Managed Access Program (MAP) for Patients Diagnosed With Secondary Progressive Multiple Sclerosis With Active Disease

Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

1. Adult patients who are able to provide written informed consent and have done soNote: proof of efficacy in the Phase III EXPAND study (Kappos et al 2018) has beenobtained in patients who were aged 18 to 61 years (inclusive) at screening

2. Diagnosis of SPMS with active disease. The SPMS diagnosis must follow an initialrelapsing-remitting disease course of multiple sclerosis (MS) and align with thediagnostic criteria published (Lublin and Reingold 1996, Rovaris et al 2006, Lublinet al 2014)

3. Patient is ambulatory, i.e., has an EDSS score of ≤6.5

4. Patient has no comparable or satisfactory alternative therapy available fortreatment of SPMS Written patient informed consent must be obtained prior to startof treatment. If consent cannot be expressed in writing, it must be formallydocumented and witnessed, ideally via an independent trusted witness.

Exclusion Criteria:

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. Disease exclusions

2. Relapsing-remitting multiple sclerosis

3. Primary progressive multiple sclerosis

4. Secondary progressive multiple sclerosis without active disease

5. Medical conditions precluding inclusion such as lab abnormalities or underlyingdiseases

6. Patients with an active or stable but treated chronic disease of the immunesystem other than MS (e.g. rheumatoid arthritis, scleroderma, Sjogren'ssyndrome, Crohn's disease, ulcerative colitis, etc.) or with a knownimmunodeficiency syndrome (AIDS, hereditary immune deficiency, drug-inducedimmune deficiency)

7. Severe active infections Patients affected by severe infections should only beincluded after full resolution of the condition

8. Second-degree AV block Mobitz type II or higher, sick-sinus syndrome,sino-atrial heart block or significant QT prolongation (QTc ≥500 msec).

9. History of cardiac arrest, recurrent syncope, symptomatic bradycardia, severecerebrovascular disease, uncontrolled hypertension or severe untreated sleepapnea.

10. Significant liver disease

11. Ongoing macular edema (patients with a history of resolved macular edema areallowed to enter the program)

12. Patients homozygous for CYP2C93 (CYP2C93*3 genotype)

13. Patients without a health-care professional confirmed history of chickenpox ordocumentation of a full course of vaccination with varicella vaccine. They haveto undergo antibody testing to varicella zoster virus (VZV) before initiatingtreatment with siponimod. A full course of vaccination for antibody-negativepatients with varicella vaccine is required prior to commencing treatment withsiponimod. Initiation of treatment with siponimod has be postponed for onemonth after completion of the vaccination course to allow full effect ofvaccination to occur.

14. History of hypersensitivity to any drugs or metabolites of similar chemicalclasses as siponimod.

15. Prior therapy precluding enrollment:

16. Natalizumab, immunosuppressive/chemotherapeutic medications (e.g. azathioprine,methotrexate) within 6 months prior to enrollment

17. Rituximab, ofatumumab, ocrelizumab, cladribine, or cyclophosphamide within oneyear prior to enrollment

18. Any mitoxantrone during previous two years prior to enrollment or evidence ofcardiotoxicity following mitoxantrone or a cumulative life-time dose of morethan 60 mg/m2

19. alemtuzumab, lymphoid irradiation, bone marrow transplantation or otherimmunosuppressive treatments with effects potentially lasting over 6 months, atany time

20. Concomitant therapy precluding enrollment:

21. Alemtuzumab, azathioprine, cyclophosphamide, cyclosporine, methotrexate,mitoxantrone, natalizumab, rituximab, ofatumumab, or ocrelizumab asimmunosuppressive or immune-modulating therapies

22. Only during treatment initiation: Class Ia (e.g. quinidine, procainamide),Class III anti-arrhythmic drugs (e.g. amiodarone, sotalol) during treatmentinitiation

23. Have any of the following out-of-range laboratory values:

24. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), orgamma-glutamyl transferase (GGT) greater than 5 times the upper limit of normal (ULN) range

25. White blood cell (WBC) count < 3,500/mm3 (< 3.5 x 109/L)

26. Lymphocyte count < 800/mm3 (< 0.8 x 109/L)

27. Serum potassium > ULN

28. Participation in a prior investigational study within 30 days prior to enrollment orwithin five half-lives of the investigational study drug or until the expectedpharmacodynamic effect has returned to baseline, whichever is longer

29. Pregnancy statements and contraception requirements

30. Pregnant or nursing (lactating) women, where pregnancy is defined as the stateof a female after conception and until the termination of gestation, confirmedby a positive hCG laboratory test (> 5 mIU/mL).

31. Women of child-bearing potential, defined as all women physiologically capableof becoming pregnant, UNLESS they are:

• Women whose partners have been sterilized by vasectomy or other means.
• Using a highly effective method of birth control for the duration oftreatment with siponimod and for at least ten days after stoppingtreatment with siponimod. Highly effective method of birth control aresuch resulting in a less than 1% per year failure rate when usedconsistently and correctly, such as implants, injectables, combined oralcontraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is notacceptable.
• Total abstinence from female-male intercourse (when this is in line withthe preferred and usual lifestyle of the subject, if accepted by localregulation)

8. Not able to understand and to comply with treatment instructions and requirements.