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An open-label safety and drug interaction study of natalizumab (Antegren^TM) in combination with interferon-beta (Avonex®) in patients with multiple sclerosis

Division of Neurology, Barrow Neurological Institute at St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA, tvollmer{at}chw.edu

J T Phillips

Multiple Sclerosis Center at Texas Neurology, Baylor University Medical Center, Dallas, TX 75214, USA

A D Goodman

Neuroimmunology Unit, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA

M A Agius

Department of Neurology, University of California at Davis, Davis, CA 95616, USA

M A Libonati

Elan Pharmaceuticals, Inc., San Diego, CA 92121, USA

J L Giacchino

Elan Pharmaceuticals, Inc., San Diego, CA 92121, USA

J S Grundy

Elan Pharmaceuticals, Inc., San Diego, CA 92121, USA

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (IV) infusion during stable treatment with intramuscular (IM) interferon beta-1a 30 mg (IFNß-1a; Avonex®). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNß-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNß-1a activity, b2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNß-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated.

The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNß-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNß-1a. The presence of antibodies to IFNß-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNß-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

Key Words: ß2-microglobulin • combination drug therapy • integrin • interferon beta-1a • monoclonal antibody • multiple sclerosis • natalizumab • neopterin • pharmacodynamics • pharmacokinetics

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