Ofatumumab Shows Superior Results Over Teriflunomide for Newly Diagnosed Multiple Sclerosis Patients. a48

Table of Contents

• Key Points
• Introduction: Why Early Treatment Matters in MS
• Study Methods: How the Research Was Conducted
• Participant Characteristics: Who Was in the Study
• Key Findings: Detailed Results with All Numbers
• Safety Profile: Treatment Side Effects and Tolerability
• Clinical Implications: What This Means for Patients
• Study Limitations: What the Research Couldn't Prove
• Recommendations: Actionable Advice for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Ofatumumab reduced annualized relapse rate by 50% compared to teriflunomide in newly diagnosed MS patients.
• Ofatumumab lowered risk of 6-month confirmed disability worsening by 46% versus teriflunomide.
• MRI lesions were reduced by 95% (gadolinium-enhancing) and 82% (new T2) with ofatumumab.
• Ofatumumab achieved NEDA-3 in 44.6% of patients over 24 months, versus 17.7% for teriflunomide.
• Serum neurofilament light chain levels were significantly lower with ofatumumab at 12 and 24 months.

Introduction: Why Early Treatment Matters in MS

Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (brain and spinal cord) in young adults, representing a leading cause of non-traumatic disability. For patients with relapsing MS (RMS), disability accumulation was previously thought to occur in stages—first driven by poor recovery from relapses, then by progression independent of relapses.

However, growing evidence shows that both relapses with incomplete recovery and progression independent of relapse activity (PIRA) contribute to disability from disease onset, though in different proportions. Research suggests that neuroaxonal loss—the main driver of neurodegeneration and irreversible progression in advanced MS—may already be significant in early RMS.

Younger patients with RMS typically show higher clinical and MRI disease activity, along with more pronounced acute axonal damage. Neuronal and brain volume loss begin early in the disease course, with high disability levels, high lesion load, and low brain volume associated with poor MS prognosis.

The effect of disease-modifying therapies (DMTs) on MS disability worsening is age-dependent, with younger patients and those earlier in their disease course showing the greatest benefit. This makes early treatment with high-efficacy DMTs that can slow disability accrual essential, though barriers often prevent early intervention with these more effective treatments.

Study Methods: How the Research Was Conducted

This analysis examined data from the phase III ASCLEPIOS I and II trials, which were randomized, double-blind, double-dummy, active-controlled, multicenter trials of identical design conducted concurrently in participants with relapsing multiple sclerosis. The trials are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

Participants were randomized (1:1 ratio) to receive either:

1. Ofatumumab: 20 mg subcutaneously every 4 weeks (starting at week 4 after initial dosing of 20 mg on days 1, 7, and 14)
2. Teriflunomide: 14 mg orally once daily

Treatment continued for up to 30 months. The analysis focused specifically on the protocol-defined recently diagnosed, treatment-naive (RDTN) subpopulation—participants who had received an RMS diagnosis within the 36-month period before screening and had no prior treatment with any disease-modifying therapy.

Researchers analyzed multiple endpoints to assess treatment benefits:

• Annualized relapse rate (ARR): number of confirmed MS relapses standardized to 1 year
• Confirmed disability worsening (CDW) at 3 and 6 months measured by Expanded Disability Status Scale (EDSS) changes
• Progression independent of relapse activity (PIRA) at 3 and 6 months
• MRI measures: gadolinium-enhancing T1 lesions, new/enlarging T2 lesions, brain volume changes
• No evidence of disease activity (NEDA-3): no relapses, no disability worsening, no MRI activity
• Neurofilament light chain (NfL) concentration: a biomarker of nerve damage
• Safety outcomes: adverse events, serious adverse events, and discontinuation rates

Participant Characteristics: Who Was in the Study

Of the 1,882 participants in the overall ASCLEPIOS trials, 615 (32.7%) met the criteria for recently diagnosed, treatment-naive MS patients. These participants were divided into:

• Ofatumumab group: 314 patients
• Teriflunomide group: 301 patients

RDTN participants had been diagnosed with MS very recently—a median of 0.35 years for ofatumumab patients and 0.36 years for teriflunomide patients, with a range of 0.1–2.9 years from diagnosis for both groups.

Key demographic and disease characteristics showed:

• Average age: 36.8 years (ofatumumab) vs. 35.7 years (teriflunomide)
• Gender: 69.1% women (ofatumumab) vs. 64.8% women (teriflunomide)
• MS type: 99% had relapsing-remitting MS (RRMS) in both groups
• Average EDSS score: 2.30 (ofatumumab) vs. 2.28 (teriflunomide)—indicating mild disability
• 44.9% of ofatumumab patients and 43.2% of teriflunomide patients had gadolinium-enhancing lesions at baseline

Compared to the overall trial population, RDTN participants were younger with lower disability scores and lower total T2 lesion volume, as expected for recently diagnosed patients.

