MAYZENT, Siponimod Fumarate Form

Siponimod (Mayzent®) is a sphingosine 1-phosphate receptor modulator. FDA Approved Indication(s) Mayzent is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 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 Mayzent is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Sclerosis (must meet all):

1. Diagnosis of one of the following (a, b, or c): a. Clinically isolated syndrome, and member is contraindicated to both or has experienced significant adverse effects to one of the following at up to maximally indicated doses: an interferon-beta agent (Avonex®, Betaseron®/Extavia®†, Rebif®, or Plegridy®), glatiramer (Copaxone®, Glatopa®); b. Relapsing-remitting MS, and failure of all of the following at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated (i, ii, iii, and iv):
   i. Dimethyl fumarate (generic Tecfidera®);
   ii. Teriflunomide (generic Aubagio®);
   iii. Fingolimod (Gilenya®); iv. An interferon-beta agent (Avonex, Betaseron/Extavia†, Rebif, or Plegridy) or glatiramer (Copaxone, Glatopa); Prior authorization may be required for all disease modifying therapies for MS
   †Betaseron is preferred for the Commercial and HIM lines of business; Extavia is preferred for the Medicaid line of business c. Secondary progressive MS;

2. Prescribed by or in consultation with a neurologist;

   3. Age ≥ 18 years;
   4. Documentation that member does not have a CYP2C93/3 genotype (see Appendix D);
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3. Mayzent is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D);
4. Documentation of both baseline number of relapses per year and expanded disability status scale (EDSS) score;
5. Dose does not exceed 2 mg per day. 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.
   II. Continued Therapy A. Multiple Sclerosis (must meet all):
8. 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);
   2. Member meets one of the following (a or b): a. If member has received < 1 year of total treatment: Member is responding positively to therapy; b. If member has received ≥ 1 year of total treatment: Member meets one of the following (i, ii, iii, or iv): i. Member has not had an increase in the number of relapses per year compared to baseline; ii. Member has not had ≥ 2 new MRI-detected lesions; iii. Member has not had an increase in EDSS score from baseline; iv. Medical justification supports that member is responding positively to therapy;

9. Mayzent is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D); Page 2 of 7

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10. If request is for a dose increase, new dose does not exceed 2 mg per day.
    Approval duration:
    If member has received < 1 year of total treatment – up to a total of 12 months of treatment If member has received ≥ 1 year of total treatment – 12 months 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.
    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 EDSS: expanded disability status scale
    FDA: Food and Drug Administration MS: multiple sclerosis 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 14 mg/day teriflunomide (Aubagio®) Avonex®, Rebif® (interferon beta-1a) 7 mg or 14 mg PO QD Avonex: 30 mcg IM Q week Rebif: 22 mcg or 44 mcg SC TIW Avonex: 30 mcg/week Rebif: 44 mcg TIW Page 3 of 7

    CLINICAL POLICY Siponimod Drug Name Dosing Regimen Dose Limit/ Maximum Dose 250 mg QOD 250 mcg SC QOD 125 mcg SC Q2 weeks Betaseron®, Extavia® (interferon beta-1b) Plegridy® (peginterferon beta-1a) glatiramer acetate (Copaxone®, Glatopa®) fingolimod (Gilenya®) dimethyl fumarate (Tecfidera®) 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. 0.5 mg PO QD 120 mg PO BID for 7 days, followed by 240 mg PO BID 20 mg/day or 40 mg TIW 0.5 mg/day 480 mg/day 20 mg SC QD or 40 mg SC TIW 125 mcg/2 weeks Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Patients with a CYP2C93/3 genotype o In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure o Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker • Boxed warning(s): none reported Appendix D: General Information • Disease-modifying therapies for MS are: glatiramer acetate (Copaxone®, Glatopa®), interferon beta-1a (Avonex®, Rebif®), interferon beta-1b (Betaseron®, Extavia®), peginterferon beta-1a (Plegridy®), dimethyl fumarate (Tecfidera®), diroximel fumarate (Vumerity®), monomethyl fumarate (Bafiertam™), fingolimod (Gilenya®, Tascenso ODT™), teriflunomide (Aubagio®), alemtuzumab (Lemtrada®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), ocrelizumab (Ocrevus®), siponimod (Mayzent®), cladribine (Mavenclad®), ozanimod (Zeposia®), ponesimod (Ponvory™), ublituximab-xiiy (Briumvi™), and ofatumumab (Kesimpta®). • The CYP2C9 genotype has a significant impact on siponimod metabolism. Mayzent is contraindicated in patients homozygous for CYP2C93 (i.e., CYP2C93/3 genotype), which is approximately 0.4%-0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. Mayzent dosage adjustment is recommended in patients with CYP2C91/3 or 2/*3 genotype because of an increase in exposure to siponimod.
    • The American Academy of Neurology 2018 MS guidelines recommend the use of Gilenya, Tysabri, and Lemtrada for patients with highly active MS. Definitions of highly active MS vary and can include measures of relapsing activity and MRI markers of disease activity, such as numbers of gadolinium-enhanced lesions. V. Dosage and Administration
    Indication MS Dosing Regimen All patients: Maximum Dose 2 mg/day Page 4 of 7

    CLINICAL POLICY Siponimod Indication Dosing Regimen Day 1 and 2: 0.25 mg PO QD Day 3: 0.5 mg PO QD Day 4: 0.75 mg PO QD CYP2C9 genotypes 1/1, 1/2, or 2/2: Day 5: 1.25 mg PO QD
    Day 6 and onward: 2 mg PO QD CYP2C9 genotypes 1/3 or 2/3: Day 5 and onward: 1 mg PO QD Maximum Dose VI. Product Availability
    Tablets: 0.25 mg, 1 mg, 2 mg VII.