Ponesimod (Ponvory) Form

Ponesimod (Ponvory™) is a sphingosine 1-phosphate receptor modulator. FDA Approved Indication(s)
Ponvory 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 Ponvory 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 clinically 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. Ponvory is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D); Page 1 of 7

   CLINICAL POLICY Ponesimod

3. Documentation of both baseline number of relapses per year and expanded disability status scale (EDSS) score;
   6. Request meets the following: a. Treatment initiation: Dose follows the 14-day titration schedule as outlined in Section V and does not exceed 1 tablet per day; b. Treatment maintenance: Dose does not exceed 20 mg (1 tablet) per day. Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):
4. 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
5. 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):

6. 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; Page 2 of 7

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7. Ponvory is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D);
8. If request is for a dose increase, new dose does not exceed 20 mg (1 tablet) 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):
9. 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

10. 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; B. Primary progressive MS. 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®) 7 mg or 14 mg PO QD Page 3 of 7

    CLINICAL POLICY Ponesimod Drug Name Dosing Regimen Dose Limit/ Maximum Dose Avonex: 30 mcg/week Rebif: 44 mcg TIW 250 mg QOD Avonex: 30 mcg IM Q week Rebif: 22 mcg or 44 mcg SC TIW 250 mcg SC QOD Avonex®, Rebif® (interferon beta-1a) 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 SC Q2 weeks 125 mcg/2 weeks Appendix C: Contraindications/Boxed Warnings • Contraindication(s): in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure; presence of Mobitz type II second-degree, third-degree atrioventricular block, sick sinus syndrome, or sino-atrial block, 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®), ofatumumab (Kesimpta®), ublituximab- xiiy (Briumvi™), and ponesimod (Ponvory™). • Of the disease-modifying therapies for MS that are FDA-labeled for clinically isolated syndrome, only the interferon products, glatiramer, and teriflunomide have demonstrated any efficacy in decreasing the risk of conversion to MS compared to placebo. This is supported by the American Academy of Neurology 2018 MS guidelines. V. Dosage and Administration Indication Dosing Regimen MS Treatment initiation: • Days 1 and 2: 2 mg PO QD • Days 3 and 4: 3 mg PO QD • Days 5 and 6: 4 mg PO QD • Day 7: 5 mg PO QD • Day 8: 6 mg PO QD Page 4 of 7 Maximum Dose 20 mg/day

    CLINICAL POLICY Ponesimod Indication Dosing Regimen Maximum Dose • Day 9: 7 mg PO QD • Day 10: 8 mg PO QD • Day 11: 9 mg PO QD • Day 12, 13, and 14: 10 mg PO QD Treatment maintenance: • Day 15 and thereafter: 20 mg PO QD Missed doses: • If fewer than 4 consecutive doses are missed:
    o During titration: Resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day.
    o During maintenance: Resume treatment with the maintenance dosage.
    • If 4 or more consecutive doses are missed during titration or maintenance:
    o Treatment should be reinitiated with Day 1 of the titration regimen (new starter pack). VI. Product Availability
    • Tablets, starter pack: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg • Tablets, maintenance dose bottle: 20 mg
    VII.