Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis

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 ofatumumab 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 ofatumumab 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.