Multiple sclerosis, natalizumab, and PML: Helping patients decide

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ABSTRACTThe treatment benefits of natalizumab in patients with multiple sclerosis (MS) appear to exceed those of other disease-modifying drugs, but progressive multifocal leukoencephalopathy (PML) has been identified as a risk in patients receiving natalizumab. As of August 2011, a total of 150 cases of natalizumab-associated PML had been reported worldwide. The overall risk is estimated at approximately 1.66 in 1,000 patients. Independent risk factors for natalizumab-associated PML are number of infusions beyond 36 and prior use of immunosuppressive drugs. Classifying JC virus antibody status appears to be useful in treatment decision-making for individual MS patients. Patient tolerance for risk plays an important role in the selection of therapy, and the treating physician’s perception and tolerance of risk may differ markedly from the patient’s. Physicians can help patients make individual informed decisions regarding the use of natalizumab, given the known risk of PML.



Multiple sclerosis (MS) is an autoimmune disease whose inflammatory process causes demyelination, axonal loss, and neurodegeneration, all of which can lead to progressive neurologic disability. Without treatment, the risk of progressive disability 15 to 20 years after the onset of MS has been estimated to be as high as 50%.1

Seven drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of MS. Of these, interferon beta drugs and glatiramer acetate are generally considered as first-line agents based on extensive experience and relative safety. Indeed, reports with followup approaching 20 years have not identified significant safety concerns. However, these agents have only modest efficacy, reducing by approximately 30% the frequency of relapse in patients with relapsing-remitting MS.2–6

Natalizumab, and more recently, fingolimod, are generally used as second-line agents. Fingolimod, the first oral agent to receive FDA approval for the treatment of relapsing-remitting MS, is a functional antagonist of sphingosine-1-phosphate receptors. The reductions in annualized relapse rates in two phase 3 controlled trials of fingolimod were approximately 55% compared with placebo7 or intramuscular interferon beta-1a.8 Because of its more convenient oral route of administration and its documented efficacy, widespread use of fingolimod is anticipated. However, adverse reactions affecting more than 10% of patients include headache, influenza, diarrhea, back pain, liver transaminase elevations, and cough.9 Because sphingosine-1-phosphate receptors are widespread in many body tissues, off-target effects of fingolimod may be problematic and long-term toxicity is unknown.

In addition to natalizumab and fingolimod, which are currently available for use as second-line agents, several other MS therapies are showing promise. Oral cladribine, teriflunomide, and laquinimod have reported positive phase 3 results in publication or at national meetings, and several other drugs are in late stages of development (alemtuzumab, BG-12, ocrelizumab) based on encouraging phase 2 results.10–12 Thus, the options for MS patients are expanding, but drugs with higher efficacy also may pose greater risk.


Natalizumab is a humanized monoclonal antibody that binds to alpha-4 integrin on leukocytes. By inhibiting alpha-4 integrin, natalizumab, the first of a new class of selective adhesion-molecule inhibitors, impedes migration of activated mononuclear leukocytes into the brain and gut.13

Significant efficacy

Two phase 3 studies demonstrated more robust efficacy of natalizumab in patients with relapsing-remitting MS than had been observed in prior studies with other agents.14,15 In the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study, which followed patients over 2 years of treatment, natalizumab was associated with a 68% reduction in the annualized relapse rate14; a 92% reduction in gadolinium-enhanced lesions on magnetic resonance imaging (MRI), which indicate new, active lesions16; and an 83% reduction in the mean number of new or enlarging T2 lesions16 compared with placebo. The likelihood of confirmed worsening on the Kurtzke Expanded Disability Status Score, which is the standard measure for MS-related disability, was also 42% lower in patients assigned to natalizumab compared with placebo.14

Other reported benefits from natalizumab therapy include a significantly increased probability of maintaining disease-free status17 and clinically significant improvements on patient-reported quality-of-life measures.18 Although there have been no head-to-head studies of natalizumab with interferon beta, glatiramer acetate, or fingolimod, there is a widespread view that treatment benefits of natalizumab exceed those of other disease-modifying drugs. In clinical practice, patients with MS who experience breakthrough disease on standard disease-modifying drugs are routinely observed to achieve disease control after switching to natalizumab. Thus, based purely on efficacy, patient-reported outcomes, and the convenience of once-monthly intravenous infusion, natalizumab represents an extremely attractive treatment option for patients with relapsing-remitting MS.

Use discontinued in 2005

Natalizumab was approved for treatment of relapsing-remitting MS in November 2004, using the FDA accelerated review pathway. The approval was based on the first-year results of the AFFIRM14 and the Natalizumab plus Interferon Beta-1a for Relapsing Remitting Multiple Sclerosis (SENTINEL)19 studies, both of which were completed in February 2005. In the 3 to 4 months between the drug’s approval and completion of the AFFIRM and SENTINEL studies, approximately 7,000 patients with relapsing-remitting MS received treatment with natalizumab. In February 2005, shortly after the release of the 2-year data, three cases of progressive multifocal leukoencephalopathy (PML) were identified in natalizumab-treated patients (one with Crohn disease, the other two with MS). Clinical and research use of natalizumab was abruptly suspended that month, pending a comprehensive safety review.

A safety study evaluated 3,116 patients who had received natalizumab over a mean exposure of 17.9 monthly doses.20 The study failed to identify any additional cases of PML and concluded that the risk of PML was approximately 1 in 1,000 patients. Abrupt discontinuation of natalizumab also allowed systematic assessment of disease behavior following treatment interruption. In 1,866 patients who had received natalizumab during clinical trials but who discontinued natalizumab after PML was recognized, MS relapses and gadolinium-enhancing lesions returned approximately to baseline levels within 4 to 7 months of natalizumab suspension. Reactivation of MS disease activity was observed even in patients who instituted one of the first-line disease-modifying drugs as substitute therapy.21

Based on the strong efficacy data and the extensive safety review, an FDA advisory committee recommended reintroduction, and natalizumab was returned to the market in June 2006. Natalizumab may be administered only in accredited infusion centers that agree to a monthly reporting regimen designed to identify all cases of PML. In the United States, natalizumab is available to patients only through the Tysabri Outreach Unified Commitment to Health (TOUCH) Prescribing Program, a restricted distribution program. Aggressive monitoring and reporting is also required in other regions of the world, so that ascertainment of PML associated with natalizumab is thought to be relatively complete.

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