Abstract
Background
Natalizumab (NTZ) (Tysabri®) is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier, thus reducing inflammation in central nervous system, and has been approved worldwide for the treatment of relapsing-remitting multiple sclerosis (RRMS).
Objectives
To evaluate the efficacy, tolerability and safety of NTZ in the treatment of patients with RRMS.
Search methods
We searched the Cochrane Multiple Sclerosis Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 1), MEDLINE (PubMed) and EMBASE, all up to 19 February 2010, and bibliographies of papers. Handsearching was carried out. Trialists and pharmaceutical companies were contacted. Furthermore, the websites of US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMA) and the National Institute for health and Clinical Excellence (NICE) were also checked.
Selection criteria
All double-blind, randomised, controlled trials analysing more than a single infusion of NTZ (dosage > 3 mg/kg intravenous infusion every 4 weeks), also including its use as add-on treatment, versus placebo or other drugs in patients with RRMS. No restrictions on the basis of duration of treatment or length of follow up.
Data collection and analysis
Three reviewers independently selected articles which met the inclusion criteria. Disagreements were solved by discussion. Two reviewers independently extracted the data and assessed the methodological quality of each trial. Missing data was sought by contacting principal authors and Biogen Idec, through Biogen-Dompé Italia.
Main results
Three studies met the inclusion criteria. These included one placebo-controlled trial (942 patients) and two add-on placebo-controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta-1a (1171 patients).
This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow-up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ-treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long-term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ.
Authors’ conclusions
Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up-to-date systematic assessment of the risk due to the maximum 2 year-duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.
All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.
Plain language summary
The use of the monoclonal antibody Natalizumab (NTZ) in patients with relapsing remitting multiple sclerosis (RRMS)
It is currently thought that inflammation is crucial in MS, leading to a disruption in the ability of nerves to conduct impulses. NTZ is the first of a new generation of anti-inflammatory treatments for MS, which is given intravenously every 4 weeks. It is usually prescribed once other drugs have failed or when the disease is rapidly worsening.
The Authors of this review evaluated the efficacy, tolerability and safety of NTZ in patients with RRMS. Among the pertinent literature, 3 studies met the inclusion criteria of methodological quality, comprising a total of 2223 participants. The results show that NTZ treatment reduces the number of patients who experienced relapses and the number of patients who progressed at 2 years. Also Magnetic Resonance scans show evidence of a beneficial effect of NTZ on disease activity.
Although information on adverse events (AEs) was limited, as most participants were followed up for 2 years only, infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginal inflammation and menstrual disorders were found to be more frequent after NTZ treatment. However, the number of patients experiencing at least one AE (including severe or serious AEs) did not differ between NTZ and control groups. On the contrary, significant safety concerns have been raised regarding Progressive Multifocal Leukoencephalopathy (PML), a rare and often fatal viral disease characterized by damage to the white matter of the brain. In the studies included in this review, PML was reported in 2 patients treated with NTZ for more than 2 years. However, our protocol was insufficient to evaluate PML risk as well as other potential rare and long-term AEs (e.g. cancers and other infections) which are important issues in considering the risk/benefit ratio of NTZ. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.
All the data in this review came from studies supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.
