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Daclizumab is a humanized monoclonal antibody that binds to the α subunit (CD25) of the interleukin-2 receptor and favorably modulates the immune environment in multiple sclerosis (MS). Blockage of CD25, among other effects, causes expansion and enhanced function of regulatory CD56bright natural killer cells, which seems to be the leading mechanism of action in MS. Phase II and III clinical trials have demonstrated that monthly subcutaneous injections of daclizumab high yield process (DAC HYP) 150 mg in patients with relapsing MS led to a significant reduction of annualized relapse rate and decreased number of contrast-enhanced lesions on brain magnetic resonance imaging. Treatment with DAC HYP had efficacy superior to treatment with weekly injections of interferon β1a. This review summarizes the development of and clinical experience with daclizumab in MS.
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) that leads to accumulation of demyelination, axonal loss and irreversible damage of the CNS resulting in disability. Immunosuppresants have been used in the treatment of autoimmune diseases, including MS, since the 1960s [Stankiewicz et al. 2013]. Further work in characterizing the pathophysiology of MS has led to the development of treatments more specifically targeting the inflammatory process. Over the last two decades, a number of treatments have been tested in a quest to stop or reduce the disease progression.
Interleukin 2 (IL-2), also called a ‘T-cell growth factor’ and IL-2 receptor (IL-2R) drive T-cell proliferation and could be targeted in the treatment of lymphoproliferative and autoimmune disorders [Waldmann, 1993, 2007]. Logically, as IL-2 and IL-2R play a key role in proliferation of autoreactive T cells in MS [Markovic-Plese et al. 2004], the manipulation of the IL-2 pathway was investigated in treating MS. The rationale for targeting this pathway is further supported by newer genetic studies which suggest that the IL-2 pathway may be aberrant in MS and responsible for a loss of immune tolerance [Cheng et al. 2011; Liao et al. 2013; Lowe et al. 2007].
Discovery of structural and functional properties of IL-2 receptors has been critical for the comprehension of the IL-2 pathway [Smith, 2006]. Not all IL-2 receptors exhibit the same level of activity. Intermediate-affinity IL-2Rs consist of the noncovalently linked IL-2Rβ chain (CD122) and the IL-2Rγ chain that contains the binding sites for kinases involved in the IL-2R signal transduction. High-affinity IL-2R includes, in addition to β and γ chains, the IL-2Rα chain (CD25), which does not induce the IL-2R signal transduction on its own, but helps to capture IL-2 on the cell surface, thereby increasing the binding affinity of the receptor 100 times [Wiendl and Gross, 2013].
Daclizumab (DAC), a humanized monoclonal antibody targeting the α subunit (CD25) of the high-affinity IL-2R expressed on activated T cells, has multiple effects on MS pathology. This review summarizes the development of and clinical experience with DAC high yield process (DAC HYP) as a new treatment option for MS.
The first formulation of DAC, a monoclonal antibody against the α chain of IL-2R (anti-CD25), was approved by the US Food and Drug Administration (FDA) in 1997 for the prophylaxis of acute organ rejection in allogenic renal transplantation (Zenapax, Hoffmann-La Roche, Nutley, NJ, USA) and used in combination with cyclosporine and corticosteroids [Wiseman and Faulds, 1999]. The initial proof-of-concept, open-label studies that provided evidence of anti-CD25 efficacy in MS used DAC manufactured by Roche [Bielekova et al. 2009, 2004; Rose et al. 2007, 2004]. Production of Zenapax was discontinued by 2010 when Roche terminated collaboration with PDL BioPharma (Incline Village, NV, USA) and stopped its clinical development [PharmaTimes, 2006]. Investigations of DAC in MS continued to be carried out by an intramural National Institutes of Health (NIH) team [Bielekova et al. 2004], which also discovered its novel mechanism of action (MOA).
The CHOICE study (Study of Subcutaneous DAC in Patients with Active Relapsing Forms of MS; a phase II, randomized, double-blind, placebo-controlled, add-on trial with interferon β, sponsored by PDL BioPharma, Incline Village, NV, USA) used a subcutaneous formulation of DAC produced in Penzberg, Germany [Wynn et al. 2010]. The final formulation of the humanized monoclonal antibody against CD25 called DAC HYP was developed jointly by Biogen Idec (Cambridge, MA, USA) and Abbott Biotherapeutics Corporation (Redwood City, CA, USA). It shares an identical amino acid sequence with the original Zenapax preparation, but a different production process resulted in a different glycosylation pattern of the molecule, which affects binding of DAC to Fc receptors and decreases antibody-dependent cellular toxicity [Bielekova, 2013]. DAC HYP and former Zenapax also differ in pharmacokinetics (PK) [Tran et al. 2016].
