Elsevier

The Lancet Neurology

Volume 10, Issue 8, August 2011, Pages 745-758
The Lancet Neurology

Review
Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring

https://doi.org/10.1016/S1474-4422(11)70149-1Get rights and content

Summary

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Introduction

Natalizumab—an α4-integrin antagonist—was approved for treatment of patients with multiple sclerosis (MS) who have the active relapsing-remitting form of disease (RRMS) on the basis of its targeted mode of action and its positive effects on various clinical and MRI outcomes in the placebo-controlled clinical studies AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting MS),1, 2, 3, 4, 5, 6, 7, 8 SENTINEL (Safety and Efficacy of Natalizumab in Combination with Avonex [IFNβ-1a] in Patients with Relapsing-Remitting MS),9 and GLANCE (Glatiramer Acetate and Natalizumab Combination Evaluation).10 Natalizumab is generally recommended for individuals who have not responded to currently available first-line disease-modifying therapy or who have very active disease.

Commercial and clinical trial dosing of natalizumab was suspended voluntarily in February, 2005, after three reports were made of progressive multifocal leukoencephalopathy (PML), an often fatal viral disease characterised by progressive inflammation and damage to the white matter, in patients treated with this agent. However, the drug was reintroduced in the USA and approved in the European Union (EU) in June, 2006, after no additional cases of PML were identified in previously treated individuals.11

On the basis of additional analyses of AFFIRM, SENTINEL, and GLANCE, including long-term follow-up and post-marketing observations, we revisit our previous Review12 of the position of natalizumab for treatment of patients with RRMS. We need to consider the conditions of use that are most likely to maintain or increase the therapeutic benefit of natalizumab while minimising patients' risk. Important factors to consider include appropriate patient selection, routine safety monitoring, and an understanding of both early recognition and timely management of PML. In this Review, we will provide general safety monitoring recommendations and a detailed update to our previous guidelines on the diagnosis and management of PML in natalizumab-treated patients,12 as developed by panels of experts in neurology and neuroradiology.

Section snippets

Natalizumab use and safety

In the 2-year, phase 3 AFFIRM study,1 natalizumab monotherapy significantly decreased annual relapse rates by 68% (p<0·001) in patients with MS and lowered disability progression rates (sustained for 3 months) by 42% (p<0·001) compared with placebo. Additional analyses showed that over 2 years, natalizumab monotherapy elicited a 54% reduction in 6 months' confirmed disability progression, a 92% decline in the number of gadolinium-enhancing lesions during the second year (p<0·001), an 83%

Background on PML

PML is an opportunistic infection of the CNS that, in cases unrelated to natalizumab, usually leads to death or severe disability.39 Active replication of the human polyoma JCV in glial cells of the brain, causing lytic death in oligodendrocytes, is the underlying pathobiology of PML. The infection typically arises in severely immunocompromised patients—eg, those with HIV infection, malignant disease, or transplanted organs. Development of PML is extremely rare in immunocompetent individuals.40

PML in natalizumab-treated patients

PML was identified in three patients (two with MS and one with Crohn's disease) from pre-marketing clinical studies.45, 46, 47 As of June 1, 2011, all 133 reported cases of PML since relaunch of natalizumab (USA [n=50], European Economic Area [76], and rest of the world [7]) arose in people with MS who had received natalizumab monotherapy for more than 1 year.13 As of May 4, 2011, on the basis of post-marketing reports, the estimated overall risk of PML is 1·51 per 1000 patients (95% CI

PML risk management

Plans for risk management of PML for patients with MS have been instituted in the EU, the USA, and elsewhere. In the EU, prescription of natalizumab is restricted to doctors skilled in the treatment of neurological diseases who have timely access to MRI facilities and have the ability to manage hypersensitivity reactions.30 Specific education of doctors with respect to management of PML is needed for all prescribers, and patients with MS are issued with a special card describing the possible

Patient selection

In the USA, natalizumab is indicated as monotherapy for patients with relapsing forms of MS. Although this agent is generally recommended for those who have had an inadequate response to—or cannot tolerate—an alternative MS treatment, the US label also allows use of natalizumab as first-line therapy in individuals with relapsing MS,29 and as a result, US patients with progressive relapsing MS are more frequently treated with natalizumab. In a re-evaluation by the European Medicines Agency,30 no

Conclusions

Natalizumab has proven a highly effective treatment for patients with RRMS. The decision to prescribe this drug entails a benefit–risk assessment for each individual. The overall risk of PML still seems to be one case per 1000 individuals with MS; risk seems lower in patients who are seronegative for anti-JCV antibodies and higher in those who are JCV antibody-positive with previous immunosuppressive treatment. The clinician and patient must consider disease activity (both in terms of relapses

Search strategy and selection criteria

We searched Medline for articles published between 2007 and 2011 (last update May, 2011) and scanned references from relevant articles with the search terms: “natalizumab”, “progressive multifocal leukoencephalopathy”, “PML”, and “JC virus and CNS”. Papers published in English, German, and French were reviewed. The final reference list was generated on the basis of originality and relevance to topics covered in the Review.

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