Ofatumumab vs. Teriflunomide: Comparing Two Multiple Sclerosis Treatments
Table of Contents
Key Points
- Ofatumumab reduced annual relapse rates by about 50% compared to teriflunomide in two phase 3 trials.
- Disability progression risk was 32-34% lower with ofatumumab than with teriflunomide.
- MRI lesions and nerve damage biomarker levels were significantly lower with ofatumumab.
- Injection-related reactions were more common with ofatumumab, but serious infection rates were similar.
- The trials lasted up to 30 months, so long-term comparisons are not yet available.
Background: Understanding MS Treatment Options
Multiple sclerosis is a complex neurological condition where the immune system mistakenly attacks the protective covering of nerve fibers. Research has shown that B cells, a type of immune cell, play a significant role in this process. Ofatumumab is a subcutaneous (under-the-skin) medication that specifically targets and depletes B cells. It's a fully human antibody that binds to CD20 receptors on B cells differently than other similar medications.
Teriflunomide, taken orally once daily, works through a different mechanism by inhibiting pyrimidine synthesis, which reduces activation of both T cells and B cells. While both medications are approved for treating relapsing multiple sclerosis, their relative effectiveness hadn't been directly compared in large clinical trials until this research.
Previous studies suggested that teriflunomide has similar effectiveness to older injectable medications like interferons and glatiramer acetate, but might be less effective than newer oral treatments and monoclonal antibodies. This study aimed to provide clear, direct comparison data to help patients and doctors make more informed treatment decisions.
Study Methods: How the Research Was Conducted
The ASCLEPIOS I and II trials were two identical phase 3 clinical trials conducted simultaneously at multiple medical centers worldwide. These were double-blind, double-dummy studies, meaning neither patients nor researchers knew who was receiving which active medication. Patients received either both active medications or both placebos to maintain the blind.
Patients were randomly assigned to receive either:
- Subcutaneous ofatumumab (20 mg every 4 weeks after loading doses on days 1, 7, and 14) plus oral placebo
- Oral teriflunomide (14 mg daily) plus subcutaneous placebo injections
The treatment period lasted up to 30 months, with a median follow-up of 1.6 years. Patients learned to self-administer the subcutaneous injections after the first month under medical supervision. The trials were designed to detect a 40% difference in annual relapse rates between the two treatments with over 90% statistical power.
Researchers measured multiple outcomes including:
- Annualized relapse rate (number of confirmed MS relapses per year)
- Disability progression confirmed at 3 and 6 months
- Disability improvement confirmed at 6 months
- MRI measures of brain lesions and volume changes
- Blood levels of neurofilament light chain (a biomarker of nerve damage)
- Safety and side effect profiles
Patient Characteristics: Who Participated in the Trials
The trials included 1,882 patients total - 946 assigned to ofatumumab and 936 to teriflunomide. Participants were between 18-55 years old with relapsing forms of multiple sclerosis, including both relapsing-remitting MS and secondary progressive MS with ongoing disease activity.
Key patient characteristics at the start of the trials:
- Average age: 37.8-38.9 years across treatment groups
- Approximately 68% were women
- 94% had relapsing-remitting MS, 6% had secondary progressive MS with activity
- Average time since symptom onset: 8.2-8.4 years
- Average time since diagnosis: 5.5-5.8 years
- Approximately 40% had not received previous disease-modifying therapy
- Average Expanded Disability Status Scale (EDSS) score: 2.86-2.97 (moderate disability)
Patients had experienced an average of 1.2-1.3 relapses in the year before joining the trial. About 60% had no gadolinium-enhancing lesions on their baseline MRI scans, indicating varying levels of disease activity among participants.
Key Findings: Detailed Results from Both Trials
The results demonstrated consistently superior outcomes for ofatumumab across both trials and multiple measurement types. The primary endpoint, annualized relapse rate, showed dramatic differences between the two treatments.
