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Add-on daclizumab treatment might reduce multiple sclerosis disease activity more than interferon beta alone

Lancet

Add-on daclizumab treatment might reduce multiple sclerosis disease activity more than standard interferon beta treatment alone. This is the conclusion of an Article published Online First and in the April edition of The Lancet Neurology, written by Dr John W Rose, Neurovirology Research Laboratory, VA Medical Center, Salt Lake City, Utah and University of Utah, USA, and colleagues.

Daclizumab, a humanised monoclonal antibody*, has reduced multiple sclerosis disease activity in previous non-randomised studies. In this new study, the authors aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving standard interferon beta treatment.

This phase 2, randomised study took place at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans (which indicate multiple sclerosis disease activity) every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of immune system cells and immune system response were assessed in an exploratory substudy.

230 patients were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4•75 in the interferon beta and placebo group compared with 1•32 in the interferon beta and high-dose daclizumab group and 3•58 in the interferon beta and low-dose daclizumab group. In the substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group. Common adverse events were equally distributed across groups.

The authors say: "This study provides confirmatory data that daclizumab treatment causes an expansion of CD56bright natural killer cells and adds support to the theory that expansion of CD56bright natural killer cells might mediate some of the effects of daclizumab on reducing multiple sclerosis lesion activity. In addition to the results of previous trials of daclizumab in multiple sclerosis, several lines of evidence have suggested a potential immunoregulatory function for CD56bright natural killer cells: they are expanded during conditions of natural immune tolerance--for example, pregnancy."

They conclude: "This randomised controlled trial indicates that daclizumab can reduce new lesion formation in relapsing multiple sclerosis compared with interferon beta alone...Multiple sclerosis treatments that have the potential to improve in risk-benefit ratios when compared with available treatments are needed; thus, additional studies to define the long-term clinical risks and benefits of daclizumab are warranted."

In an accompanying Comment, Dr Olaf Stüve, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA and Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, USA, and Dr Benjamin M Greenberg Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA, say: "All clinical and paraclinical evidence suggests that daclizumab mediates its beneficial effects at least partly through expanding regulatory CD56bright natural killer cells. It might now be time to explore further how these cells can be expanded in patients by other means... Identifying the physiological mechanism or mechanisms that lead to the expansion of these cells during disease remission might prove crucial in further understanding disease mechanisms and in developing novel therapeutics."

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Dr John W Rose, Neurovirology Research Laboratory, VA Medical Center, Salt Lake City, UT, USA. T) +1 801 581-5862 E) jrose@genetics.utah.edu

Dr Olaf Stüve, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA and Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, USA. T) +1-214-648 8816 E) olaf.stuve@utsouthwestern.edu

For full Article and Comment see: http://press.thelancet.com/tlnrose.pdf

Note to editors: humanised monoclonal antibody: a genetically engineered antibody with a human structure and specific binding sites

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