Addition of Belimumab to B-cell Depletion in Relapsing-remitting Multiple Sclerosis
Addition of Belimumab to B-cell Depletion in Relapsing-remitting Multiple Sclerosis
Multiple sclerosis is the most common inflammatory disease of the central nervous system and
 a common cause of disability in young adults. Depleting B cells from the circulation with an
 anti-cluster of differentiation (CD) 20 antibodies has proven to be an effective strategy in
 reducing relapses and disability in patients with the relapsing-remitting disease. However,
 continuous and long-term depletion of B-cells can result in reduced immunoglobulin levels,
 immunosuppression, and an increased tendency for severe infections and perhaps, even
 malignancy.

 Blocking B-cell Activating Factor (BAFF) is effective for the treatment of several autoimmune
 disorders. Belimumab, a BAFF blocking antibody, has been approved by the Food and Drug
 Administration for the treatment of systemic lupus erythematosus. Belimumab has been shown to
 have immunomodulatory properties, without resulting in overt immunosuppression.

 The investigators hypothesize that belimumab, given to patients who received a short course
 of treatment with B-cell depleting antibody (ocrelizumab), will be safe and equally effective
 in reducing MS disease activity (as compared to patients receiving continuous treatment with
 ocrelizumab); while resulting in less immunosuppression, as measured by antibody response to
 pneumococcal vaccination. Currently, available treatment strategies in relapsing MS sacrifice
 higher efficacy for long-term safety or vice versa. The proposed strategy in this application
 combines the long-term safety and high efficacy to treat patients with relapsing-remitting
 multiple sclerosis (RRMS) and, if eventually proven effective, can be adopted in a large
 proportion of patients with this chronic disease.

 This is a randomized, open-labeled trial. Forty eligible participants will be randomized 1:1
 to either receiving a form of standard of care, ocrelizumab (300 mg two infusions two weeks
 apart at baseline and then 600 mg as a single infusion every six months) or belimumab (200 mg
 subcutaneous (SC) weekly for 36 months) plus two courses of ocrelizumab (300 mg two infusions
 two weeks apart at baseline and 600 mg as a single infusion six months later). Co-primary
 outcomes of the study include pneumococcal vaccine antibody response, the return of MS
 disease activity, and proportions of patients with adverse events and serious adverse events.
Inclusion Criteria:

 -  Diagnosis of RRMS based on McDonald criteria 2017

 -  Age > 18

 -  A clinical relapse in the past 12 months OR an enhancing lesion on brain/ spinal cord
 MRI in the past 6 months OR a new T2/FLAIR lesion on a brain/spinal cord MRI obtained
 in the past 6 months (compared to a previous MRI obtained within one year from the
 latest MRI)

 -  Pre-existing pneumococcal antibody titers (>1.0 mg/mL) to =<9 of 23 vaccine serotypes

 -  Female Subjects: Not pregnant or nursing and at least one of the following conditions
 apply: a. Non- childbearing potential defined as pre-menopausal females with a
 documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of
 spontaneous amenorrhea. b. Child-bearing potential and agrees to use one of the
 contraception methods as described by the investigator or designee, from Day 0 until
 24 weeks after the last dose of study medications (See details below).

 -  Liver function at the time of screening: alanine aminotransferase (ALT) < 2x upper
 limit of normal (ULN); bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable
 if bilirubin is fractionated and direct bilirubin <35%).

 Exclusion Criteria:

 -  Prior therapy at any time: has ever received any of the following: a) B-cell targeted
 therapy (e.g., rituximab, ocrelizumab, other anti-cluster of differentiation (CD)20
 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], B lymphocyte stimulator
 (BLyS)-receptor fusion protein [BR3], Transmembrane activator and CAML interaction
 (TACI) fragment, crystallizable (Fc), or belimumab)

 -  Prior use of cladribine, mitoxantrone, cyclophosphamide, or hematopoietic stem cell
 transplantation (HSCT)

 -  Lymphopenia: a lymphocyte count <500/ millimeter (mm)^3

 -  Neutrophils <1.5X10E9/L.

 -  Drug sensitivity: a history of sensitivity to any of the study medications, or
 components thereof or a history of drug or other allergies including a previous
 anaphylactic reaction to parenteral administration contrast agents, human or murine
 proteins or monoclonal antibodies

 -  Treatment with steroids in the last 30 days

 -  Clinically unstable medical or psychiatric disorder

 -  Have evidence of serious suicide risk including any history of suicidal behavior in
 the last 6 months and/or any suicidal ideation in the last 2 months or who in the
 investigator's judgment, poses a significant suicide risk

 -  Have a history of an anaphylactic reaction to parenteral administration of contrast
 agents, human or murine proteins or monoclonal antibodies

 -  Substance abuse: has evidence of current drug or alcohol abuse or dependence

 -  365 Day prior therapy: has received a biologic investigational agent other than B-cell
 targeted therapy [e.g., abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC 131;
 investigational agent applies to any drug not approved for sale in the country in
 which it is being used]

 -  30 Day prior therapy: has received any of the following within 30 days before Day 0:
 a) Any other MS disease-modifying therapy, not mentioned above (including fumaric acid
 esters, sphingosine-1-phosphate (S1P) receptor modulators, teriflunomide, and
 natalizumab). Glatiramer acetate and interferons are permitted up to the day of
 starting the investigational medication. Intravenous, oral, and Inhaled steroids and
 new topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed.

 -  30 Day prior therapy: has received a live virus vaccine or a non-biologic
 investigational agent.

 -  Malignancy: has a history of malignancy in the past 5 years except for adequately
 treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the
 uterine cervix.

 -  Have a history of a primary immunodeficiency

 -  Have a significant IgG deficiency (IgG level < 400 mg/dL)

 -  Have an IgA deficiency (IgA level < 10 mg/dL)

 -  Infection history:

 -  Currently on any suppressive therapy for chronic infection (such as tuberculosis,
 pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical
 mycobacteria)

 -  Hospitalization for treatment of infection within 60 days of Day 0.

 -  Use of parenteral (IV or IM) antibiotics (anti-bacterial, antiviral, anti-fungal,
 or anti-parasitic agents) within 60 days of Day 0

 -  Other disease/conditions: has any of the following: a) clinical evidence of
 significant unstable or uncontrolled acute or chronic diseases (i.e., cardiovascular,
 pulmonary, hematologic, gastrointestinal, hepatic, neurological, malignancy or
 infectious diseases) which, in the opinion of the investigator, could confound the
 results of the study or put the subject at undue risk; b) a surgical procedure planned
 in the 6 months after Day 0; c) a known history of any other medical disease (e.g.,
 cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access)
 that, in the opinion of the investigator, makes the subject unsuitable for the study

 -  Hepatitis status:

 -  Serologic evidence of current or past Hepatitis B (HB) infection based on the
 results of testing for HBsAg and HBcAb as follows: Patients positive for HBsAg or
 HBcAb are excluded

 -  A positive test for Hepatitis C antibody

 -  HIV: known to have a historically positive HIV test or tests positive at screening for
 HIV.

 -  Laboratory abnormalities: has an abnormal laboratory assessment, which is judged
 clinically significant by the investigator.

 -  Drug Sensitivity: has a history of sensitivity to any of the study medications, or
 components thereof or a history of drug or other allergies including a previous
 anaphylactic reaction to parenteral administration contrast agents, human or murine
 proteins or monoclonal antibodies that, in the opinion of the investigator or Medical
 Monitor, contraindicates their participation.

 -  Any contraindication to undergoing MRI