In ASCLEPIOS I Trial:
- Ofatumumab group: 0.11 relapses per year
- Teriflunomide group: 0.22 relapses per year
- Difference: -0.11 (95% CI: -0.16 to -0.06)
- Statistical significance: P<0.001 (highly significant)
In ASCLEPIOS II Trial:
- Ofatumumab group: 0.10 relapses per year
- Teriflunomide group: 0.25 relapses per year
- Difference: -0.15 (95% CI: -0.20 to -0.09)
- Statistical significance: P<0.001 (highly significant)
When the data from both trials were combined, the disability outcomes also favored ofatumumab:
- Disability worsening confirmed at 3 months: 10.9% with ofatumumab vs. 15.0% with teriflunomide (hazard ratio 0.66, P=0.002)
- Disability worsening confirmed at 6 months: 8.1% with ofatumumab vs. 12.0% with teriflunomide (hazard ratio 0.68, P=0.01)
- Disability improvement confirmed at 6 months: 11.0% with ofatumumab vs. 8.1% with teriflunomide (hazard ratio 1.35, P=0.09)
MRI results showed substantial benefits for ofatumumab:
- Number of gadolinium-enhancing lesions per scan: 0.03-0.05 with ofatumumab vs. 0.24-0.51 with teriflunomide (rate ratios 0.10-0.11, P<0.001)
- Annual rate of new or enlarging T2 lesions: 0.72-1.41 with ofatumumab vs. 4.00-5.01 with teriflunomide (rate ratios 0.18-0.28, P<0.001)
- Serum neurofilament light chain levels (a biomarker of nerve damage) were significantly lower with ofatumumab at month 3 and beyond
- Brain volume changes showed no significant difference between treatments
Safety Profile: Side Effects and Adverse Events
Both treatments demonstrated generally favorable safety profiles, though with some differences in specific side effects. The most notable difference was in injection-related reactions, which were more common with ofatumumab.
Key safety findings:
- Injection-related reactions: 20.2% with ofatumumab vs. 15.0% with teriflunomide (placebo injections)
- Serious infections: 2.5% with ofatumumab vs. 1.8% with teriflunomide
- No unexpected safety signals emerged for either treatment
- The safety profile was consistent with what was previously known about these medications
The similar rates of serious infections between the two treatments is particularly noteworthy, as B-cell depleting therapies like ofatumumab might be expected to carry higher infection risks. The fact that infection rates were comparable suggests that ofatumumab's targeted mechanism provides efficacy without excessively compromising infection-fighting capability.
Conclusions: What the Research Means for Patients
This head-to-head comparison provides strong evidence that ofatumumab is more effective than teriflunomide across multiple important measures of multiple sclerosis disease activity. The approximately 50% reduction in annual relapse rates represents a clinically meaningful difference that could significantly impact patients' quality of life.
The disability outcomes are particularly important, as preventing long-term disability accumulation is a primary goal of MS treatment. The 32-34% reduction in risk of disability progression with ofatumumab suggests this treatment may provide better long-term protection against permanent neurological damage.
The MRI results provide biological evidence supporting the clinical findings, showing substantially reduced inflammatory activity and lesion formation in the ofatumumab group. The reduction in neurofilament light chain levels further supports that ofatumumab more effectively reduces the underlying nerve damage process in MS.
Study Limitations: What the Research Couldn't Show
While these trials provide valuable comparative data, several limitations should be considered. The follow-up period of approximately 1.6 years is relatively short for a chronic condition like MS that evolves over decades. Longer-term data would be needed to understand how these treatments compare over extended periods.
The trials excluded patients with certain comorbidities and those who had received specific previous treatments, so the results may not fully apply to all MS patients in clinical practice. Additionally, the study population was primarily patients with relapsing-remitting MS, so the results may be less applicable to those with progressive forms without relapse activity.
The double-dummy design meant all patients received both injections and pills, which might affect how these results translate to real-world settings where patients typically receive only one formulation. Patient preferences for injection versus oral therapy weren't assessed in this study.
