Comparing Ocrelizumab and Natalizumab for Multiple Sclerosis: A 5-Year Real-World Study

Table of Contents

• Introduction: Understanding MS Treatments
• How the Research Was Conducted
• Detailed Study Results
• Treatment Safety Comparison
• How Long Patients Stayed on Treatment
• What This Means for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Understanding MS Treatments

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, including the brain and spinal cord. Over the past two decades, treatment options have expanded dramatically with the development of numerous disease-modifying therapies (DMTs) that work through different mechanisms to control the disease.

Among the most effective treatments are monoclonal antibodies, including natalizumab (sold as Tysabri) and ocrelizumab (sold as Ocrevus). These high-efficacy therapies are often recommended early in the disease course to prevent irreversible damage and disability accumulation. However, until now, limited long-term data has been available comparing these two treatments in real-world settings outside of clinical trials.

Natalizumab works by preventing immune cells from crossing into the brain and spinal cord, while ocrelizumab targets and depletes B-cells that contribute to inflammation in MS. This study aimed to provide patients and clinicians with comprehensive 5-year data on how these treatments compare in terms of effectiveness, safety, and how long patients typically continue taking them.

How the Research Was Conducted

Researchers conducted a retrospective analysis of 308 MS patients treated at two Italian university hospitals - Sapienza University in Rome and University of Naples "Federico II." The study included 168 patients treated with natalizumab and 140 treated with ocrelizumab, with an average follow-up period of 75.7 months (approximately 6.3 years).

To ensure fair comparisons between the two treatment groups, researchers used a statistical method called propensity score matching. This technique created 70 matched pairs of patients (140 total patients) who were similar in terms of age, sex, previous treatment status, MS type, disease duration, and disease activity at baseline. After matching, both groups had an average follow-up of 55.9 months (approximately 4.7 years).

The study evaluated three main outcomes:

• Effectiveness: Measured by "no evidence of disease activity" (NEDA-3), which means no relapses, no new MRI lesions, and no confirmed disability progression
• Safety: Documented all adverse events using standard medical classification systems
• Persistence: How long patients continued treatment before stopping or switching

Researchers used sophisticated statistical models to account for differences in treatment duration and ensure accurate comparisons between the two medications.

Detailed Study Results

The study revealed several important findings about how these two treatments perform in real-world clinical practice over nearly 5 years of observation.

At the 5-year mark, 50.5% of natalizumab patients and 65% of ocrelizumab patients achieved NEDA-3 status (no evidence of disease activity). While this suggests a numerical advantage for ocrelizumab, the difference was not statistically significant [HR 0.64 (0.34–1.24), p=0.187], meaning it could have occurred by chance.

Regarding relapses, the research team observed 7 relapses in the natalizumab group and 3 in the ocrelizumab group. One relapse occurred within a month of starting natalizumab and was excluded from analysis as it likely represented rebound activity from previous treatment. The difference in relapse rates between the two treatments was not statistically significant [HR 0.41 (0.11–1.57), p=0.193].

MRI activity showed similar patterns - 7 patients on natalizumab and 3 patients on ocrelizumab experienced new lesions, with no significant difference between treatments [HR 0.37 (0.10–1.44), p=0.152]. Disability progression, specifically progression independent of relapse activity (PIRA), occurred in both groups without significant differences [HR 1.43 (0.60–3.40), p=0.417].

The probability of remaining free from disease activity at specific time points was:

• At 1 year: 85.7% for natalizumab vs 92.9% for ocrelizumab free from relapses
• At 3 years: 82.9% vs 90% free from relapses
• At 5 years: 82.9% vs 90% free from relapses

Treatment Safety Comparison

The safety analysis revealed important differences between the two treatments. Patients receiving ocrelizumab had a significantly higher risk of developing adverse events compared to those on natalizumab [OR 4.50 (1.53–16.50), p=0.011].

Out of 140 matched patients, 19 experienced adverse events - 4 from the natalizumab group and 15 from the ocrelizumab group. Importantly, none of these events were life-threatening, and most were classified as mild to moderate.

The adverse events reported included:

• Infusion-related reactions (more common with ocrelizumab)
• COVID-19 infections requiring treatment or hospitalization
• Other infections
• Blood test abnormalities including anemia, lymphocytopenia, and hypogammaglobulinemia
• Development of autoimmune conditions (psoriasis, autoimmune thrombocytopenia)
• One case of breast cancer
• Minor surgeries (endometrial polyp removal)

Seven of the 15 ocrelizumab patients who experienced adverse events were originally part of clinical trial cohorts, which may have influenced the reporting frequency.

