Ofatumumab is a novel immunoglobulin G (IgG) 1ĸ lytic monoclonal antibody (mAb) that specifically binds to the human CD20 antigen of which expression is restricted to B lymphocytes from the pre-B cell stage to the plasmacytoid immunoblast stage only. A recent trial with rituximab demonstrated that targeting B-cells reduces the number of gadolinium-enhancing (GdE) T1 lesions and the relapse rate in Relapsing-Remitting Multiple Sclerosis (RRMS). The intravenous (IV) formulation of ofatumumab has been shown to be both well-tolerated and efficacious in Phase I/II & III clinical trials within in B-cell Chronic Lymphocytic Leukemia (B-CLL), non-Hodgkin's Follicular Lymphoma (FL), and active Rheumatoid Arthritis (RA). A Phase II study of ofatumumab in Relapsing Remitting Multiple Sclerosis (RRMS) subjects, OMS115102 (also known as Study GEN414) is ongoing as of the development of this protocol. The primary objective of the OMS115102 protocol was to investigate the safety of a range of doses (100mg, 300 mg, and 700 mg) of ofatumumab in RRMS subjects, using an IV formulation. The treatment period for OMS115102 has been completed; there are currently 4 subjects ongoing in the Individualized Follow up Phase. In the Week 0 to 24 period the majority of subject who were exposed to active treatment with ofatumumab (active/placebo) had Cluster of Differentiation 19 (CD19+) and CD20+ levels that were suppressed to zero; recovery started for the 100 mg and 300 mg active/placebo groups, at approximately, 12 and 20 weeks after discontinuation of dosing with ofatumumab, respectively. In the 700 mg active/placebo group, all but one subject had a persistent and complete CD19+ suppression at Week 24. In the Week 24 to 48 period, when those who had previously been exposed to placebo were treated with ofatumumab (placebo/active), the majority of the subjects treated with ofatumumab had CD19+ and CD20+ cell levels suppressed to zero (mm3) within one week. Recovery started for the subjects in the 100 mg placebo/active group after approximately 16 weeks (from these subjects' first infusion). In the 300 mg and 700 mg placebo/active groups, all subjects except one (700 mg) had persistent and complete CD19+ suppression at Week 48.

This study will evaluate the magnetic resonance imaging (MRI) efficacy and will investigate the safety of <em>ofatumumab</em> using a subcutaneous (SQ) formulation in subjects with RRMS. This Phase II study will be a multi-center, randomized, double-blind, placebo-controlled, dose ranging study in subjects with RRMS. Randomization will be stratified based on the absence or presence of GdE brain lesions present at screening. The core 54 week period of the study is made up of an up to 6-week Screening Phase, a 24-week Treatment Phase, and a 24-week Follow-up Phase. Subjects will attend the clinic a total of approximately twelve times (including Screening) during this core 54-week period of the study. Subjects who have remained enrolled and participate in the study from Screening though the end of the 24-Week Follow-Up Period (Week 48 Visit) will be considered completers. Upon completion or withdrawal from the core study period, subjects will be followed in the Individualized Follow-up Phase. Subjects will return to the clinic every 12 weeks for a B-cell count and other safety assessments. Subjects will remain in Individualized Follow-up (IFU) until CD19+ B-lymphocyte counts recover to LLN or baseline (if <LLN);OR if B-cell counts have not recovered by the Week 120 visit (100 weeks after the last possible treatment dose at Week 20), until either the B-cell counts or circulating IgG are>>LLN or baseline levels (if <LLN). Male and female subjects with a diagnosis of RRMS will be screened for eligibility for the study. All non-MRI screening procedures should generally be completed within 14 days of informed consent being given. To the extent possible, investigators are to verify subjects meet all non MRI-related entry criteria before performing screening MRIs. Subjects who meet all inclusion and exclusion criteria will be centrally randomized into the study at the Baseline Visit (Week 0) to receive one of the following treatment arms: SQ administration of <em>ofatumumab</em> 3 mg, 30 mg, or 60 mg every 12 weeks, 60 mg every 4 weeks, or placebo. Half of the subjects randomized to the 30 mg group, or to either of the 60 mg groups, will receive a 3 mg conditioning dose at Week 0. Based on tolerability observed in other indications, the 3 mg conditioning dose may produce a more gradual lysis of B-cells, thereby reducing the cytokine release reactions to the initial 30 mg or 60 mg dose and potentially improve tolerability for subjects. The Treatment Phase lasts for 24 weeks and the subject will be seen 8 times during this phase. Upon completion or discontinuation of the Treatment Phase, subjects will enter a 24-week Follow-up Phase, during which they will not receive investigational product. Ideally, no other MS disease-modifying therapies should be taken during this period in order to allow for a clean analysis of safety data and the potential for Cluster of Differentiation (CD)+19 B-lymphocyte cell and immunoglobulin normalization to be assessed. However, if the start of a MS disease-modifying therapy is considered medically necessary, follow up will continue through the completion of the 24-Week Follow-up Phase. The subject will then be withdrawn from the study, and will not enter into the Individualized Follow-up Phase. Upon completion of the 24-Week Follow-up Phase, all subjects who have not started an MS disease modifying therapy (DMT) will enter the Individualized Follow up. During this Phase, subjects will return to the clinic every 12 weeks for a B-cell count and other safety assessments. If a subject starts a MS DMT during this follow-up phase they will be withdrawn from the study. To the extent possible, subjects experiencing a relapse during the study should return immediately to the clinic for evaluation. All MRI scans will be sent to a central reader for analysis. An Independent Data Monitoring Committee (IDMC) will evaluate risks relative to benefits through review of safety and efficacy information on an ongoing basis during the study. Approximately 245 subjects will be screened to provide around 196 subjects for randomization into the study. Assuming an attrition rate of 10% between the baseline visit and the six-month treatment visit, this will provide approximately 176 evaluable subjects.

