Daclizumab, a new injectable therapy administered every four weeks, has been approved by Health Canada for the treatment of adult patients with relapsing-remitting MS who have had a poor response or tolerability to at least one prior disease-modifying therapy. The drug received approval on December 8, 2016, and will be marketed as Zinbryta. An intravenous formulation was approved two decades ago (Zenapax) as an anti-rejection drug post-transplant. Zinbryta previously received approval for MS from the U.S. FDA and the European Medicines Agency.
Daclizumab in a humanized monoclonal antibody targeting the CD25 subunit of the interleukin (IL)-2 receptor expressed on activated T cells. IL-2 is primarily produced by CD4+ T cells and, to a lesser degree, by CD8+ T cells, dendritic cells and natural-killer cells (recently reviewed in Cohan S. Biologics 2016:10;119-138). IL-2 signalling is not affected in resting lymphocytes (Huss et al. J Immunol 2015;194:84-92). However, it has been suggested that the clinical effects of daclizumab are not due to direct inhibition of T cell proliferation since daclizumab-treated MS subjects demonstrate normal T cell activation and proliferation (Reardon & Perumal. Drug Des Devel Ther 2013;7:1187-1193).
Of emerging interest is the effect of treatment on NK cells. IL-2 blockade on lymphocytes increases the availability of IL-2 for receptors expressed on CD56bright NK cells, which lack CD25. CD56bright cells cross the blood-brain barrier and lyse activated T cells in the CNS (Bielekova et al. Neurology 2011;77:1877-1886). However, it has been suggested that there is an insufficient number of CD56bright cells to account for the full clinical effects of daclizumab (Elkins et al. Neurol Neuroimmunol Neuroinflamm 2015; 2:e65).
Drug approval was based on the results of the SELECT and DECIDE trials. In the phase IIb SELECT study, 621 subjects were randomized to placebo or subcutaneous daclizumab 150 mg or 300 mg q4wks for 1 year (Gold et al. Lancet 2013;381:2167-2175). The annualised relapse rate (ARR) was lower for the two active treatment groups (ARR 0.21 and 0.23) compared to placebo (0.46). There was one death due to complications from psoas abscess; and one death due to autoimmune hepatitis in the extension study (SELECTION).
In the phase III DECIDE trial, subjects received daclizumab 150 mg q4wks or intramuscular interferon-beta-1a once-weekly for up to 144 weeks (Kappos et al. N Engl J Med 2015;373:1418-1428). ARR was 0.22 versus 0.39, respectively. There was also a reduction in the number of T2-weighted lesions with daclizumab. There was no significant difference between the two groups with respect to 12-week confirmed progression. Daclizumab was associated with more infections, including serious infections, cutaneous events, and elevations in liver enzymes.
The Canadian product monograph includes a warning about a risk of severe liver injury, including autoimmune hepatitis, with cases occurring up to four months after drug discontinuation. Serum ALT, AST and bilirubin levels must be obtained prior to starting daclizumab, and prior to each monthly dose. Liver function tests should be continued for at least 6 months after the last dose. Treatment is contraindicated in patients with hepatic dysfunction (including ALT or AST >2 x ULN).
There is also a severe warning about the risk of immune-mediated disorders, such as skin reactions, lymphadenopathy, autoimmune hemolytic anemia and GI disorders (e.g. colitis). Daclizumab may exacerbate pre-existing skin disorders, such as psoriasis or eczema. Also noteworthy is an increased incidence of depression with daclizumab (5% vs. 1% with placebo; 8% vs. 6% with IFNbeta).
The most common adverse effects reported with daclizumab include rash, elevated ALT and depression (vs. placebo); and nasopharyngitis, upper respiratory tract infection, influenza, oropharyngeal pain, rash and lymphadenopathy (vs. IFNbeta).