Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis

Abstract

Despite the availability of multiple disease-modifying therapies for relapsing multiple sclerosis (MS), there remains a need for highly efficacious targeted therapy with a favorable benefit-risk profile and attributes that encourage a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Daclizumab treatment leads to antagonism of proinflammatory, activated T lymphocyte function and expansion of immunoregulatory CD56(bright) natural killer cells, and has the potential to, at least in part, rectify the imbalance between immune tolerance and autoimmunity in relapsing MS. The clinical pharmacology, efficacy, and safety of subcutaneous daclizumab have been evaluated extensively in a large clinical study program. In pivotal studies, daclizumab demonstrated superior efficacy in reducing clinical and radiologic measures of MS disease activity compared with placebo or intramuscular interferon beta-1a, a standard-of-care therapy for relapsing MS. The risk of hepatic disorders, cutaneous events, and infections was modestly increased. The monthly subcutaneous self-injection dosing regimen of daclizumab may be advantageous in maintaining patient adherence to treatment, which is important for optimal outcomes with MS disease-modifying therapy. Daclizumab has been approved in the US and in the European Union and represents an effective new treatment option for patients with relapsing forms of MS, and is currently under review by other regulatory agencies.

Keywords: daclizumab; disease-modifying therapy; humanized monoclonal antibody; relapsing multiple sclerosis; therapeutic use.

Figure 1

The SELECT and DECIDE studies and their extension studies.,,–, Notes: (A) In SELECT, patients with RMS were randomized to receive daclizumab 150 or 300 mg subcutaneously every 4 weeks or placebo for 52 weeks. Patients who completed SELECT were eligible to enroll in the SELECTION extension study. In SELECTION, patients from the placebo group in SELECT were re-randomized to receive daclizumab 150 or 300 mg subcutaneously every 4 weeks for 52 weeks; patients from the daclizumab 150 and 300 mg treatment arms in SELECT were re-randomized to continue their assigned dosage of daclizumab or to 20 weeks of placebo treatment followed by reinitiation of their previously assigned dosage of daclizumab for 32 weeks. In the placebo washout group, the period of time between the last daclizumab dose in SELECT and reinitiation of daclizumab in SELECTION was a total of 24 weeks. Patients who completed SELECTION were eligible to enroll in the ongoing open-label SELECTED study in which all patients received daclizumab 150 mg for up to 6 years., (B) In DECIDE, patients were randomized to receive daclizumab 150 mg subcutaneously every 4 weeks or IFN beta-1a 30 mcg IM once weekly for a minimum of 96 weeks up to a maximum of 144 weeks; the study ended when the last enrolled patient completed the week 96 visit. Patients who completed DECIDE were eligible to enroll in the ongoing EXTEND safety extension study in which all patients received daclizumab 150 mg for up to 6 years of total time on treatment. Abbreviations: IM, intramuscular; IFN, interferon; RMS, relapsing multiple sclerosis.

Figure 2

Proposed mechanism of action of daclizumab and effects on key immune cell populations. Notes: (A) IL-2 binds with higher affinity to the heterotrimeric IL-2R complex composed of CD25, CD122, and CD132 than to the heterodimeric intermediate-affinity IL-2R composed of the CD122 and CD132 subunits. (B) Daclizumab binds to CD25 and prevents formation of the high-affinity receptor complex, which increases the availability of IL-2 to bind and signal through the intermediate-affinity receptor complex.,, (C) Blockade of CD25 has effects on several different immune cell populations in patients with MS, most notably proinflammatory, activated T lymphocytes, CD56^bright NK cells, and T_REG cells.,,,–,, Abbreviations: IL-2R, interleukin 2 receptor; IL-2, interleukin 2; MS, multiple sclerosis; Tact, activated T cell; NK, natural killer; T_REG, regulatory T cell.

Figure 3

Changes from baseline to weeks 52 and 96 in health-related quality-of-life endpoints in SELECT and DECIDE., Notes: ^aNominal P-value. Comparison was not considered statistically significant within the sequential closed testing procedure for secondary endpoints. (A) Change from baseline to week 52 or 96 in MSIS-29 PHYS and PSYCH subscale scores. (B) Change from baseline to week 52 or 96 in EQ-5D VAS and Index scores. In both the DECIDE and SELECT studies, between treatment group differences in MSIS-29 PHYS and PSYCH scores and EQ-5D VAS and index scores were evaluated using analysis of covariance models adjusting for baseline factors. The statistical models are detailed in the original articles., SELECT data adapted with permission from Elsevier (The Lancet, 2013, 381, 2167–75). Abbreviations: MSIS-29, 29-item Multiple Sclerosis Impact Scale; PHYS, physical impact subscale; PSYCH, psychological impact subscale; IM, intramuscular; IFN, interferon; EQ-5D, EuroQol 5-Dimensions; VAS, visual analog scale.