Four-Year Ofatumumab Treatment Shows Strong Results for Relapsing Multiple Sclerosis Patients

Table of Contents

• Introduction: Understanding This Long-Term MS Treatment Study
• Study Design and Patient Groups
• Key Findings: How Well Ofatumumab Worked Over 4 Years
• Safety Results: Understanding Treatment Side Effects
• What These Results Mean for MS Patients
• Study Limitations and Considerations
• Recommendations for Patients
• Source Information

Introduction: Understanding This Long-Term MS Treatment Study

Ofatumumab is a fully human monoclonal antibody treatment that targets specific immune cells (B-cells) involved in multiple sclerosis. It's administered as a subcutaneous injection (under the skin) with an initial three weekly doses followed by monthly maintenance doses. The medication was originally approved based on two large Phase 3 clinical trials called ASCLEPIOS I and II, which showed superior effectiveness compared to teriflunomide (another MS medication) over approximately 2.5 years.

This current analysis extends our understanding of ofatumumab's performance by examining data from up to 4 years of treatment. The study combines information from the original trials with additional data from extension studies where patients continued receiving ofatumumab. This longer-term perspective is crucial for MS patients who typically require lifelong treatment, helping them and their doctors understand both the sustained benefits and long-term safety profile of this medication.

Study Design and Patient Groups

The research analyzed data from 1,882 patients with relapsing forms of MS who participated in the original ASCLEPIOS I and II trials. These patients were followed for up to 4 years through an open-label extension study called ALITHIOS. The study compared two main groups of patients to understand the importance of early versus delayed treatment with ofatumumab.

The continuous ofatumumab group included 946 patients who started ofatumumab at the beginning of the original trials and continued it throughout the extension period. The newly switched group included 936 patients who began with teriflunomide in the original trials and then switched to ofatumumab in the extension study. Patient characteristics were well-balanced between groups at the start of the study, with an average age of 38 years, approximately 67% female participants, and average Expanded Disability Status Scale (EDSS) scores around 2.9 (indicating moderate disability).

Researchers measured several important outcomes including annualized relapse rates (how often relapses occur), disability progression, MRI lesion activity (visible brain changes on scans), blood levels of neurofilament light chain (a marker of nerve damage), and a composite measure called NEDA-3 (no evidence of disease activity across three parameters). The safety analysis included 1,969 patients who received at least one dose of ofatumumab across all study phases.

Key Findings: How Well Ofatumumab Worked Over 4 Years

The results demonstrated impressive long-term effectiveness for both patient groups, with particularly strong outcomes for those who started ofatumumab earlier in their treatment journey.

Relapse Reduction

Patients continuously treated with ofatumumab maintained exceptionally low relapse rates throughout the 4-year period. The annualized relapse rate decreased from 0.11 relapses per year during the core study period to just 0.05 relapses per year during the extension period - a 49.4% reduction that translates to approximately one relapse every 20 years. Patients who switched from teriflunomide to ofatumumab experienced an even more dramatic 71.7% reduction in relapse rates, from 0.23 to 0.06 relapses per year.

The cumulative number of confirmed relapses was 43.4% lower in the continuous ofatumumab group compared to the switched group, demonstrating that earlier initiation provided better long-term relapse control. This difference was statistically highly significant (p < 0.001), meaning there's less than a 0.1% chance this result occurred by random chance.

Disability Progression

Ofatumumab effectively limited disability progression over the 4-year period. The cumulative rates of 3-month confirmed disability worsening (3mCDW) at month 48 were 19.1% for the continuous group versus 23.1% for the switched group. For 6-month confirmed disability worsening (6mCDW), the rates were 15.8% versus 18.9% respectively.

The continuous ofatumumab group experienced 17.9% fewer 3mCDW events and 16.0% fewer 6mCDW events compared to the switched group. These results suggest that earlier treatment initiation helps preserve physical function and mobility over the long term for MS patients.

MRI Lesion Activity

Brain MRI scans showed remarkable suppression of disease activity in both groups. The continuous ofatumumab group maintained near-complete suppression of gadolinium-enhancing (Gd+) T1 lesions (active inflammation markers), with rates decreasing from 0.02 to 0.01 lesions per scan between the core and extension periods - a 65% reduction.

Patients switching from teriflunomide experienced a dramatic 97.4% reduction in Gd+ T1 lesions after starting ofatumumab. The continuous group showed 95% fewer cumulative Gd+ T1 lesions compared to the switched group. Similarly, new/enlarging T2 lesions (indicating areas of disease activity) reduced by 87.9% in the continuous group and 86.6% in the switched group after transitioning to ofatumumab.

Blood Biomarker Results

Serum neurofilament light chain (sNfL) levels, a sensitive marker of nerve damage, remained significantly lower with continuous ofatumumab treatment compared to teriflunomide during the core period (8.03 pg/mL vs 10.25 pg/mL at month 12). Levels remained low throughout the extension period with continuous treatment. Patients switching from teriflunomide to ofatumumab experienced reduced sNfL levels, though they remained slightly higher than the continuous group for the first 6 months after switching.

