Daclizumab is an IgG1 anti-CD25 monoclonal antibody that blocks IL-2-mediated lymphocyte activation. The drug (Zenapax) was originally used to prevent tissue rejection but was withdrawn by Roche in 2009 due to declining demand.     

Results from the phase II SELECT study of daclizumab (now called Zinbryta) in MS were published last year (Gold et al. Lancet 2013;381:2167-2175). A total of 621 patients were randomized to placebo or subcutaneous daclizumab (150 mg or 300 mg) every 4 weeks. At one year, the annualized relapse rate was lower with daclizumab 150 mg (0.21) and 300 mg (0.23) versus placebo (0.46). Relapse-free rates were 81%, 80% and 64%, respectively. There was one death (psoas abscess) in the daclizumab 150 mg group.

For the SELECTION extension study, placebo patients were randomized to one of two doses of daclizumab q4weeks for 52 weeks (Giovannoni et al. Lancet Neurol 2014;13:472-481). Patients on active treatment continued in their group assignment but were randomized to continue either with or without a 20-week washout period. A total of 517 patients (83%) entered SELECTION. There was a low incidence (< 2%) of neutralizing antibodies to daclizumab. The rate of serious adverse events (excluding MS relapse) was slightly higher in the continuous treatment group (8%) compared to those in the washout/daclizumab or placebo/daclizumab groups (6%). One patient in the washout/300 mg group died of autoimmune hepatitis.

Comment
Dr. François Grand’Maison: These phase II results are quite similar to those obtained in the recently completed phase III trial, the DECIDE study, as reported by the sponsor (see Update below). In the DECIDE study, over 1,800 patients received either monthly SC daclizumab 150 mg or weekly IM interferon beta-1a for 2-3 years. Annualized relapse rate, the primary endpoint, was 45% lower in the daclizumab cohort. The number of new or enlarging T2 lesions was 54% lower in the daclizumab group. Sustained progression of disease also favoured daclizumab but did not reach statistical significance. The drug, an immunomodulator, is well tolerated. Cutaneous reactions and liver toxicity are slightly more common than with interferon beta-1a. If approved, it will represent a welcome addition to the rapidly growing MS armamentarium; it will probably be used as a first-line drug. Although no head-to-head trials have been conducted, it appears more effective than teriflunomide and better tolerated than dimethyl fumarate.

Update:

Efficacy and safety results for the phase III DECIDE trial were presented at ACTRIMS/ECTRIMS 2014. A total of 1,841 patients (mean age 36.3 years, mean EDSS 2.5) were randomized to daclizumab 150 mg SC q4wks or IFNbeta-1a IM once-weekly for 96-144 weeks (Kappos et al. ECTRIMS 2014; abstract FC1.1). ARR was 0.216 with daclizumab versus 0.393 with IFNbeta, a 45% reduction. Three-month sustained disability progression was nonsignificantly reduced by 16% (20% with IFNbeta); results for six-month sustained disability progression did achieve significance.

Improvements in MRI parameters were seen at week 24 and sustained to week 96. The mean number of new/enlarging T2 lesions and new enhancing lesions at week 96 was 4.3 (vs. 9.4 with IFNbeta) and 0.4 (vs. 1.0 with IFNbeta), respectively (Arnold et al. ECTRIMS 2014; abstract P051). Daclizumab was associated with higher rates of serious adverse effects (24% vs. 21%) and adverse events leading to discontinuation (15% vs. 12%) compared to IFNbeta. The most common serious adverse event was MS relapse (DAC 11% vs. IFN 13%). The most common adverse events leading to discontinuation were abnormal liver function tests (5% vs. 4%), and skin disorders (5% vs. < 1%) (Selmaj et al. ECTRIMS 2014; abstract P094). The most common adverse effects with daclizumab versus IFNbeta were MS relapse (32% vs. 47%), nasopharyngitis (25% vs. 21%), headache (17% vs. 19%), and upper respiratory tract infection (16% vs. 13%). There were nine malignancies in the daclizumab group compared to eight in the IFNbeta group. There were five deaths, none of which was attributed to treatment.