Ofatumumab for Multiple Sclerosis: A Comprehensive Patient Guide to the Monthly Self-Injection Treatment

Table of Contents

• Introduction to Multiple Sclerosis and Ofatumumab
• The Role of B Cells and T Cells in MS
• How Anti-CD20 Antibodies Work Against MS
• Ofatumumab's Unique Mechanism of Action
• The 20 mg Subcutaneous Dosing Regimen
• Pharmacokinetics and Pharmacodynamics
• Clinical Trial Results and Efficacy
• Safety and Tolerability Profile
• What This Means for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction to Multiple Sclerosis and Ofatumumab

Multiple sclerosis (MS) is an autoimmune disease where the body's immune system attacks the protective covering of nerve fibers in the central nervous system, causing communication problems between your brain and the rest of your body. Approximately 2.8 million people worldwide live with MS, with about 309 cases per 100,000 people in the United States alone.

The most common form is relapsing-remitting MS (RRMS), which affects 85% of patients at diagnosis. Treatment options have expanded significantly, with ofatumumab representing a major advancement as the first fully human anti-CD20 monoclonal antibody approved for MS treatment.

Ofatumumab stands out because it's self-administered as a monthly subcutaneous injection rather than requiring intravenous infusions at medical facilities. Its human antibody structure means your body is less likely to develop antibodies against it compared to earlier treatments like rituximab.

The Role of B Cells and T Cells in MS

For decades, MS was considered primarily a T-cell mediated disease, but research now shows B cells play equally important roles. B cells contribute to MS through several mechanisms: presenting antigens to T cells, producing inflammatory chemicals that damage nerve cells, and forming abnormal lymphoid structures in the brain's protective membranes.

These B cell activities contribute to both MS relapses and the gradual progression of disability. CD20, a protein found on the surface of B cells throughout most of their life cycle, has become an important therapeutic target. While mainly on B cells, a small subset of T cells also carries CD20, and these particular T cells show increased inflammatory activity in MS patients.

How Anti-CD20 Antibodies Work Against MS

Anti-CD20 antibodies selectively target memory B cells while sparing plasma cells (which don't express CD20). These treatments rapidly deplete circulating CD20+ B cells but have limited effects on B cells in lymph nodes and spleen.

In MS patients, peripheral B cells show abnormal pro-inflammatory responses, including excessive secretion of:

• Lymphotoxin-α
• TNF-alpha (tumor necrosis factor alpha)
• IL-6 (interleukin-6)
• GM-CSF (granulocyte macrophage-colony stimulating factor)

By depleting B cells, these treatments significantly reduce inflammatory activity in both CD4+ and CD8+ T cells, providing strong control over clinical relapses and inflammatory disease activity visible on MRI scans.

Ofatumumab's Unique Mechanism of Action

Ofatumumab is a fully human IgG1 monoclonal antibody with a molecular weight of approximately 146 kDa. It binds to a different part of the CD20 protein compared to rituximab, specifically targeting amino acid residues 74-80 and 145-161 on the extracellular loops.

This unique binding position near the cell membrane enhances complement-dependent cytotoxicity (CDC), which is ofatumumab's primary mechanism of action. In laboratory tests, ofatumumab showed 77.1% complement-dependent B-cell lysis compared to just 7.1% for ocrelizumab after 2 hours of exposure.

Ofatumumab also demonstrates approximately two-fold higher antibody-dependent cellular cytotoxicity (ADCC) activity compared to rituximab. It binds more tightly to B cells and dissociates more slowly, resulting in more efficient B-cell destruction and better suppression of inflammatory activity.

The 20 mg Subcutaneous Dosing Regimen

Ofatumumab is administered via subcutaneous injection using a specific dosing schedule: 20 mg weekly for the first three doses, followed by 20 mg monthly starting at week 4. This route of administration allows the medication to be absorbed through the lymphatic system, potentially enhancing targeting of B cells within this circulatory network.

Studies comparing delivery methods found subcutaneous ofatumumab demonstrates 20-fold higher potency for depleting circulating B cells compared to intravenous ocrelizumab, with comparable effects on non-circulating B cells. Research established that both 20 mg and 40 mg monthly subcutaneous doses achieve rapid and nearly complete B-cell depletion, while lower doses (1, 2, 5, or 10 mg) failed to achieve comparable results.

Pharmacokinetics and Pharmacodynamics

Ofatumumab has a steady-state half-life of approximately 16 days. A 20 mg subcutaneous dose every 4 weeks results in a mean maximum plasma concentration of 1.43 mcg/mL. The medication distributes through a volume of about 5.42 liters in the body.

The pharmacodynamic effects are impressive: in clinical trials, most patients achieved B cell counts below 10 cells/μL by day 14, with over 95% maintaining this reduction throughout treatment. In Phase III trials, 94% of patients reached B cell counts below 10 cells/μL by week 4.

