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Two-Year Benefit from Natalizumab for MS

Two studies show a sustained benefit and a low short-term risk for PML, underscoring the promise of target-specific therapies.

Three articles provide perspective on new trends in understanding and treating multiple sclerosis (MS).

Frohman and colleagues review current understanding of the pathogenesis of MS, focusing on novel therapeutic targets. They describe key factors associated with an upregulated T-cell response, proposed to be a central feature of inflammatory demyelination in MS. These factors include interleukin (IL)-12, IL-23, IL-17; toll-like receptors; transcription factors (T-bet, Stat-4); and cell-surface receptor (integrin) expression. Axonal injury, which correlates highly with disability, may result from the reversal of the sodium-calcium exchanger, glutamate excitotoxicity, and factors that inhibit axonal growth, such as neurite outgrowth inhibitor receptor agonists. Remyelination, centered upon the regulation of oligodendrocytes, involves transcription factors, chemokine-receptor pathways, and growth-inhibiting pathways.

Natalizumab, a monoclonal antibody that specifically targets alpha-4 integrin, is the first approach targeting these pathways to be tested in phase III studies in MS. In one new study, the manufacturer-sponsored AFFIRM trial, investigators randomized 942 patients with relapsing MS in a 2:1 ratio to receive natalizumab (300 mg) or placebo infusions for up to 116 weeks. The natalizumab group had a 68% relative reduction in clinical relapse rate at 1 year and a 42% relative reduction in risk for sustained progression at 2 years. They also had 83% fewer new or enlarging T2 MRI lesions and 92% fewer gadolinium-enhanced lesions than the placebo group had. Twenty-seven hypersensitivity reactions occurred in natalizumab recipients and none in placebo recipients. These reactions were associated with the development of persistent antibodies to natalizumab and a subsequent loss of efficacy.

In the manufacturer-sponsored SENTINEL study, investigators randomized 1196 relapsing patients to receive interferon ß-1a plus either natalizumab or placebo. The natalizumab-combination group had a 54% relative reduction in relapse rate at 1 year and a 24% relative reduction in risk for sustained progression at 2 years. They also had 83% fewer new or enlarging T2 lesions than did the placebo group, and 89% fewer gadolinium-enhancing lesions over 2 years. Hypersensitivity reactions occurred in 11 natalizumab recipients and in 2 recipients of interferon ß-1a only. Progressive multifocal leukoencephalopathy (PML) in two combination-therapy recipients led to the death of one patient, prompting the FDA to halt the drug’s marketing. (Possible re-release is pending FDA review as of this article’s publication.)

Comment: Through recent scientific advancements, MS treatment has evolved to include target-specific therapeutic interventions. In both trials, natalizumab clearly demonstrated an efficacy surpassing previous phase III clinical trials in MS. The development of PML dampened the excitement of these results and underscores the need to balance safety and efficacy as we move forward in the treatment of immune-mediated diseases such as MS.

The risk for PML derived from all clinical trial patients treated with natalizumab was reported to be 1 in 1000 with a mean exposure of 17.9 months (N Engl J Med 2006; 354:924); however, the risk with monotherapy or with longer treatment exposures remains unknown. If natalizumab were to be re-released, patients who experience clinical relapses and new MRI lesions while on standard therapy would be feasible candidates. Treatment options for these patients are often limited to immunosuppressive therapy, which also has long-term safety risks as well as the potential to cause sterility. Thus, if natalizumab becomes available, it will be important to select appropriate patients and to consider the necessity of monitoring for evidence of PML (see Journal Watch Neurology Jul 7 2005).

— Susan A. Gauthier, DO, MPH

Dr. Gauthier is Instructor, Harvard Medical School, and Associate Neurologist, Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston. She was an investigator for the SENTINEL trial but was not an author.

Published in Journal Watch Neurology April 6, 2006

Citation(s):

Frohman EM et al. Multiple sclerosis — The plaque and its pathogenesis. N Engl J Med 2006 Mar 2; 354:942-55.

• Original article (Subscription may be required)
• Medline abstract (Free)

Polman CH et al. for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006 Mar 2; 354:899-910.

• Original article (Subscription may be required)
• Medline abstract (Free)

Rudick RA et al. for the SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006 Mar 2; 354:911-23.

• Original article (Subscription may be required)
• Medline abstract (Free)