Patient Recommendations: Considering Your Options
Based on these findings, patients and clinicians should consider several factors when choosing between these treatments:
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Efficacy priorities: If maximizing relapse reduction and disability protection is the primary goal, ofatumumab demonstrated superior effectiveness
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Administration preferences: Ofatumumab requires monthly subcutaneous injections after initial loading doses, while teriflunomide is a daily oral medication
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Side effect profile: Ofatumumab had higher rates of injection reactions, while both had similar infection risks
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Individual risk factors: Personal medical history and specific concerns should guide shared decision-making with your neurologist
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Insurance coverage: Practical considerations like insurance approval and out-of-pocket costs may influence treatment choices
These results provide the highest quality evidence available for comparing these two treatment approaches. Patients currently taking teriflunomide who continue to experience disease activity might discuss with their doctors whether switching to ofatumumab or another higher-efficacy therapy could provide better disease control.
Frequently Asked Questions
Which MS treatment is more effective: ofatumumab or teriflunomide?
According to the ASCLEPIOS I and II trials, ofatumumab was more effective than teriflunomide across multiple measures. It reduced annual relapse rates by about half, lowered the risk of disability progression by roughly one-third, and showed greater reductions in MRI lesions and nerve damage biomarkers. These results suggest ofatumumab provides better disease control for relapsing MS.
What are the side effects of ofatumumab compared to teriflunomide?
Both treatments had generally favorable safety profiles. Injection-related reactions occurred in 20.2% of ofatumumab patients versus 15.0% with teriflunomide placebo injections. Serious infection rates were similar: 2.5% with ofatumumab and 1.8% with teriflunomide. No unexpected safety signals emerged, and the infection risk with ofatumumab was comparable despite its B-cell depleting mechanism.
Why does MS come back after treatment with teriflunomide?
The article explains that teriflunomide may be less effective than newer treatments like ofatumumab. In the trials, patients on teriflunomide had higher relapse rates and more disability progression. This suggests that for some patients, teriflunomide does not adequately control disease activity, leading to ongoing relapses and lesion formation. Switching to a higher-efficacy therapy may be considered.
How long did the clinical trials comparing ofatumumab and teriflunomide last?
The treatment period in the ASCLEPIOS I and II trials lasted up to 30 months, with a median follow-up of 1.6 years. This relatively short duration for a chronic condition like multiple sclerosis means longer-term data are still needed to understand how these treatments compare over extended periods.
What types of multiple sclerosis were included in the trials?
The trials included patients aged 18-55 with relapsing forms of multiple sclerosis, including relapsing-remitting MS and secondary progressive MS with ongoing disease activity. About 94% had relapsing-remitting MS and 6% had secondary progressive MS with activity. Patients with progressive forms without relapse activity were not included.
Were there any differences in serious infections between the two treatments?
Serious infections occurred in 2.5% of patients taking ofatumumab and 1.8% of those taking teriflunomide. This difference was not statistically significant, and the rates were similar. This is noteworthy because B-cell depleting therapies like ofatumumab might be expected to carry higher infection risks, but the data did not show that.
What should patients consider when choosing between ofatumumab and teriflunomide?
Patients should weigh efficacy priorities, administration preferences, side effect profiles, individual risk factors, and insurance coverage. Ofatumumab is more effective in reducing relapses and disability progression but requires monthly subcutaneous injections and has higher rates of injection reactions. Teriflunomide is a daily oral medication with similar infection risks. Shared decision-making with a neurologist is recommended.
Source Information
Original Article Title: Ofatumumab versus Teriflunomide in Multiple Sclerosis
Authors: S.L. Hauser, A. Bar-Or, J.A. Cohen, G. Comi, J. Correale, P.K. Coyle, A.H. Cross, J. de Seze, D. Leppert, X. Montalban, K. Selmaj, H. Wiendl, C. Kerloeguen, R. Willi, B. Li, A. Kakarieka, D. Tomic, A. Goodyear, R. Pingili, D.A. Häring, K. Ramanathan, M. Merschhemke, and L. Kappos, for the ASCLEPIOS I and ASCLEPIOS II Trial Groups
Publication: New England Journal of Medicine 2020;383:546-57
DOI: 10.1056/NEJMoa1917246
This patient-friendly article is based on peer-reviewed research from a major medical journal. It maintains all original data and findings while making the information accessible to patients and caregivers.
