Long-Term Safety of Ofatumumab for Relapsing Multiple Sclerosis: 3.5-Year Follow-Up Results

Table of Contents

• Introduction: Understanding Ofatumumab Treatment
• Study Methods and Patient Population
• Patient Demographics and Treatment Exposure
• Key Safety Findings
• Detailed Infection Analysis
• Immunoglobulin Level Changes
• What These Findings Mean for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Understanding Ofatumumab Treatment

Ofatumumab is the first fully human anti-CD20 monoclonal antibody approved for treating relapsing forms of multiple sclerosis (RMS). Unlike other medications derived from animal sources, ofatumumab is created entirely from human gene sequences, which typically means it has lower potential to cause immune reactions. This medication works by targeting CD20 receptors on B-cells, which play a significant role in multiple sclerosis inflammation and damage.

The treatment involves subcutaneous injections with an initial loading dose at weeks 0, 1, and 2, followed by monthly 20 mg maintenance doses. Previous research established its effectiveness in controlling RMS, but understanding long-term safety requires extended follow-up studies. This analysis provides comprehensive safety data from patients treated with ofatumumab for up to 3.5 years, offering valuable insights for patients considering long-term treatment.

Study Methods and Patient Population

This analysis combined data from multiple clinical trials to assess long-term safety. Patients who completed the phase 3 ASCLEPIOS I/II trials, phase 2 APLIOS trial, or phase 2 APOLITOS trial could enter the ALITHIOS extension study. ALITHIOS is an ongoing phase 3b, open-label trial that began in November 2018 and is expected to continue until 2029.

The safety analysis included 1,969 patients divided into two groups: 1,292 patients who continued ofatumumab treatment from previous studies (continuous group), and 677 patients who switched from teriflunomide to ofatumumab (newly switched group). Researchers collected comprehensive safety data, including adverse events, laboratory values, and specific monitoring for infections, malignancies, and immunoglobulin levels.

The analysis period extended from each patient's first ofatumumab dose until 100 days after their last dose, with data collected up to January 29, 2021. This thorough approach ensured capture of both immediate and delayed safety signals, providing a complete picture of the medication's safety profile.

Patient Demographics and Treatment Exposure

The patient population reflected typical multiple sclerosis demographics. The 1,969 patients had a mean age of 38.7 years, with 68.3% being female. Most patients (94.9%) had relapsing-remitting MS, while 5.1% had secondary progressive MS. The average time since diagnosis was 6.4 years, and patients had moderate disability levels with an average Expanded Disability Status Scale (EDSS) score of 2.9.

Treatment exposure varied between groups. The continuous ofatumumab group had substantial treatment duration with a median time-at-risk of 35.5 months (approximately 3 years), totaling 3,253 patient-years of exposure. The newly switched group had a median time-at-risk of 18.3 months (approximately 1.5 years), totaling 986 patient-years. Importantly, 92.1% of patients who entered the extension study were still receiving ofatumumab at the time of data analysis, indicating good treatment persistence.

Key Safety Findings

The overall safety profile remained consistent with previous shorter-term studies. Among all 1,969 patients, 1,650 (83.8%) experienced at least one adverse event. However, most events were mild to moderate in severity. Only 9.0% of patients experienced grade 3 or 4 (severe) adverse events, and just 9.7% experienced serious adverse events.

The exposure-adjusted incidence rates (EAIR) per 100 patient-years were:

• 148.7 for any adverse event
• 4.8 for serious adverse events
• 5.8 for adverse events leading to treatment discontinuation

Injection-related reactions were common but generally manageable. Systemic reactions (occurring within 24 hours of injection) affected 24.8% of patients, while injection-site reactions affected 11.5%. These reactions were most frequent after the first injection and decreased with subsequent doses. Only six patients discontinued treatment due to injection-related reactions.

Two deaths occurred during the study, both in the continuous treatment group. One patient died from COVID-19 pneumonia, and another died by suicide. Neither death was considered related to ofatumumab treatment by the investigators.

Detailed Infection Analysis

Infections were carefully monitored throughout the study. Overall, 1,070 patients (54.3%) experienced infections, with an exposure-adjusted incidence rate of 44.1 per 100 patient-years. The most common infections were:

• Nasopharyngitis (common cold): 16.8% of patients
• Upper respiratory tract infections: 10.3% of patients
• Urinary tract infections: 9.8% of patients
• COVID-19: 5.8% of patients

Serious infections occurred in 58 patients (2.9%), with an exposure-adjusted incidence rate of 1.4 per 100 patient-years. The most frequent serious infections were appendicitis (0.6%), pneumonia (0.5%), and COVID-19 pneumonia (0.4%). Importantly, researchers identified no opportunistic infections, hepatitis B reactivations, or cases of progressive multifocal leukoencephalopathy (PML), which are serious concerns with some immunosuppressive therapies.

