphohistiocytosis (must meet all):

1. Diagnosis of primary HLH (i.e., familial (inherited) HLH);

2. Diagnosis is confirmed based on one of the following (a, b, or c): a. Genetic mutation known to cause HLH (e.g., PRF1, UNC13D, STX11 and STXBP2); b. Family history consistent with primary HLH;
   c. Five of the following criteria are satisfied (1-8):
   1) Fever; 2) Splenomegaly; 3) Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin < 9 g/dL (or < 10 g/dL in infants), platelets < 100 x 109 /L, neutrophils < 1 x 109/L);
   4) Hypertriglyceridemia (fasting TG ≥ 3 mmol/L or ≥ 265 mg/dL) and/or hypofibrinogenemia (fibrinogen ≤ 1.5 g/L); 5) Hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy;
   6) Low or absent NK-cell activity;
   7) Ferritin ≥ 500 mcg/L;
   8) Soluble CD25 (sCD25; i.e. soluble IL-2 receptor) ≥ 2,400 U/mL;

   3. Prescribed by or in consultation with a hematologist or immunologist; Page 1 of 7

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   4. Failure of conventional HLH therapy that includes an etoposide- and dexamethasone- based regimen, unless contraindicated or clinically significant adverse effects are experienced;
   5. Gamifant is prescribed in combination with dexamethasone;
3. Documentation of a scheduled bone marrow or hematopoietic stem cell transplantation (HSCT) or identification of a transplant donor is in process;
   7. Dose does not exceed 10 mg/kg per dose, two doses per week. Approval duration: 2 months 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, 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
   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, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      II. Continued Therapy A. Primary Hemophagocytic Lymphohistiocytosis (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 – including but not limited to improvement in any of the following parameters: a. Fever reduction; b. Splenomegaly; c. Central nervous system symptoms; d. Complete blood count; e. Fibrinogen and/or D-dimer; f. Ferritin; g. Soluble CD25 (also referred to as soluble interleukin-2 receptor) levels;
4. Member has not yet received a successful bone marrow transplant or HSCT;

5. Gamifant is prescribed in combination with dexamethasone; Page 2 of 7

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   5. If request is for a dose increase, new dose does not exceed 10 mg/kg per dose, two doses per week.
      Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):
   6. 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
   7. 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 FDA: Food and Drug Administration HLH: hemophagocytic lymphohistiocytosis
      HSCT: hematopoietic stem cell transplantation 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.
      Dosing Regimen Drug Name Dose Limit/ Maximum Dose 150 mg/m2 per dose etoposide (Toposar®) 150 mg/m2 IV twice weekly for 2 weeks and then weekly for an additional 6 weeks. Continuation therapy from week 9 until HSCT: 150 mg/m2 every alternating second week Page 3 of 7

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   Drug Name Dosing Regimen dexamethasone 10 mg/m2 PO or IV for 2 weeks followed by 5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks, 1.25 mg/m2 for 1 week, and 1 week of tapering Continuation therapy from week 9 until HSCT: 1010 mg/m2 for 3 days every second week Dose Limit/ Maximum Dose See dosing regimen 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: General Information
   • Overall response in the Gamifant clinical trial (NCT01818492) was evaluated using an algorithm that included the following objective clinical and laboratory parameters: fever, splenomegaly, central nervous system symptoms, complete blood count, fibrinogen and/or D-dimer, ferritin, and soluble CD25 (also referred to as soluble interleukin-2 receptor) levels.
   o Complete response was defined as normalization of all HLH abnormalities (i.e., no fever, no splenomegaly, neutrophils > 1x109/L, platelets > 100x109/L, ferritin < 2,000 µg/L, fibrinogen > 1.50 g/L, D-dimer < 500 ug/L, normal CNS symptoms, no worsening of sCD25 > 2-fold baseline).
   o Partial response was defined as normalization of ≥ 3 HLH abnormalities.
   o HLH improvement was defined as ≥ 3 HLH abnormalities improved by at least 50% from baseline. • Gamifant is currently not indicated for the treatment of secondary HLH. Secondary HLH generally presents in adults and is triggered by autoimmune disease, infections, or cancer. Treatment for secondary HLH is focused on the triggering condition. V. Dosage and Administration
   Indication Primary HLH Dosing Regimen Initial: 1 mg/kg IV twice per week (every three to four days) Subsequent doses may be increased based on clinical and laboratory criteria. Maximum Dose 10 mg/kg/dose VI. Product Availability
   Single-dose vial: 10 mg/2 mL, 50 mg/10 mL, 100 mg/20 mL
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   VII.