How Long Patients Stayed on Treatment

Treatment persistence, meaning how long patients continued their medication without switching or stopping, showed interesting patterns. Initially, the analysis found no significant difference in discontinuation rates between the two treatments [OR 0.58 (0.26–1.26), p=0.174].

However, when researchers performed a sensitivity analysis excluding patients who transferred to other MS centers (1 natalizumab patient, 8 ocrelizumab patients), they found that natalizumab patients had a higher probability of treatment discontinuation [OR=0.26 (0.09–0.67), p=0.008] compared to ocrelizumab patients.

The reasons for discontinuing treatment differed between the two groups:

Natalizumab discontinuations (21 patients):

• 15 due to John Cunningham virus (JCV) positivity
• 1 due to adverse events
• 2 due to pregnancy
• 1 transferred to another center
• 1 lost to follow-up
• 1 due to disability progression

Ocrelizumab discontinuations (14 patients):

• 8 transferred to another MS center
• 2 due to disability progression
• 1 due to adverse events
• 1 due to pregnancy
• 1 lost to follow-up
• 1 due to patient decision

Most patients who discontinued treatment switched to another DMT, with cladribine being the most common choice after natalizumab discontinuation.

What This Means for Patients

This study provides valuable real-world evidence that both natalizumab and ocrelizumab are highly effective treatments for controlling multiple sclerosis over the long term. The comparable effectiveness findings mean that treatment decisions can be based more on individual patient factors rather than perceived superiority of one medication over the other.

For patients concerned about disease activity, both medications showed strong performance in preventing relapses, new MRI lesions, and disability progression over nearly 5 years of treatment. The similar NEDA-3 rates suggest that either treatment can provide comprehensive disease control when appropriate for the patient's specific MS type and characteristics.

The safety findings indicate that ocrelizumab carries a higher risk of mild to moderate adverse events, particularly infusion reactions, infections, and blood abnormalities. However, no life-threatening events occurred in either group during the study period. This information can help patients and doctors make informed decisions based on individual risk tolerance and health history.

The persistence data suggests that once patients start ocrelizumab, they may be more likely to continue treatment long-term compared to natalizumab, especially when considering the common need to switch from natalizumab due to JCV positivity development.

Study Limitations

While this study provides valuable real-world evidence, several limitations should be considered when interpreting the results. The retrospective design means researchers analyzed existing medical records rather than following patients prospectively with predetermined assessment schedules.

The study population came from only two Italian centers, which may limit how well the findings apply to more diverse populations or different healthcare systems. Additionally, the inclusion of patients who participated in clinical trials may have introduced some bias, as these patients typically receive more intensive monitoring.

The matching process, while statistically rigorous, cannot account for all possible confounding factors that might influence treatment outcomes. Some baseline differences remained between the groups, particularly in treatment duration, which required statistical adjustment.

Finally, the study excluded patients who switched between natalizumab and ocrelizumab, which means the findings may not apply to this specific patient population that sometimes requires sequential treatment with both medications.

Patient Recommendations

Based on this research, patients and clinicians can consider the following when making treatment decisions:

1. Both treatments are highly effective: Neither medication showed clear superiority in controlling MS disease activity over 5 years
2. Consider safety profiles: Ocrelizumab carries a higher risk of mild-to-moderate side effects, particularly infusion reactions and infections
3. Discuss JCV status: Natalizumab requires regular monitoring for John Cunningham virus antibodies, and positive status often necessitates treatment switching
4. Evaluate treatment persistence: Ocrelizumab may offer better long-term treatment continuity for some patients
5. Consider individual factors: Treatment choice should consider disease type, previous treatments, reproductive planning, and personal preference

Patients should have detailed discussions with their neurologists about these findings and how they apply to their individual situation. Regular monitoring and follow-up remain essential regardless of which treatment is chosen.

Source Information

Original Article Title: Comparative effectiveness, safety and persistence of ocrelizumab versus natalizumab in multiple sclerosis: A real-world, multi-center, propensity score-matched study

Authors: Elena Barbutia, Alessia Castiellob, Valeria Pozzillic, Antonio Carotenutob, Ilaria Tomassoa, Marcello Mocciad, Serena Ruggierie, Giovanna Borriellof,g, Roberta Lanzillob, Vincenzo Brescia Morrab, Carlo Pozzillia, Maria Petraccaa

Publication: Neurotherapeutics 22(2025)e00537

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.