After stopping treatment, the median time for B cells to recover to normal levels (40 cells/μL) was approximately 24.6 weeks, with modeling suggesting a range of 23 to 40 weeks. Importantly, ofatumumab's B cell depletion effectiveness doesn't vary based on patient weight, age, or initial B-cell count.

Clinical Trial Results and Efficacy

Ofatumumab has demonstrated strong efficacy across multiple clinical trials involving thousands of patients. The Phase 2 MIRROR study showed a 65% reduction in new gadolinium-enhancing brain lesions across all ofatumumab groups compared to placebo. Post-analysis revealed even greater reductions ranging from 71% to 92%.

The large ASCLEPIOS I and II Phase 3 trials compared ofatumumab to teriflunomide, a standard MS therapy. Results showed:

• ASCLEPIOS I: Annualized relapse rate of 0.11 with ofatumumab vs. 0.22 with teriflunomide
• ASCLEPIOS II: Annualized relapse rate of 0.10 with ofatumumab vs. 0.25 with teriflunomide
• Confirmed disability worsening reduced by 34% at 3 months and 32% at 6 months

The APOLITOS trial demonstrated a 93.6% reduction in gadolinium-enhancing T1 lesions compared to placebo, with consistent results across different regions. Patients who switched from placebo to ofatumumab saw their annualized relapse rate drop from 0.684 to 0.083.

The long-term ALITHIOS extension study followed patients for up to 6 years, showing:

• 44% fewer relapses
• 96.4% and 82.7% reductions in MRI lesions (Gd+ T1 and new/enlarging T2)
• 24.5% and 21.6% fewer confirmed disability worsening events

Safety and Tolerability Profile

Ofatumumab exhibits a manageable safety profile with adverse events primarily comprising infections and injection-related reactions. In clinical trials, injection-related reactions occurred in 20.2% of ofatumumab patients compared to 15.0% in the teriflunomide group.

Most adverse events were mild to moderate in severity. Serious adverse events were comparable between treatment groups, and no deaths were attributed to ofatumumab treatment across the clinical trial program. The medication showed no increased risk of opportunistic infections or malignancies compared to other MS treatments.

The human structure of ofatumumab contributes to lower immunogenicity, meaning patients are less likely to develop antibodies against the treatment itself, which can sometimes reduce effectiveness with other biologic medications.

What This Means for Patients

Ofatumumab represents a significant advancement in MS treatment by offering patients a highly effective therapy they can self-administer at home. The monthly subcutaneous injection provides comparable or superior efficacy to intravenous alternatives while offering greater convenience and flexibility.

The near-complete B-cell depletion achieved with the 20 mg monthly dosing regimen translates to robust control of disease activity, with clinical trials demonstrating reductions in relapse rates exceeding 50%, MRI lesion reduction over 90%, and significant delay in disability progression.

For patients who have struggled with infusion reactions to other medications, ofatumumab's human antibody structure may offer better tolerability. The predictable pharmacokinetics mean effectiveness doesn't vary based on patient weight, making dosing straightforward across diverse patient populations.

Study Limitations

While the clinical data for ofatumumab is compelling, some limitations should be noted. The comparison in most trials was against teriflunomide rather than other high-efficacy B-cell therapies, making direct comparisons to other anti-CD20 treatments more difficult.

Long-term safety data beyond 6 years is still being collected, though the ongoing ALITHIOS extension study continues to provide valuable information. As with all MS treatments, individual responses may vary, and some patients may not achieve the same level of B-cell depletion or clinical benefit.

The studies primarily included patients with relapsing forms of MS, so data for progressive forms without relapse activity is more limited. Additionally, while the self-administration is convenient, it requires proper training and comfort with injection techniques.

Patient Recommendations

If you're considering ofatumumab for your MS treatment, here are important points to discuss with your neurologist:

1. Evaluate treatment goals: Ofatumumab may be particularly suitable if you seek high efficacy with convenient monthly self-administration
2. Review vaccination status: Since ofatumumab depletes B cells, ensure vaccinations are up-to-date before starting treatment
3. Understand monitoring requirements: Regular blood tests will be needed to monitor B-cell levels and overall health
4. Learn proper injection technique: Training will be provided, but comfort with self-injection is important
5. Discuss infection precautions: While the infection risk is manageable, you should understand signs to watch for
6. Consider insurance coverage: Verify that your insurance covers this medication and understand any out-of-pocket costs

Ofatumumab has shown particularly strong results for patients who have had inadequate response to other therapies or who prefer the convenience of home-based administration over regular infusion center visits.

Source Information

Original Article Title: Profile of Ofatumumab in the Treatment of Multiple Sclerosis: Design, Development and Place in Therapy

Authors: Zeinab Awada, Natasha Hameed, Asaff Harel

Affiliation: Northwell Comprehensive Multiple Sclerosis Center, Department of Neurology, New York, NY, USA

Publication: Drug Design, Development and Therapy 2024:18 5985–5996

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible while preserving all scientific data and findings from the original publication.