TY - JOUR
T1 - Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis
AU - Bielekova, Bibiana
AU - Howard, Thomas
AU - Packer, Amy N.
AU - Richert, Nancy
AU - Blevins, Gregg
AU - Ohayon, Joan
AU - Waldmann, Thomas A.
AU - McFarland, Henry F.
AU - Martin, Roland
PY - 2009/4
Y1 - 2009/4
N2 - 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 in- terferon 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 mono- therapy, 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 da- clizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab mono- therapy. 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.
AB - 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 in- terferon 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 mono- therapy, 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 da- clizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab mono- therapy. 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.
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U2 - 10.1001/archneurol.2009.50
DO - 10.1001/archneurol.2009.50
M3 - Article
C2 - 19364933
AN - SCOPUS:65249138318
SN - 0003-9942
VL - 66
SP - 483
EP - 489
JO - Archives of Neurology
JF - Archives of Neurology
IS - 4
ER -