Long-term safety and efficacy of daclizumab beta in relapsing–remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study

Abstract

Objective SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED. Methods Eligible participants who completed 1–2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION. Results Ninety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0–24 was 0.21 (0.16–0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time. Conclusions The effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED. Trial registration Clinicaltrials.gov NCT01051349; first registered on January 15, 2010.

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

“…Daclizumab beta (Zinbryta™) was approved in 2016 by the FDA and European Medicines Agency (EMA) based on findings from two large phase IIb (CHOICE and SELECT) [ 30 , 31 ] and one phase III (DECIDE) [ 32 ] study. SELECT was followed by the extension studies SELECTION [ 33 ] and SELECTED [ 34 ], while patients of the DECIDE were followed in the EXTEND study [ 35 ].…”

“…Overall, frequencies of AEs and SAEs were similar between the treatment initiation and continuous treatment groups [ 33 ]. 90% (410/455) participants who completed SELECT and SELECTION received DAC-HYP 150 mg s.c. every 4 weeks for up to 6 years in the open-label extension study SELECTED (NCT01051349) (69% for > 3 years, 39% for > 4 years, and 9% for > 5 years) [ 34 ]. The efficacy of DAC-HYP on clinical and radiological disease activity was maintained throughout the study for up to ~ 8 years [ 34 ].…”

“…A variety of cutaneous AEs, mainly rash and eczema, occurred in up to one-third of patients, were mostly mild to moderate in intensity and resolved either spontaneously or after standard interventions [ 38 ]. Serious cutaneous events (e.g., exfoliative rash or dermatitis, toxic skin eruption, drug reaction with eosinophilia, and systemic symptoms (DRESS) syndrome) developed in < 1 to 2% under 150 mg DAC-HYP in the pivotal studies and up to 4% in the extension studies [ 30 , 34 , 35 ].…”

“…Across all clinical studies, immune-mediated disorders occurred in 28% of patients on DAC-HYP, including lymphadenopathy and skin reactions [ 27 , 39 ]. Immune-mediated SAEs developed in three patients in the SELECT trial under 300 mg daclizumab (thyroiditis, Crohn’s disease, hypersensitivity) [ 30 ], in five patients in the SELECTION trial (hepatitis, Graves’ disease, glomerulonephritis, and two cases of ulcerative colitis) [ 33 ], and in eight patients in SELECTED (two cases of hepatitis and uveitis, one case of vitiligo, morphoea, rheumatoid arthritis, and Sjögren’s syndrome) [ 34 ]. Surprisingly, no immune-mediated condition secondary to daclizumab treatment was reported in the DECIDE trial [ 32 ].…”

Monoclonal Antibodies as Neurological Therapeutics

“…Its net effect is thought to be a suppression of T-cell responses and expansion of CD56bright natural killer cells [ 18 ]. It was tested in subcutaneous injections against placebo and interferon-β-1α and demonstrated efficacy in RRMS [ 19 , 20 , 21 ]. Nevertheless, the high affinity IL-2 receptor is also present on natural regulatory T cells (CD4CD25Foxp3 Tregs), which are decreased by 60% under daclizumab treatment [ 22 ].…”