Natalizumab Treatment for Relapsing Multiple Sclerosis: A Comprehensive Patient Guide

Table of Contents

• Introduction: Understanding the Study
• Study Methods: How the Research Was Conducted
• Key Findings: Detailed Results
• Safety Information: Side Effects and Risks
• Conclusions and Clinical Implications
• Study Limitations
• Source Information

Introduction: Understanding the Study

Relapsing multiple sclerosis is characterized by intermittent development of inflammatory lesions in the brain and spinal cord, resulting in areas of damage to the protective nerve covering (demyelination) and nerve fiber loss. This groundbreaking research investigated a new approach to treating MS by targeting the migration of immune cells into the nervous system.

The study focused on natalizumab (brand name Tysabri), which belongs to a new class of medications called selective adhesion-molecule inhibitors. This medication works by blocking α4 integrin, a protein on the surface of lymphocytes (immune cells), preventing these cells from crossing the blood-brain barrier and causing inflammation in the central nervous system.

Before this study, available MS therapies including interferon beta and glatiramer acetate were only moderately effective, typically reducing annual relapse rates by about one-third. This two-year phase 3 trial aimed to confirm the effectiveness and safety of long-term natalizumab treatment for people with relapsing multiple sclerosis.

Study Methods: How the Research Was Conducted

The study enrolled 942 patients across 99 clinical centers in Europe, North America, Australia, and New Zealand beginning November 6, 2001. Participants were between 18-50 years old with a diagnosis of relapsing multiple sclerosis, Expanded Disability Status Scale (EDSS) scores of 0-5.0, and had experienced at least one medically documented relapse within the previous 12 months.

Patients were randomly assigned in a 2:1 ratio to receive either natalizumab (627 patients) or placebo (315 patients). The natalizumab group received 300 mg by intravenous infusion every four weeks for up to 116 weeks. The study used a sophisticated design where examining neurologists were separate from treating neurologists to maintain objectivity in disability assessments.

The primary endpoints measured were:

• The rate of clinical relapse at one year
• The rate of sustained progression of disability (measured by EDSS) at two years

Secondary measurements included MRI scans to detect new or enlarging brain lesions at both one and two years. The study was powered to detect significant differences with 90% statistical power, accounting for an estimated 15-20% dropout rate over the two-year period.

Key Findings: Detailed Results

The results demonstrated substantial benefits for patients receiving natalizumab compared to placebo. After two years of treatment, natalizumab reduced the risk of sustained disability progression by 42% (hazard ratio 0.58; 95% confidence interval 0.43 to 0.77; P<0.001). The cumulative probability of disability progression was 17% in the natalizumab group versus 29% in the placebo group.

At one year, natalizumab reduced the rate of clinical relapse by 68% (P<0.001). The annualized relapse rate was 0.26 in the natalizumab group compared to 0.81 in the placebo group. This benefit was maintained at two years, with natalizumab reducing relapse risk by 59% over the full study period.

MRI results were particularly impressive. Natalizumab led to an 83% reduction in the accumulation of new or enlarging hyperintense lesions detected by T2-weighted MRI over two years. The mean number of lesions was 1.9 with natalizumab versus 11.0 with placebo (P<0.001). Even more strikingly, gadolinium-enhanced MRI detected 92% fewer lesions in the natalizumab group at both one and two years (P<0.001).

Additional significant findings included:

• 57% of natalizumab patients had no new or enlarging lesions over two years versus only 15% of placebo patients
• 77% of natalizumab patients were relapse-free at one year versus 56% of placebo patients
• 67% of natalizumab patients were relapse-free at two years versus 41% of placebo patients
• 97% of natalizumab patients had no gadolinium-enhanced lesions at two years versus 72% of placebo patients

Safety Information: Side Effects and Risks

Over the two-year study, 95% of natalizumab patients and 96% of placebo patients reported at least one adverse event. Side effects that were significantly more common in the natalizumab group included fatigue (27% vs. 21% with placebo, P=0.048) and allergic reactions (9% vs. 4%, P=0.012).

Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4%), with serious hypersensitivity reactions occurring in 8 patients (1%). The severity of adverse events was similar between groups, with most events rated as moderate in severity.

Serious adverse events were actually less common in the natalizumab group (19%) compared to the placebo group (24%, P=0.06), primarily due to fewer MS relapses requiring treatment. The most common serious adverse event was MS relapse itself (6% with natalizumab vs. 13% with placebo, P<0.001).

Two deaths occurred during the study, both in the natalizumab group. One patient died from malignant melanoma and another from alcohol intoxication. The investigators determined that neither death was related to the study medication.

An important finding was that patients who discontinued natalizumab did not experience rebound disease activity, though their MS symptoms returned to pre-treatment levels.

Conclusions and Clinical Implications

This study demonstrated that natalizumab significantly reduces both disability progression and clinical relapse rates in patients with relapsing multiple sclerosis. The 42% reduction in disability progression and 68% reduction in relapse rate at one year represent some of the most substantial treatment effects observed in MS clinical trials.

The dramatic reduction in MRI lesion activity (83-92% reduction) provides objective evidence that natalizumab effectively suppresses the inflammatory process in multiple sclerosis. This confirms that targeting immune cell migration across the blood-brain barrier is a valid therapeutic approach for MS.

For patients, these results suggest that natalizumab may offer superior disease control compared to previously available therapies. The medication showed significant benefits on both clinical measures (relapses and disability) and radiographic measures (MRI lesions), indicating comprehensive disease-modifying effects.

Study Limitations

While this study demonstrated impressive results, several limitations should be considered. The trial duration of two years may not capture long-term benefits or risks that could emerge with extended treatment. The study excluded patients with progressive forms of MS (primary progressive, secondary progressive, or progressive relapsing), so the results only apply to those with relapsing forms of the disease.

Patients with more advanced disability (EDSS >5.0) were excluded, limiting our understanding of how natalizumab works in later stages of MS. The study also excluded patients who had recently used other MS medications, which means we don't know how natalizumab compares directly to other therapies or how it works in combination with them.

The 2:1 randomization ratio meant more patients received the active drug than placebo, which could potentially influence the results, though statistical methods accounted for this design. Finally, the long-term safety profile beyond two years requires further investigation.

Source Information

Original Article Title: A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Authors: Chris H. Polman, Paul W. O'Connor, Eva Havrdova, Michael Hutchinson, Ludwig Kappos, David H. Miller, J. Theodore Phillips, Fred D. Lublin, Gavin Giovannoni, Andrzej Wajgt, Martin Toal, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, and the AFFIRM Investigators

Publication: New England Journal of Medicine, March 2, 2006, Volume 354, Number 9, Pages 899-910

ClinicalTrials.gov Identifier: NCT00027300

This patient-friendly article is based on peer-reviewed research originally published in the New England Journal of Medicine. It preserves all significant findings, data points, and conclusions from the original scientific publication while making the information accessible to patients and caregivers.