The trial consists of two phases, a 48 week treatment period, followed by an individualized treatment period of up to two years.

Patients are treated in cohorts of increasing doses (100 mg, 300 mg and 700 mg) with 12 patients in each dose cohort. Within each cohort patients are randomized asymmetrically in a 2:1 ratio such that eight patients will receive ofatumumab and four patients will receive placebo. After 24 weeks the patients randomized to placebo will be treated with the active dose for the cohort. For blinding purposes, patients randomized to the active dose will be treated with placebo after 24 weeks. Thus, each patient will receive two administrations of trial product with 24 weeks follow-up resulting in a total treatment period of 48 weeks duration. An Independent Data Monitoring Committee (IDMC) will review and evaluate the safety data of each cohort, a minimum of 4 weeks data including the week 4 Magnetic Resonance Imaging (MRI) from at least 10 patients, to consider if progression to the next higher dose cohort is acceptable.

The trial product is administered as two infusions separated by two weeks. Clinical assessment and Gadolinium enhanced (Gd-enhanced) MRI scan will be performed at weeks -4, 0, 2, 4, and every 4 weeks until week 48. The MRI scan at week 2 is carried out for safety assessment prior to administering the second infusion in the first treatment course. When patients in all dose cohorts have been dosed and have had week 4 MRI scans performed, an IDMC will review all available safety data.

After completion of week 48 patients will be followed to monitor B-cell and IgG normalization. B-cell levels will be monitored every 12 weeks until CD19+ cells have returned to baseline level (Visit 3) or normalized level. If the B-cell levels are not normalized after two years the patient should be followed until either the IgG or the B-cell levels are normalized (see Section 9.2.4 for details). During this period Gd-enhanced MRI follow up scans will be performed every 12 weeks to evaluate potential rebound, safety and for Progressive Multifocal Leukoencephalopathy (PML) monitoring.

This is a randomized, double-blind, double-dummy, active comparator-controlled, parallel-group, multi-center study with variable treatment duration in approximately 900 patients with relapsing MS. The maximal treatment duration in the study for an individual patient will be 2.5 years.

Eligible patients will be randomized to receive either experimental ofatumumab subcutaneous (sc) injections every 4 weeks or active comparator teriflunomide orally once daily. In order to blind for the different formulations, double-dummy masking will be used i.e. all patients will take injections (containing either active ofatumumab or placebo) and oral capsules (containing either active teriflunomide or placebo).

This is a randomized, double-blind, double-dummy, active comparator-controlled, parallel-group, multicenter study with variable treatment duration in approximately 900 patients with relapsing MS. The maximal treatment duration in the study for an individual patient will be 2.5 years.

Eligible patients will be randomized to receive either experimental ofatumumab subcutaneous (sc) injections every 4 weeks or active comparator teriflunomide orally once daily. In order to blind for the different formulations, double-dummy masking will be used i.e. all patients will take injections (containing either active ofatumumab or placebo) and oral capsules (containing either active teriflunomide or placebo).

This study has 2 parts: A controlled Core and an open-label Extension.

- Core part: A 24-week, randomized, double-blind, placebo controlled, parallel-group, multicenter study to evaluate the efficacy, safety and tolerability and PK of ofatumumab in patients with relapsing MS.

- Extension part: The Core part is followed by an Extension part in which all patients receive open-label ofatumumab. In the Extension part, patients are treated for at least 24 weeks and no longer than 48 weeks.

Approximately 60 patients will be randomized in a 2:1 ratio to ofatumumab or placebo in the Core part; half of the study patients will be from Japan and the other half from the other countries.

This is a single-arm multi-center, study in approximately 100 participants with relapsing multiple sclerosis who were previously treated with aCD20 mAb therapy. Eligible participants will receive open label ofatumumab 20 mg subcutaneous every 4 weeks for 12 months following initial loading regimen of 20 milligrams subcutaneous doses on Days 1, 7 and 14. Assessments will include but are not limited to Magnetic Resonance Imaging (MRI) assessed for quality by central reading center, multiple Patient Reported Outcome measurements and safety assessments..Participants that do not continue onto commercial ofatumumab or another therapy within one month of the End of Study Visit must continue into the safety Follow Up phase, consisting of every 3 month visits including B cell monitoring until they are able to start on commercial ofatumumab or switch to another therapy or until their B cells are repleted defined as a B cell concentration greater than the individual participant's baseline value or greater than the lower limit of normal. All participants will have a safety follow-up phone call at 30 days post study.