Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study

Abstract

Background: Daclizumab is a humanized monoclonal antibody against CD25 that modulates interleukin 2 signaling. The SELECT TRILOGY of clinical studies (SELECT/SELECTION/SELECTED) evaluated the safety and efficacy of daclizumab in patients with relapsing-remitting multiple sclerosis (RRMS). We report the long-term safety and efficacy of daclizumab 150 mg subcutaneous every 4 weeks in patients with RRMS in the SELECTED open-label extension study.

Methods: An interim intent-to-treat analysis of all enrolled patients was performed in January 2014 for this ongoing study.

Results: The SELECTED study enrolled 90% of patients who completed SELECTION. In the safety and efficacy analysis (N = 410), median treatment time in SELECTED was 25 months (range, <1-45). Adverse events (AEs) were reported in 76% of patients, serious AEs (SAEs) excluding MS relapse in 16%, and treatment discontinuation due to AEs including multiple sclerosis (MS) relapse in 12%. AEs were primarily of mild to moderate severity, and common AEs (≥10%), excluding MS relapse, were nasopharyngitis (12%) and upper respiratory tract infection (12%). Most commonly reported SAEs (in ≥3 patients), excluding MS relapses, were increased serum hepatic enzymes, pneumonia, ulcerative colitis, and urinary tract infection (<1% each). Incidences of AE groups of interest include cutaneous events (28%), cutaneous SAEs (2%), gastrointestinal SAEs (2%), hepatic SAEs, (1%) and malignancies (1%). The incidence of AEs, SAEs, and treatment-related study discontinuations did not increase over time and no deaths were reported. The adjusted annualized relapse rate (95% confidence interval (CI)) analyzed at 6-month intervals was 0.15 (0.10-0.22) for weeks 97-120 and 0.15 (0.10-0.21) for weeks 121-144. In year 3, the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93-1.72) and the mean (median) annualized change in brain volume was -0.32% (-0.34%).

Conclusions: The AE incidence did not increase with extension of therapy into year 3 in SELECTED; the safety profile was similar to that previously observed. The clinical efficacy of daclizumab was sustained over the 3 years comprising the SELECT TRILOGY, although potential selection bias cannot be excluded.

Trial registration: Clinicaltrials.gov NCT01051349; first registered January 15, 2010.

Keywords: Daclizumab; Efficacy; Relapsing-remitting multiple sclerosis; Safety.

Fig. 1

SELECT TRILOGY study design. The dosing regimen for study drug (ie, placebo or daclizumab) was subcutaneous (SC) every 4 weeks in all three studies of the SELECT TRILOGY [3, 4]. *Gold et al. [3]. ^†Giovannoni et al. [4]

Fig. 2

SELECTED trial profile. Since the duration of SELECTED is over 5 years, based on first patient dosed date of 31 March 2010, no patient had completed the study as of the data cutoff for this manuscript. AE Adverse event

Fig. 3

Adjusted annualized relapse rate (ARR) by 6-month intervals. Results from the SELECT placebo group have been published previously [3]. Adjusted ARR in SELECTED was estimated from a Poisson regression adjusted for the number of relapses in the year before study entry. Rates were estimated by time interval from the first dose of daclizumab received. *Gold et al. [3]

Fig. 4

Adjusted mean number of new/newly enlarging T2 hyperintense lesions. Results from the SELECT placebo group have been published previously [3]. The adjusted mean number of T2 hyperintense lesions was estimated from a negative binomial regression adjusted for baseline number of T2 hyperintense lesions. *Gold et al. [3]

Fig. 5

Mean (median) annualized percentage brain volume change (PBVC). Results from the SELECT placebo group have been published previously [3]. The annualized PBVC was determined with Structural Image Evaluation using Normalization of Atrophy (SIENA) and was calculated as percentage change divided by the number of days since the last scan multiplied by 365.25. For PBVC endpoints, patients with any post-baseline magnetic resonance imaging assessment in the efficacy population were included in the analysis. *Gold et al. [3]