Treatment exposure was substantial:

• Median duration: 1.7 years (ofatumumab) vs. 1.6 years (teriflunomide)
• 90% of patients received treatment for more than 1 year
• Over 25% received treatment for more than 2 years

Compliance was excellent—98.8% for ofatumumab and 98.9% for teriflunomide, with 54.5% and 58.5% achieving perfect compliance, respectively.

Key Findings: Detailed Results with All Numbers

The results demonstrated significant advantages for ofatumumab across multiple measures of MS disease activity and progression.

Relapse Reduction: Ofatumumab reduced the annualized relapse rate by 50% compared to teriflunomide:

• ARR: 0.09 (ofatumumab) vs. 0.18 (teriflunomide)
• Rate ratio: 0.50 (95% CI: 0.33, 0.74)
• Statistical significance: p < 0.001

Disability Progression: Ofatumumab significantly delayed confirmed disability worsening:

• 3-month CDW: 38% risk reduction (HR: 0.62; 95% CI: 0.37, 1.03; p = 0.065)
• 6-month CDW: 46% risk reduction (HR: 0.54; 95% CI: 0.30, 0.98; p = 0.044)

Over half of all disability worsening events occurred without relapses (progression independent of relapse activity):

• 3mCDW events: 13/24 (ofatumumab) vs. 20/37 (teriflunomide) were PIRA
• 6mCDW events: 9/17 (ofatumumab) vs. 17/30 (teriflunomide) were PIRA

PIRA (Progression Independent of Relapse Activity): In patients without confirmed relapses:

• 3mPIRA: 6.6% (ofatumumab) vs. 9.1% (teriflunomide); HR: 0.55 (0.27, 1.11); p = 0.096
• 6mPIRA: 3.6% (ofatumumab) vs. 7.7% (teriflunomide); HR: 0.44 (0.20, 1.00); p = 0.049

MRI Outcomes: Ofatumumab dramatically reduced MRI disease activity:

• Gadolinium-enhancing T1 lesions: 95% reduction (0.02 vs. 0.39 lesions per scan; rate ratio: 0.05; p < 0.001)
• New/enlarging T2 lesions: 82% reduction (0.86 vs. 4.78 lesions per year; rate ratio: 0.18; p < 0.001)
• Brain volume loss: No significant difference between groups (-0.30% vs. -0.31% annually; p = 0.9)

No Evidence of Disease Activity (NEDA-3): Ofatumumab significantly increased the odds of achieving NEDA-3 (no relapses, no disability worsening, no MRI activity):

• Year 1: 47.0% vs. 24.7% (Odds ratio: 3.31; p < 0.001)
• Year 2: 92.1% vs. 46.8% (Odds ratio: 14.68; p < 0.001)
• Overall (0-24 months): 44.6% vs. 17.7% (Odds ratio: 4.63; p < 0.001)

Neurofilament Light Chain (Biomarker): Serum NfL concentrations (a marker of nerve damage) were significantly lower with ofatumumab:

• Month 3: 8.72 vs. 9.13 pg/mL (not significant)
• Month 12: 6.60 vs. 8.61 pg/mL (24% reduction; p < 0.001)
• Month 24: 6.47 vs. 8.10 pg/mL (20% reduction; p < 0.001)

Safety Profile: Treatment Side Effects and Tolerability

The safety findings in recently diagnosed, treatment-naive participants were manageable and consistent with the overall ASCLEPIOS population.

Overall Adverse Events:

• Ofatumumab: 84.7% of participants experienced any adverse event
• Teriflunomide: 86.0% of participants experienced any adverse event

Common Adverse Events (occurring in ≥10% of patients):

For ofatumumab:

• Nasopharyngitis (common cold)
• Injection-related systemic reactions
• Headache
• Upper respiratory tract infections

For teriflunomide:

• Nasopharyngitis
• Alopecia (hair loss)
• Upper respiratory tract infection
• Injection-related systemic reactions (from placebo injections)
• Headache
• Fatigue

Serious Adverse Events:

• Ofatumumab: 22 participants (7.0%)
• Teriflunomide: 16 participants (5.3%)
• No deaths occurred in either treatment group

Injection-Related Reactions:

• Injection-related systemic reactions: 20.1% (ofatumumab) vs. 15.0% (teriflunomide—receiving placebo injections)
• Injection-site reactions: 14.0% (ofatumumab) vs. 7.0% (teriflunomide)
• After the first injection, frequency of systemic reactions was similar between groups

Clinical Implications: What This Means for Patients

This analysis provides compelling evidence that ofatumumab offers superior efficacy compared to teriflunomide for recently diagnosed, treatment-naive multiple sclerosis patients. The 50% reduction in relapse rate, 46% reduction in disability progression, and significantly higher rates of achieving no evidence of disease activity demonstrate substantial clinical benefits.

For newly diagnosed MS patients, these findings suggest that starting with a high-efficacy therapy like ofatumumab may provide better long-term outcomes by more effectively controlling disease activity from the beginning. The significant reduction in progression independent of relapse activity is particularly important, as this type of disability accumulation occurs silently without obvious relapses.

