Subcutaneous Ofatumumab for Relapsing-Remitting Multiple Sclerosis: A Comprehensive Patient Guide to the MIRROR Study

Table of Contents

• Introduction: Understanding the MIRROR Study
• Study Methods and Design
• Patient Characteristics and Recruitment
• Key Findings and Results
• Safety and Side Effects
• What This Means for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Understanding the MIRROR Study

Multiple sclerosis (MS) is a chronic neurological condition where the immune system mistakenly attacks the protective covering of nerve fibers. Relapsing-remitting multiple sclerosis (RRMS) is the most common form, characterized by periods of new or worsening symptoms (relapses) followed by periods of recovery. This groundbreaking study, called the MIRROR trial (Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis), investigated a new treatment approach using subcutaneous (under-the-skin) injections of ofatumumab.

Ofatumumab is a monoclonal antibody that targets CD20, a protein found on the surface of B cells. These immune cells play a significant role in the inflammation that damages nerves in MS. Previous research showed that intravenous (IV) anti-CD20 treatments could substantially reduce MS disease activity by depleting circulating B cells. However, this study explored whether subcutaneous administration could be equally effective while offering the convenience of at-home injections rather than clinic-based IV infusions.

The researchers specifically wanted to identify the minimally effective dose that could provide meaningful benefits while potentially minimizing side effects. This is particularly important for long-term treatment of chronic conditions like MS, where finding the right balance between efficacy and safety is crucial. The study also examined whether complete B-cell depletion was necessary for treatment effectiveness or if partial depletion could still provide significant benefits.

Study Methods and Design

The MIRROR study was a phase 2b clinical trial conducted at multiple medical centers following rigorous scientific standards. This was a randomized, double-blind, placebo-controlled study, meaning patients were randomly assigned to different treatment groups, and neither patients nor researchers knew who received the active drug versus placebo during the treatment period. This design helps eliminate bias and provides more reliable results.

The study involved 232 patients with relapsing forms of MS who were divided into five treatment groups:

• Placebo (inactive substance) group
• Ofatumumab 3 mg every 12 weeks
• Ofatumumab 30 mg every 12 weeks
• Ofatumumab 60 mg every 12 weeks
• Ofatumumab 60 mg every 4 weeks

The treatment period lasted 24 weeks, followed by a 24-week safety follow-up phase. Patients receiving placebo were given a single 3 mg dose of ofatumumab at week 12 for ethical reasons, ensuring no one remained on placebo for the entire study period. Some patients received a "conditioning dose" of 3 mg one week before their first full treatment dose to potentially reduce injection-related reactions by allowing more gradual B-cell depletion.

All patients received acetaminophen and an antihistamine before each injection to minimize potential reactions. The primary measurement of effectiveness was the cumulative number of new gadolinium-enhancing (GdE) lesions on brain MRI scans at week 12. Gadolinium is a contrast agent that highlights active inflammation and blood-brain barrier disruption, making new MS lesions visible on MRI scans.

Patient Characteristics and Recruitment

The study enrolled 231 patients who received at least one dose of study medication, with 228 included in the final efficacy analysis. Participants were between 18-55 years old with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5.5, meaning they had varying levels of disability from none to significant impairment affecting daily activities.

Patient characteristics were well-balanced across treatment groups:

• 67% were women
• 97% were white
• Average age was 37.2 years
• Average body mass index was 25.7 kg/m²
• Average disease duration was 4.38 years
• Patients had experienced an average of 1.3 relapses in the previous year
• 43% had active lesions on MRI scans in the previous year

Patients with prior use of experimental agents, most monoclonal antibodies (except natalizumab), or immunosuppressive agents were excluded from participation. However, prior use of other disease-modifying therapies was allowed, making the study population representative of typical MS patients seeking new treatment options.

Key Findings and Results

The primary results demonstrated that all ofatumumab dose groups showed significant reduction in new brain lesions compared to placebo. The cumulative number of new GdE lesions was reduced by 65% for all ofatumumab groups combined compared to placebo (p < 0.001), indicating a highly statistically significant treatment effect.

Post-hoc analysis (excluding weeks 1-4 to account for disease activity that began before treatment could take full effect) showed even more impressive results:

• All cumulative ofatumumab doses ≥30 mg per 12 weeks achieved ≥90% reduction in new lesions
• The reduction ranged from 71% to 92% across different dose groups
• These results were statistically significant (p ≤ 0.002) for all comparisons

The study revealed a clear dose-dependent B-cell depletion pattern:

• 60 mg every 4 weeks reduced B cells to <2% of baseline levels
• 30 mg and 60 mg every 12 weeks reduced B cells to approximately 5% of baseline
• 3 mg every 12 weeks reduced B cells to about 25% of baseline

Remarkably, complete B-cell depletion was not necessary for a robust treatment effect. Even the 3 mg dose (which only partially depleted B cells) significantly reduced new MRI lesions. This finding challenges the conventional thinking that near-complete B-cell depletion is required for effective MS treatment.

Clinical relapse rates showed a pattern consistent with MRI findings, though the differences did not reach statistical significance during the short 12-week placebo-controlled period. Over 24 weeks, 25% of placebo patients experienced relapses compared to 9%-22% across ofatumumab groups.

