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Blockade von Adhäsionsmolekülen mit Natalizumab in der Therapie der Multiplen Sklerose

Aktueller Studienstand

Blocking adhesion molecules with natalizumab in multiple sclerosis

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Zusammenfassung

Natalizumab ist ein humanisierter, monoklonaler Antikörper, der Adhäsionsmoleküle (α4-Integrine) auf der Oberfläche von Immunzellen bindet. Diese Adhäsionsmoleküle sind für die Bindung von Lymphozyten an die Endothelzellen der Blutgefäße und das Eindringen von Entzündungszellen in Gewebe wichtig. Natalizumab befindet sich gegenwärtig in der klinischen Prüfung für die Therapie der Multiplen Sklerose (MS) und anderer Autoimmunerkrankungen (entzündliche Darmerkrankungen, rheumatoide Arthritis). Nachdem erste klinische Phase-I- und -II-Studien die Verträglichkeit und potenzielle Wirksamkeit von Natalizumab in der Behandlung der MS in kürzeren Beobachtungszeiträumen (≤6 Monate) demonstriert haben, wird zurzeit in zwei großen, doppelblinden, plazebokontrollierten Phase-III-Studien (AFFIRM und SENTINEL) die Frage nach der Effektivität bei Patienten mit schubförmig-remittierender MS hinsichtlich primär klinischer Zielgrößen (Schubrate, Behinderungsprogression) bewertet. Basierend auf den Ergebnissen der Einjahresinterimsanalyse dieser Studien wurde Natalizumab kürzlich durch die Food and Drug Administration für die Behandlung schubförmiger Formen der MS zur Reduzierung der Frequenz klinischer Schübe in den USA zugelassen und die Zulassung in Europa beantragt. Nach mehr als 2-jähriger Kombinationstherapie mit TYSABRI® (Natalizumab) und Avonex® (Interferon β-1a) in der sog. SENTINEL-Studie kam es unerwartet zu einem Todes- und einem Erkrankungsfall durch eine progressive multifokale Leukoenzephalopathie. Aus diesem Grunde haben die Herstellerfirmen Biogen/Elan im Februar 2005 alle Studien zu TYSABRI® gestoppt und das in den USA bereits zugelassene Medikament vom Markt genommen. Derzeit laufende Untersuchungen sollen, um weitere Erkenntnisse zu bringen, insbesondere auch das Risiko für die in der TYSABRI®-Studie behandelten Patienten erfassen. Der vorliegende Artikel fasst den aktuellen Studienstand zu Natalizumab bei der MS zusammen.

Summary

Natalizumab is a humanized, monoclonal antibody, that inhibits adhesion molecules (α4-integrins) on the surface of immune cells. These adhesion molecules are important for binding of lymphocytes to endothelial cells of blood vessels and infiltration of inflammatory cells into tissues. Natalizumab is currently being tested in large clinical trials for the treatment of multiple sclerosis (MS) and other autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis). After demonstrating the safety and potential effectiveness of natalizumab in MS therapy during shorter treatment periods (≤6 months) in clinical phase I and II studies, two ongoing large, double-blinded, placebo-controlled phase III trials (named AFFIRM and SENTINEL) are evaluating its efficacy for patients with relapsing-remitting MS in respect to primary clinical endpoints (relapse rate, disease progression). Based a 1-year interim analysis of these studies, natalizumab was recently authorized by the U.S. Food and Drug Administration for treatment in reducing the frequency of clinical surges in multiple sclerosis, and an application was also made for its use in Europe. After more than 2 years of combined natalizumab (Tysabri) and interferon beta-1a (Avonex) therapy in the so-called Sentinel Study, there was one unexpected death and one appearance of progressive multifocal leukoencephalopathy. As a result, in February 2005 the manufacturers (Biogen/Elan) stopped all running studies of natalizumab and removed the drug from the market. New studies are underway to gain more understanding and especially to determine the risk to patients treated in the Sentinel Study. This article summarizes and updates the results of previous and ongoing natalizumab trials in the context of MS.

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Authors and Affiliations

  1. Neurologische Klinik und Poliklinik der Julius-Maximilians-Universität Würzburg

    B. Schreiner &  H. Wiendl

  2. Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf

    B. C. Kieseier & H.-P. Hartung

  3. Institut für Klinische Neuroimmunologie, Klinikum Großhadern, Ludwig-Maximilians-Universität München

    R. Hohlfeld

  4. Klinische Forschungsgruppe MS, Neurologische Klinik der Universität Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Deutschland

    H. Wiendl

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  1. B. Schreiner
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  2. B. C. Kieseier
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  3. H.-P. Hartung
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  4. R. Hohlfeld
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  5. H. Wiendl
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Correspondence to H. Wiendl.

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Schreiner, B., Kieseier, B.C., Hartung, HP. et al. Blockade von Adhäsionsmolekülen mit Natalizumab in der Therapie der Multiplen Sklerose. Nervenarzt 76, 999–1005 (2005). https://doi.org/10.1007/s00115-005-1900-2

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  • DOI: https://doi.org/10.1007/s00115-005-1900-2

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