The manageable safety profile and option for home administration without premedication make ofatumumab a practical choice for early treatment. The high compliance rates observed in the study suggest that patients generally tolerate the treatment well.

The dramatic reductions in MRI lesions (95% reduction in gadolinium-enhancing lesions and 82% reduction in new T2 lesions) indicate strong suppression of inflammatory activity, which may translate to better preservation of brain tissue over time.

Study Limitations: What the Research Couldn't Prove

While this analysis provides valuable insights, several limitations should be considered:

This was a post hoc analysis of a subset of participants from larger trials, not a pre-specified primary endpoint. The findings should be interpreted as exploratory rather than definitive.

The study duration of approximately 1.7 years median exposure is relatively short for assessing long-term disability outcomes in MS, which typically evolves over decades. Longer follow-up is needed to understand the full impact on disability progression.

The comparison was limited to teriflunomide rather than other high-efficacy disease-modifying therapies. The results don't demonstrate how ofatumumab compares to all available first-line treatment options.

The analysis focused on clinical and MRI outcomes but didn't include patient-reported outcomes or quality of life measures, which are important aspects of MS management from the patient perspective.

Finally, while the RDTN population represents an important subgroup, the results may not generalize to all MS patient populations, particularly those with longer disease duration or previous treatment exposure.

Recommendations: Actionable Advice for Patients

Based on these research findings, patients with recently diagnosed multiple sclerosis should consider the following:

Discuss High-Efficacy Early Treatment: Have a detailed conversation with your neurologist about the potential benefits of starting with high-efficacy therapy like ofatumumab rather than escalating from moderate-efficacy treatments. The evidence suggests this approach may better control disease activity from the beginning.

Understand Treatment Options: Learn about the different administration methods—ofatumumab is a monthly subcutaneous injection you can self-administer at home, while teriflunomide is a daily oral medication. Consider which approach best fits your lifestyle and preferences.

Monitor for Side Effects: Be aware of potential side effects with each medication. Ofatumumab may cause injection-related reactions, especially early in treatment, while teriflunomide may cause hair loss. Report any concerns to your healthcare team.

Regular Monitoring: Regardless of which treatment you choose, commit to regular follow-up and MRI monitoring as recommended by your neurologist. Early detection of disease activity allows for timely treatment adjustments.

Shared Decision-Making: Work collaboratively with your healthcare team to make treatment decisions that align with your goals, values, and lifestyle while considering the latest evidence about treatment efficacy and safety.

Frequently Asked Questions

How does ofatumumab compare to teriflunomide for newly diagnosed MS?

In the ASCLEPIOS trials, ofatumumab showed superior results over teriflunomide for recently diagnosed, treatment-naive MS patients. Ofatumumab reduced the annualized relapse rate by 50% and lowered the risk of 6-month confirmed disability worsening by 46%. MRI activity was also dramatically reduced, with 95% fewer gadolinium-enhancing lesions and 82% fewer new T2 lesions.

What are the side effects of ofatumumab versus teriflunomide?

The safety profiles were manageable for both drugs. Common side effects with ofatumumab included nasopharyngitis, injection-related systemic reactions, headache, and upper respiratory infections. Teriflunomide commonly caused nasopharyngitis, alopecia, and fatigue. Injection-site reactions occurred more with ofatumumab (14%) than teriflunomide placebo injections (7%). No deaths occurred in either group.

Why does MS disability progress even without relapses?

The article explains that progression independent of relapse activity (PIRA) contributes to disability from disease onset. In the study, over half of disability worsening events occurred without relapses. Ofatumumab reduced 6-month PIRA risk by 56% compared to teriflunomide, suggesting it may help slow this silent progression.

What are the common side effects of ofatumumab and teriflunomide in newly diagnosed MS patients?

Common side effects for ofatumumab include nasopharyngitis (common cold), injection-related systemic reactions, headache, and upper respiratory tract infections. For teriflunomide, common side effects include nasopharyngitis, alopecia (hair loss), upper respiratory tract infection, injection-related systemic reactions (from placebo injections), headache, and fatigue.

How is ofatumumab administered compared to teriflunomide?

Ofatumumab is given as a 20 mg subcutaneous injection every 4 weeks after initial dosing on days 1, 7, and 14. It can be self-administered at home without premedication. Teriflunomide is taken as a 14 mg oral tablet once daily. Both treatments were continued for up to 30 months in the trials.

Source Information

Original Article Title: "Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II"

Authors: Jutta Gärtner, Stephen L Hauser, Amit Bar-Or, Xavier Montalban, Jeffrey A Cohen, Anne H Cross, Kumaran Deiva, Habib Ganjgahi, Dieter A Häring, Bingbing Li, Ratnakar Pingili, Krishnan Ramanathan, Wendy Su, Roman Willi, Bernd Kieseier, Ludwig Kappos

Publication: Multiple Sclerosis Journal, 2022, Vol. 28(10) 1562–1575

Note: This patient-friendly article is based on peer-reviewed research from the ASCLEPIOS I and II clinical trials, which are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).