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Eight-year immunogenicity and safety of interferon beta-1a-Avonex®treatment in patients with multiple sclerosis

University of Mississippi, VA Medical Center, Jackson, MS, USA, rherndon{at}neurology.umsmed.edu

Richard A Rudick

Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, Cleveland, OH, USA

Frederick E Munschauer, III

The Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, New York, USA

Michele K Mass

The Multiple Sclerosis Center of Oregon, Oregon Health Sciences University, Portland, OR, USA

Andres M Salazar

Oncovir, Inc., Washington, DC, USA

Michael E Coats

Oncovir, Inc., Washington, DC, USA

Robert Labutta

Oncovir, Inc., Washington, DC, USA

John R Richert

Georgetown University Medical Center, Washington, DC, USA

Stanley L Cohan

Providence Pacific Northwest Multiple Sclerosis Center, Portland, OR, USA

Claude Genain

University of California San Francisco, Multiple Sclerosis Center, San Francisco, CA, USA

Donald Goodkin

Biogen Idec, Inc., Cambridge, MA, USA

Martin Toal

Biogen Idec, Inc., Cambridge, MA, USA

Katherine Riester

Biogen Idec, Inc., Cambridge, MA, USA

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNß-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNß-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNß-1a-Avonex 30 mg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNß-1a-Avonex in the phase III trial. Serum levels of IFNß antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNß-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNß-naïve. At baseline, 281 patients were negative for IFNß antibodies (NAb-). NAbs (titre 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNß-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNß-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres <100; 36 of these 39 seroconverted to NAb-while on IFNß-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres 100; five remained NAb+ during six years on IFNß-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNß-1a-Avonex during the clinical trial were NAb+ with titres <100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNß-1a-Avonex had NAb titres 100; five of these remained NAb+ at six years. No patient with a NAb titre >1000 seroconverted to NAb-, whether initially treated with IFNß-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNß-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNß product.

Key Words: Avonex • extension study • interferon beta-1a • long-term safety • multiple sclerosis • neutralizing antibodies

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