The infection rates remained stable over time and did not increase with longer treatment duration, which is reassuring for patients considering long-term therapy.

Immunoglobulin Level Changes

Immunoglobulin levels were closely monitored because ofatumumab affects B-cells, which produce these important immune proteins. The study found that mean IgG levels remained stable throughout the treatment period. However, mean IgM levels decreased over time but remained above the lower limit of normal in most patients.

Specifically, 10.9% of patients experienced decreased IgM levels, and this was the most common reason for treatment discontinuation (53 patients, representing 46.1% of all discontinuations). The study protocol required treatment interruption if immunoglobulin levels dropped significantly, which contributed to these discontinuations.

Crucially, decreased immunoglobulin levels were not associated with an increased risk of serious infections. This is an important finding because it suggests that the observed changes in immunoglobulin levels may not have clinical significance for infection risk in most patients.

What These Findings Mean for Patients

This extended follow-up study provides reassuring data for patients considering long-term ofatumumab treatment. The safety profile remains consistent over time, with no new safety concerns emerging with up to 3.5 years of continuous treatment. The low rates of serious infections and absence of opportunistic infections or PML are particularly encouraging.

For patients switching from teriflunomide to ofatumumab, the safety profile was similar to that of patients continuing long-term treatment, though the newly switched group had slightly lower rates of adverse events overall (77.1% versus 87.3% in the continuous group). This suggests that switching to ofatumumab is generally well-tolerated.

The stable IgG levels and manageable IgM decreases, without associated increased infection risk, suggest that the biological effects of B-cell depletion with ofatumumab do not translate to clinically significant immune impairment for most patients. This supports the medication's favorable benefit-risk profile for long-term RMS management.

Study Limitations

While this study provides valuable long-term safety data, several limitations should be considered. The study was open-label, meaning both patients and doctors knew they were receiving ofatumumab, which could potentially influence reporting of adverse events. However, this design reflects real-world clinical practice more accurately than double-blind studies.

The follow-up duration, while substantial at up to 3.5 years, may still be insufficient to detect very rare or very late-occurring adverse events. The ongoing nature of the ALITHIOS trial will provide even longer-term data as the study continues through 2029.

The patient population consisted of clinical trial participants who met specific inclusion criteria, which may not fully represent all multiple sclerosis patients in clinical practice. However, the large sample size (1,969 patients) and diverse geographic representation strengthen the generalizability of the findings.

Patient Recommendations

Based on these comprehensive safety findings, patients considering ofatumumab treatment can be reassured about its long-term safety profile. However, several practical recommendations emerge from this research:

1. Expect manageable injection reactions: Most injection-related reactions occur after the first dose and decrease with subsequent injections. Premedication may help reduce these reactions.
2. Monitor for infections: While serious infections were uncommon, patients should remain vigilant about infection prevention and report any signs of infection promptly to their healthcare providers.
3. Regular monitoring is important The study protocol included regular laboratory monitoring, particularly for immunoglobulin levels. Patients should maintain recommended laboratory follow-up as advised by their physicians.
4. Long-term treatment appears sustainable: The high continuation rate (92.1% of patients remaining on treatment) suggests that most patients tolerate long-term ofatumumab well.
5. Discuss switching considerations: For patients considering switching from other therapies, the data show that transitioning to ofatumumab is generally well-tolerated with a similar safety profile to long-term users.

Source Information

Original Article Title: Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years

Authors: Stephen L Hauser, Anne H Cross, Kevin Winthrop, Heinz Wiendl, Jacqueline Nicholas, Sven G Meuth, Paul S Giacomini, Francesco Saccà, Linda Mancione, Ronald Zielman, Morten Bagger, Ayan Das Gupta, Dieter A Häring, Valentine Jehl, Bernd C Kieseier, Ratnakar Pingili, Dee Stoneman, Wendy Su, Roman Willi, Ludwig Kappos

Publication: Multiple Sclerosis Journal 2022, Vol. 28(10) 1576–1590

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 patients and caregivers.