No Evidence of Disease Activity (NEDA-3)

The proportion of patients achieving NEDA-3 status (no relapses, no disability progression, and no MRI activity) was significantly higher with early ofatumumab initiation. During the core period, 36.7% of continuous ofatumumab patients maintained NEDA-3 compared to 16.1% of teriflunomide patients. During the extension period, these rates improved to 78.8% and 51.0% respectively.

Overall, the likelihood of maintaining NEDA-3 for up to 4 years was over three times higher with early ofatumumab initiation. Patients who achieved NEDA-3 status in the first year of treatment were significantly more likely to maintain this status long-term, highlighting the importance of early effective treatment.

Safety Results: Understanding Treatment Side Effects

The safety profile of ofatumumab remained consistent with previous reports, with no new safety signals identified during the extended 4-year observation period. Among 1,969 patients in the safety analysis, 86.23% experienced at least one adverse event, with an exposure-adjusted incidence rate of 135.11 per 100 patient-years.

The most frequently reported adverse events were infections and infestations, affecting 58.35% of patients. However, serious infections were uncommon, occurring at a rate of 1.53 per 100 patient-years. The most frequent serious infections included COVID-19 infections (0.05% of patients) and appendicitis (0.7% of patients). Most serious infections (3.7% of patients) resolved without requiring treatment discontinuation.

Monitoring of immunoglobulin levels showed that mean IgG levels remained stable within the normal range throughout treatment. Mean IgM levels decreased but remained above the lower limit of normal. Very few patients required treatment interruption (0.1% for low IgG, 9.5% for low IgM) or discontinuation (0.1% for low IgG, 3.0% for low IgM) due to immunoglobulin changes.

What These Results Mean for MS Patients

This 4-year analysis provides compelling evidence supporting the long-term use of ofatumumab for relapsing multiple sclerosis. The data demonstrates that ofatumumab maintains its effectiveness over an extended period, with patients experiencing:

• Very low relapse rates (approximately one relapse every 20 years with continuous treatment)
• Minimal disability progression (15.8-19.1% risk over 4 years with continuous treatment)
• Near-complete suppression of new brain lesions on MRI scans
• High rates of disease activity freedom (78.8% achieving NEDA-3 with continuous treatment)

The study also provides important insights about treatment timing. Patients who started ofatumumab earlier showed better outcomes across all measures compared to those who switched from teriflunomide later. This supports the growing evidence that early initiation of high-efficacy therapies in MS leads to better long-term outcomes.

The safety profile remained consistent and manageable over 4 years, which is reassuring for patients considering long-term treatment with ofatumumab. The convenience of monthly subcutaneous self-administration at home, combined with this strong efficacy and safety data, makes ofatumumab a valuable treatment option for relapsing MS patients.

Study Limitations and Considerations

While this study provides valuable long-term data, several limitations should be considered. As an open-label extension study, both patients and doctors knew they were receiving ofatumumab, which could potentially influence some subjective measurements. The study compared early versus delayed ofatumumab initiation but did not include a concurrent control group receiving other treatments or placebo over the full 4-year period.

The patient population consisted of clinical trial participants who met specific inclusion criteria, which may not fully represent all MS patients in clinical practice. Additionally, the follow-up period of 4 years, while substantial, may not capture very long-term effects that could emerge over decades of treatment.

Despite these limitations, the study provides robust evidence supporting the long-term benefits of ofatumumab for relapsing MS patients, particularly when started early in the disease course.

Recommendations for Patients

Based on these findings, MS patients should consider the following:

1. Discuss high-efficacy treatment options early - The study supports early initiation of effective therapies like ofatumumab for better long-term outcomes
2. Understand the benefits of continuous treatment - Patients maintaining ofatumumab treatment showed excellent disease control over 4 years
3. Monitor for infections - While most infections were manageable, patients should be vigilant about infection prevention and report any signs promptly
4. Regular monitoring is important - Continue with recommended MRI scans and clinical assessments to track treatment effectiveness
5. Discuss switching considerations - If considering switching from another therapy, this study shows that transitioning to ofatumumab can significantly improve disease control

Patients should have detailed conversations with their neurologists about whether ofatumumab is appropriate for their individual situation, considering these long-term efficacy and safety results.

Source Information

Original Article Title: Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Authors: Stephen L Hauser, Ronald Zielman, Ayan Das Gupta, Jing Xi, Dee Stoneman, Goeril Karlsson, Derrick Robertson, Jeffrey A Cohen, Ludwig Kappos

Publication: Multiple Sclerosis Journal 2023, Vol. 29(11-12) 1452–1464

DOI: https://doi.org/10.1177/13524585231195346

This patient-friendly article is based on peer-reviewed research published in Multiple Sclerosis Journal.