Ocrelizumab Discontinuation in Relapsing Multiple Sclerosis

Inclusion Criteria:

1. Have at least one clinical episode that satisfies McDonald 2017 criteria for earlyMultiple sclerosis (MS) with a dissemination in time that can be met clinically, byMagnetic Resonance Imaging (MRI), or based on oligoclonal band (OCB) positivity

2. Have a length of disease duration, from first symptom, of ≤ 3 years at time ofinformed consent

3. For women of childbearing potential: Agreement to remain abstinent (refrain fromheterosexual intercourse) or use effective methods of contraception during thetreatment period and for at least 6 months after the last dose of study drug:

4. A woman is considered to be of childbearing potential if she is postmenarcheal,has not reached a postmenopausal state (≥12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus)

5. Examples of contraceptive methods include bilateral tubal ligation, malesterilization, established hormonal contraceptives that inhibit ovulation,hormone- releasing intrauterine devices, and copper intrauterine devices

6. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of theparticipant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpost ovulation methods) and withdrawal are not acceptable methods ofcontraception

7. Barrier methods must always be supplemented with the use of a spermicide

Exclusion Criteria:

1. Inability or unwillingness of a participant to give written informed consent orcomply with study protocol

2. History of primary progressive multiple sclerosis (PPMS), progressive relapsingmultiple sclerosis (PRMS), or secondary progressive multiple sclerosis (SPMS)

3. Any metallic material or electronic device in the body, or condition that precludesthe participant from undergoing MRI

4. Known presence or history of other neurological disorders, including but not limitedto the following:

• Ischemic cerebrovascular disorders, including but not limited to transientischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebralembolism, or cerebral hemorrhage

• CNS or spinal cord tumor, metabolic or infectious cause of myelopathy,genetically inherited progressive CNS disorder, CNS sarcoidosis, or systemicautoimmune disorders potentially causing progressive neurologic disease oraffecting ability to perform the study assessments

5. Pregnancy or lactation

• Female participants of childbearing potential must have a negative urine pregnancytest at screening

6. Any concomitant disease that may require chronic systemic treatment withcorticosteroids or immunosuppressants during the course of the study

7. Lack of peripheral venous access

8. History of severe allergic or anaphylactic reactions to humanized or murinemonoclonal antibodies

9. Significant, inadequately controlled (e.g., diagnostic evaluations indicated orchange in medications warranted) disease, such as cardiovascular (including cardiacarrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic,endocrine, and gastrointestinal or any other significant disease that in the opinionof the investigator may preclude participant from participating in the study

10. Functional status of New York Heart Association (NYHA) Class III or higher for heartfailure at the screening visit

11. Known active bacterial, viral, fungal, mycobacterial infection or other infection (including tuberculosis (TB) or atypical mycobacterial disease but excluding limitedsuperficial fungal or viral infections of the skin or nails) or any severe episodeof infection requiring hospitalization or treatment with IV antibiotics within 4weeks prior to Mo 0/Day 0 infusion or oral antibiotics within 2 weeks prior to Mo 0/Day 0 infusion

12. Active or chronic infection with human immunodeficiency virus (HIV), syphilis or TB (see laboratory tests below)

13. Evidence of past hepatitis B (including treated hepatitis B) or untreated hepatitisC infection (treated hepatitis C is not considered exclusionary). Hepatitis Bsurface antibody following hepatitis B immunization is not considered to be evidenceof past infection (see laboratory tests below).

14. Known active malignancy or active monitoring for recurrence of malignancy, includingsolid tumors and hematological malignancies, except basal cell, in situ squamouscell carcinoma of the skin, and in situ carcinoma of the cervix or the uterus thathave been excised with clear margins

15. Substance use disorder, including the recurrent use of alcohol and/or drugs withinthe past year associated with clinically significant impairment associated withfailure to meet major responsibilities at work, school, or home

16. Receipt of live or live-attenuated vaccines within 4 weeks prior to Mo 0/Day 0infusion

17. Contraindications to or severe intolerance of oral or IV corticosteroids, includingIV methylprednisolone administered according to the country label, including:

• Psychosis not controlled by a treatment

• Hypersensitivity to any of the constituents or excipients of the precedingsteroids

18. Current or prior treatment with the following MS DMTs: fingolimod and other S1Preceptor modulators, cladribine, natalizumab, anti-CD20 molecules, alemtuzumab, andchemotherapeutic agents

19. Treatment with fumarates within 30 days prior to collection of Mo 0/Day 0mechanistic samples, Mo 0/Day 0 MRI, and Mo 0/Day 0 infusion

20. (a) Current or prior treatment with any approved or experimental immunomodulatorytherapies, unless reviewed and approved by the SAC (Section 3.6), or (b) Treatmentwith any experimental procedure for MS (e.g., treatment for chronic cerebrospinalvenous insufficiency)

21. Systemic corticosteroid therapy within 4 weeks prior to the collection of screeningmechanistic samples and the screening MRI

22. Systemic corticosteroid therapy within 4 weeks prior to the Mo 0/Day 0 infusion

23. Screening laboratory test results as follows:

• Positive infection screening tests for: i. Hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (HbcAb) ii.Hepatitis C (HCV) antibody if positive screen for HCV RNA Polymerase ChainReaction (PCR) iii. Rapid plasma reagin (RPR)

• A reactive RPR test unless followed by a subsequent negative RPR OR

• A reactive RPR test unless successful completion of treatment has beendocumented as well as a consultation with and clearance by infectious diseasedepartment iv. HIV v. At or within twelve months of screening:

• Positive QuantiFERON®-TB Gold test or positive purified protein derivativetuberculin skin test (PPD) (>5mm induration, regardless of BacilleCalmette-Guerin (BCG) vaccine administration) unless completion of treatmenthas been documented for active TB OR

• An indeterminate QuantiFERON®-TB Gold test unless followed by a subsequentnegative PPD or negative QuantiFERON®-TB Gold test as well as a consultationwith and clearance by infectious disease department

• Levels of serum immunoglobulin G (IgG) < 3.3g/L

• Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 using ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) equation

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.0 x theupper limit of normal (ULN)

• Platelet count < 100,000 plt/µL (<100 x 10⁹/L)

• Hemoglobin < 10 g/dL

• Absolute neutrophil count < 1.5 x 10⁹/L

• Absolute lymphocyte count < 1.2 x 10⁹/L

24. Past or current medical problems or findings from physical examination or laboratorytesting that are not listed above, which, in the opinion of the investigator, maypose additional risks from participation in the study, may interfere with theparticipant's ability to comply with study requirements, or that may impact thequality or interpretation of the data obtained from the study.