Safety and Side Effects

The safety profile of subcutaneous ofatumumab was generally manageable and consistent with existing data on ofatumumab. During the first 12 weeks, 64% of placebo patients and 74% of ofatumumab patients experienced adverse events. These events were largely mild to moderate in severity, and no patient deaths occurred during the study.

The most common adverse event was injection-related reactions (IRRs), which occurred in:

• 52% of ofatumumab patients overall (ranging from 41%-66% across dose groups)
• 15% of placebo patients
• 97% of these reactions were mild to moderate in severity
• Reactions were most common with the first dose (29%-50% of patients) and diminished with subsequent dosing (1%-18% at week 12)

Serious adverse events occurred in 3% of patients during weeks 0-12, including injection-related reactions in 3 patients. One patient experienced cytokine release syndrome within hours of the first 60 mg dose but continued in the study. Other serious events included cholelithiasis (gallstones), hypokalemia (low potassium), angioedema, and urticaria (hives), each occurring in single patients.

Infection rates were similar across treatment groups, with no cases of opportunistic infections (including progressive multifocal leukoencephalopathy) or hepatitis B reactivation. Only four patients developed antibodies against ofatumumab (human anti-human antibodies), and B-cell depletion occurred as expected in all these patients.

During the follow-up periods (weeks 24-48 and individualized follow-up), safety findings remained consistent with no new unexpected safety concerns. Most patients (64%-74%) across ofatumumab groups achieved B-cell repletion by study end, with median time to repletion approximately 11-14 months depending on the dose.

What This Means for Patients

This study provides compelling evidence that subcutaneous ofatumumab offers a promising new treatment approach for relapsing-remitting multiple sclerosis. The convenience of subcutaneous administration could significantly improve quality of life by potentially allowing at-home treatment rather than requiring regular clinic visits for IV infusions.

The finding that complete B-cell depletion isn't necessary for efficacy is particularly important. This suggests that lower doses might provide meaningful clinical benefits while potentially reducing the risk of side effects associated with complete immune cell depletion. However, the optimal balance between efficacy and safety requires further investigation in longer-term studies.

The robust reduction in MRI lesions (65% overall, up to ≥90% with higher doses) strongly suggests that ofatumumab effectively suppresses the inflammatory activity that drives MS progression. While the study was relatively short for assessing clinical outcomes like disability progression, the dramatic reduction in lesion formation typically correlates with long-term clinical benefits.

The manageable safety profile, with injection reactions that predominantly occur with the first dose and diminish thereafter, suggests that most patients could tolerate this treatment well with appropriate premedication. The lack of serious opportunistic infections is reassuring, though longer and larger studies are needed to fully establish the safety profile.

Study Limitations

While the MIRROR study provides valuable insights, several limitations should be considered when interpreting the results. The relatively short 12-week primary efficacy period limits our understanding of long-term benefits and risks. Multiple sclerosis is a lifelong condition, and treatments must demonstrate sustained effectiveness and safety over years, not just months.

The study wasn't powered to detect differences in clinical outcomes like relapse rates or disability progression due to its short duration and relatively small sample size. While MRI lesions are important indicators of disease activity, they are surrogate markers that don't always perfectly correlate with how patients actually feel or function.

The population was predominantly white (97%), which may limit how well these findings apply to people of other racial and ethnic backgrounds. Additionally, the study excluded patients with more advanced disability (EDSS >5.5), so the results may not generalize to all MS patients.

Finally, the conditioning dose design (where some patients received a small 3 mg dose before their full treatment dose) may have influenced the results, though researchers believe this effect was minimal in the context of overall drug exposure.

Patient Recommendations

Based on the MIRROR study findings, patients with relapsing-remitting MS should consider the following:

1. Discuss subcutaneous treatment options with your neurologist, as this study demonstrates that subcutaneous administration can be highly effective while offering greater convenience than intravenous treatments.
2. Understand that injection reactions are common but typically diminish after the first dose. Premedication with acetaminophen and antihistamines can help manage these reactions.
3. Recognize that complete B-cell depletion may not be necessary for effective treatment. This could potentially allow for more flexible dosing strategies that maintain efficacy while minimizing side effects.
4. Participate in shared decision-making with your healthcare provider about treatment options, considering both the potential benefits and risks of any new therapy.
5. Stay informed about ongoing research, as longer-term phase 3 studies will provide more comprehensive data on clinical outcomes and long-term safety.

While these results are promising, patients should work closely with their healthcare providers to determine the most appropriate treatment approach based on their individual circumstances, disease activity, and treatment goals. Always consult with your neurologist before making any changes to your treatment regimen.

Source Information

Original Article Title: Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study

Authors: Amit Bar-Or, MD, Richard A. Grove, MSc, Daren J. Austin, PhD, Jerry M. Tolson, PhD, Susan A. VanMeter, MD, Eric W. Lewis, MD, Frederick J. Derosier, DO, Monica C. Lopez, Sarah T. Kavanagh, MPH, Aaron E. Miller, MD, and Per S. Sorensen, MD

Publication: Neurology 2018;90:e1805-e1814. doi:10.1212/WNL.0000000000005516

Note: This patient-friendly article is based on peer-reviewed research and aims to accurately represent the original study findings while making them accessible to non-specialist readers. For complete details, please refer to the original publication.