Plasminogen (Ryplazim) Form

Plasminogen (Ryplazim®) is a plasma-derived human plasminogen. FDA Approved Indication(s) Ryplazim is indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia). 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 Ryplazim is medically necessary when the following criteria are met:
I. Initial Approval Criteria A. Plasminogen Deficiency Type 1 (must meet all):

1. Diagnosis of symptomatic congenital plasminogen deficiency (C-PLGD) as evidenced by documentation of two of the following (a - c): a. Presence of a PLG mutation; b. Plasminogen activity level ≤ 45%; c. Signs or symptoms consistent with C-PLGD (see Appendix D);
2. Prescribed by or in consultation with a hematologist;
   
   3. Age ≥ 11 months;
   4. Dose does not exceed 6.6 mg/kg every second, third, or fourth day (based upon individual pharmacokinetics). Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):

3. 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: Page 1 of 6

   CLINICAL POLICY Plasminogen, Human-tvmh CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

4. 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. Plasminogen Deficiency Type 1 (must meet all):
   
   1. 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);
5. Member is responding positively to therapy as evidenced by, including but not limited to, improvement in C-PLGD-associated signs or symptoms (e.g., improvement in the size of visible lesions, imaging of nonvisible lesions, or spirometry if pulmonary involvement (see Appendix D));
6. If request is for a dose increase, new dose does not exceed 6.6 mg/kg every second, third, or fourth day (based upon individual pharmacokinetics). Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
7. 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

8. 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 – Page 2 of 6

   CLINICAL POLICY Plasminogen, Human-tvmh 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 C-PLGD: congenital plasminogen deficiency FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
   Not applicable Appendix C: Contraindications/Boxed Warnings • Contraindication(s): known hypersensitivity to plasminogen, or other components of Ryplazim • Boxed warning(s): none reported Appendix D: Clinical Signs and Symptoms of Congenital Plasminogen Deficiency C-PLGD (also known as type 1 plasminogen deficiency or hypoplasminogenemia) is a rare autosomal-recessive disorder of the fibrinolytic system. The primary manifestation is development of abnormal extravascular accumulation or growth of fibrin-rich, woody (ligneous) pseudomembranous lesions on mucous membranes throughout the body. Wound healing also may be impaired. The disease appears to be most severe in infants and children. Examples of lesion locations and associated complications (not all inclusive): • Conjunctival lesions “ligneous conjunctivitis” - most common lesion (may result in visual impairment or blindness) • Tracheobronchial or renal lesions (may result in respiratory or renal failure) • Lesions in the cerebral ventricular system (may result in congenital occlusive hydrocephalus) • Lesions in the ears, nasopharynx, and oral cavity (may result in hearing loss, ligneous tonsillitis or ligneous gingivitis with tooth loss) • Lesions in the genitourinary tract (may result in dysmenorrhea, abnormal menses, dyspareunia or infertility) ___ Shapiro, Amy D. et al. An international registry of patients with plasminogen deficiency (HISTORY). Haematologica. 2020 Mar; 105(3):554-561.
   Appendix E: Ryplazim Pivotal Trial • In a pivotal phase 2/3 clinical trial for the treatment of C-PLGD, 15 patients with C- PLGD were enrolled, including six pediatric patients, for 48 weeks of therapy with Ryplazim.
   • All patients treated with Ryplazim achieved the targeted increase from baseline in their • individual trough plasminogen activity levels through 12 weeks of therapy.
   In addition, all patients who had active visible lesions when enrolled in the trial had complete healing of their measurable lesions within 48 weeks of initiating therapy.
   • Adverse events reported in the clinical study were characterized as mild, with no patient deaths, serious adverse events or adverse events that caused study discontinuation. Page 3 of 6

   CLINICAL POLICY Plasminogen, Human-tvmh V. Dosage and Administration
   Indication Dosing Regimen C-PLGD 6.6 mg/kg body weight given every 2 to 4 days (based upon individual pharmacokinetics) Maximum Dose 6.6 mg/kg VI. Product Availability
   Single-dose vial: 68.8 mg in 50 mL vial (5.5 mg/mL of plasminogen after reconstitution) VII.