Tysabri Review Launched in Europe

Pauline Anderson

May 08, 2015

In light of rapidly growing scientific evidence, the European Medicines Agency (EMA) has been asked to launch a review of the multiple sclerosis (MS) drug natalizumab (Tysabri, Biogen Idec Inc.) to assess whether advice on managing known risks for progressive multifocal leukoencephalopathy (PML) should be revised.

PML is a rare brain infection caused by the JC virus (JCV), which has symptoms that may resemble those of an MS attack and may be fatal or result in severe disability. In addition to the presence of anti-JCV antibodies, other risk factors for PML in the setting of natalizumab therapy are treatment duration, especially beyond 2 years, and immunosuppressant use before receiving natalizumab. Patients with all of the above risk factors have a significantly higher risk for PML.

Natalizumab was approved in the European Union (EU) in June 2006 as a single disease-modifying therapy in highly active relapsing remitting MS (RRMS). It's indicated for patients with high disease activity despite treatment with a β-interferon or glatiramer acetate and in those with rapidly evolving severe RRMS. Natalizumab was first approved by the US Food and Drug Administration (FDA) in November 2004.

Three Key Issues

The European Commission has requested the review of natalizumab. The review will involve evaluating the data on the risk for PML, with the aim of better defining the risk and identifying further measures to minimize it.

The review will be carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), which will make a set of recommendations. The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use.

The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable to all EU member states.

The EMA has recently been made aware of new information in three key related issues, a statement from the agency notes:

Risk estimates: Natalizumab treatment decisions are based on an algorithm in which the estimated PML incidences are calculated in a static way by pooling data from all sources (clinical studies, registries, spontaneous reports). However, interim data from the STRATIFY 2 study for patients with positive anti-JCV antibody status with and without a history of immunosuppressive treatment suggested a higher risk for PML than currently described in the algorithm.

"It is therefore appropriate to review the calculations to ensure that accurate risk estimates are available for treatment decisions" according to background materials provided by the EMA.

Diagnosis of PML before the development of clinical symptoms: New data seem to suggest that asymptomatic PML cases have a higher survival rate (95.6%) than do symptomatic cases (77.1%). Current recommendations are to perform MRI within 3 months before initiating treatment and then annually. Recent literature suggests that more frequent MRI testing may detect a greater proportion of asymptomatic cases.

Anti-JCV antibodies: It was thought that a negative serologic anti-JCV antibody test suggested a very low probability of PML (about 0.01%), but evidence from the AFFIRM and STRATIFY 1 studies showed that nearly 13% of negative patients could become positive during follow-up.

Currently, it's recommended that these patients be retested every 6 months for antibodies, but a more sensitive second-generation enzyme-linked immunosorbent assay was recently developed. Whether this affects current recommendations for antibody testing needs to be assessed.

Natalizumab is a monoclonal antibody, administered through intravenous injection, that is designed to recognize and attach to a protein on the surface of leucocytes. By blocking this protein, the drug prevents leukocytes from going from the blood to the brain, thereby reducing inflammation and nerve damage caused by MS.


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