Safety and efficacy of daclizumab beta in patients with relapsing multiple sclerosis in a 5-year open-label study (EXTEND): final results following early termination

Abstract

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study.

Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors.

Results: The total safety population (N = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years.

Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.

Keywords: autoimmunity; daclizumab; encephalitis; multiple sclerosis.

Figure 1.

EXTEND study design. ^aIn DECIDE, participants with MS who met key eligibility criteria were randomly assigned 1:1 to receive DAC beta 150 mg SC every 4 weeks or IM IFN beta-1a 30 µg once weekly for ⩾96 weeks and up to 144 weeks (or until the last enrolled participant completed the week 96 study visit, whichever came first). ^bApproximately 300 participants who transitioned from the long-term, open-label SELECTED extension study and the open-label OBSERVE immunogenicity and pharmacokinetics study entered EXTEND at week 144. This paper reports only on participants who enrolled from DECIDE; it does not include data from those who transitioned from SELECTED or OBSERVE. DAC, daclizumab; IFN, interferon; IM, intramuscular; MS, multiple sclerosis; SC, subcutaneous.

Figure 2.

Disposition of participants in the EXTEND study. AE, adverse event; DAC, daclizumab; IFN, interferon; ITT, intention-to-treat. ^aOne participant assigned to the Continuous DAC beta group discontinued before receiving treatment in EXTEND.

Figure 3.

ARR for treatment groups in DECIDE and for IFN/DAC beta and continuous DAC beta-treated participants in EXTEND. ARR, annualized relapse rate; CI, confidence interval; DAC, daclizumab; IFN, interferon; IM, intramuscular.

Figure 4.

Time to (a) first relapse and (b) 24-week CDP^a among IFN/DAC beta- and continuous DAC beta-treated participants in the DECIDE-EXTEND population.^{b,c a}CDP was defined as a ⩾1.0-point increase in EDSS score from a DECIDE baseline EDSS score of ⩾1.0 sustained for 24 weeks or a ⩾1.5-point increase in EDSS score from a DECIDE baseline EDSS score of 0 sustained for 24 weeks. ^bIFN/DAC beta refers to participants who received IM IFN beta-1a in DECIDE and switched to DAC beta in EXTEND and participants who received IM IFN beta-1a in DECIDE and did not enroll in EXTEND. Continuous DAC beta refers to participants who received DAC beta in DECIDE and EXTEND and participants who received DAC beta in DECIDE and did not enroll in EXTEND. ^cParticipants in DECIDE were treated with IM IFN beta-1a or DAC beta for 96–144 weeks before they enrolled in EXTEND open-label treatment with DAC beta. BL, baseline; CDP, confirmed disability progression; DAC, daclizumab; EDSS, Expanded Disability Status Score; IFN, interferon; IM, intramuscular.