Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis

Abstract

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 CD56bright 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.

Figures

Figure 1. Trial design, patient enrollment and outcomes

CEL = contrast-enhancing lesions

Figure 2. Clinical and MRI trial results

A. Effect of daclizumab on primary outcome measures: the number of new and total CEL and volume of CEL. B. Effect of daclizumab on secondary (clinical) outcome measures: EDSS, Scripps NRS and MSFC. C. Effect of daclizumab on secondary (MRI) outcome measures: T2LV, T1lesion volume (BHV) and brain atrophy (BFV). For each patient the averages of the treatment periods are depicted. The medians of the whole cohort are highlighted. Statistically significant differences (P<0.05) between time-points are indicated by an asterix (*).

Figure 3. Immunological results

A. Changes in the subpopulations of CD56bright NK cells and CD8+ and CD4+ T cells during daclizumab therapy. The medians of the whole cohort are highlighted. Statistically significant differences (P<0.05) between baseline, combination therapy and monotherapy time points are indicated by horizontal bidirectional arrows (↔) in the individual graphs. B. The ratio of CD8+, CD4+ T cells and CD56bright NK cells (responding populations) and CD56bright NK cells (regulatory population). Each patient-point represents the average of several (see Figure 1) treatment period time points. Statistically significant differences (P<0.05) are indicated by an asterix (*). C. Differences in immunological markers between full-(FR; N=8; Table 1) and partial responders (PR; N=7) to daclizumab monotherapy. Individualized percent changes in biomarkers compared to baseline were calculated for all subjects and are depicted as box plots. Black horizontal line represents medians and red horizontal line represents group average. Blue dashed line depicts baseline (100%) values.