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Bibiana Bielekova, MD; Thomas Howard; Amy N. Packer; Nancy Richert, MD; Gregg Blevins, MD; Joan Ohayon, CRNP; Thomas A. Waldmann, MD; Henry F. McFarland, MD; Roland Martin, MD

Arch Neurol. 2009;66(4):483-489.

Background  Several questions arise concerning the use of the anti-CD25 antibody daclizumab to treat multiple sclerosis (MS).

Objectives  To answer the following 3 questions related to the efficacy of daclizumab therapy in patients with MS: Is the therapeutic effect of daclizumab dependent on combination with interferon beta? Is a higher dosage of daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to daclizumab?

Design  An open-label baseline vs treatment phase II clinical trial of daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta–daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of daclizumab was doubled.

Setting  Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Patients  Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images.

Intervention  Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5).

Main Outcome Measures  The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta–daclizumab combination therapy, and daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability.

Results  Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and daclizumab therapy was discontinued. Although daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta–daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56^bright natural killer cells and decrease in CD8⁺ T cells) were identified that can differentiate between full and partial daclizumab responders.

Conclusions  Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta–daclizumab combination therapy or higher dosages of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS.

Trial Registration  clinicaltrials.gov Identifier: NCT00001934

Author Affiliations: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke (Drs Bielekova, Richert, Blevins, and McFarland and Mr Howard and Mss Packer and Ohayon), and Metabolism Branch, National Cancer Institute (Dr Waldmann), National Institutes of Health, Bethesda, Maryland; Division of Neurology, University of Alberta, Edmonton, Alberta, Canada (Dr Blevins); and Institute of Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology Hamburg, University Clinic Eppendorf, Hamburg, Germany (Dr Martin).

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