The initial therapeutic rationale for use of DAC in MS was based on the presumption that blocking the IL-2R on autoreactive T cells and breaking the autocrine IL-2 signaling loop will directly suppress T-cell expansion and thus inhibit disease activity. However, an observation in the first open-label trial with DAC in MS, that the suppression of contrast-enhanced lesions was not immediate, but gradual over the first 2 months of treatment, suggested that the drug may act through different immunomodulatory effects [Bielekova et al. 2004]. DAC therapy was associated with a relatively mild decline in circulating T cells, but significant expansion of CD56 bright natural killer (NK) cells and this effect correlated with the treatment response [Bielekova et al. 2006]. Since then, it has been shown that this unexpected expansion of NK cells is driven by increased availability of IL-2 to intermediate activity IL-2Rs on CD56 bright NK cells as a result of anti-CD25 blockage [Martin et al. 2010]. As we currently understand the effects of DAC in MS, the blockage of CD25 results in several changes [Wiendl and Gross, 2013; Bielekova et al. 2011]:
DAC HYP has characteristics of a typical immunoglobulin G, subclass 1 (IgG1) monoclonal antibody with slow absorption, linear PK at doses above 100 mg administered subcutaneously, high bioavailability, small volume distribution and slow clearance. Baseline CD25 levels, age and sex did not influence DAC HYP PK, and variability related to body weight does not seem to be clinically relevant [Diao et al. 2016; Tran et al. 2016].
NIH pioneered the initial open-label trials of intravenously administered DAC in patients with relapsing MS (see Table 1). These studies have demonstrated that monthly intravenous administration of DAC in patients with an incomplete response to interferon β leads to a significant decline in contrast-enhanced lesions on brain magnetic resonance imaging (MRI) and stabilization of clinical outcomes [Bielekova et al. 2009, 2004; Rose et al. 2007, 2004]. Although limited in design and size, these studies provided an important insight into the MOA and a strong lead for future clinical development of this treatment strategy (described in detail by Bielekova) [Bielekova, 2013].
The first placebo-controlled trial of DAC, the CHOICE study, used DAC in a high dose (2 mg/kg) and a low dose (1 mg/kg) administered subcutaneously every 4 weeks as an add-on to interferon β. The high-dose treatment led to a 72% decrease and the low dose to a 25% decrease in the number of contrast-enhanced lesions in comparison to placebo plus interferon β treatment [Wynn et al. 2010].
The clinical development of DAC HYP (Table 2) started with a phase IIb SELECT trial (Safety and Efficacy Study of DAC HYP to Treat Relapsing–Remitting Multiple Sclerosis) [ClinicalTrials.gov identifier: NCT00390221] [Gold et al. 2013]. This multicenter, double-blind, placebo-controlled, dose-ranging study tested two doses of DAC HYP monotherapy (150 mg and 300 mg) administered subcutaneously every 4 weeks for 1 year. The study was open to patients with relapsing MS, an Expanded Disability Status Scale (EDSS) score under 5.5 and disease activity within 1 year before randomization as evidenced by a presence of one new gadolinium-enhanced lesion on a brain MRI scan or an occurrence of a relapse. Six hundred and twenty-one patients, mostly treatment naïve (over 75%), with a mean EDSS score of 2.7 were randomized equally into three treatment groups. The primary endpoint was the annualized relapse rate (ARR) at week 52 and secondary endpoints included a cumulative number of new gadolinium-enhanced lesions on brain MRI scans obtained in a subset of 307 patients at months 2–6 of treatment and a number of new or enlarging T2 hyperintensities at week 52. The primary endpoint was met in both treatment groups by a decrease in ARR (54.3% in the high-dose group, 50% in the low-dose group) in comparison to the placebo group (p < 0.001). Both doses of DAC inhibited the formation of gadolinium-enhanced lesions (by 68.8% and 79.2%; p < 0.001) and new or enlarging T2 lesions (by 70.4% and 79.0%; p < 0.001) on brain MRI [Gold et al. 2013]. The therapy was well tolerated with a similar discontinuation rate in the placebo and DAC HYP arms.
Ninety-one percent of patients (n = 517) from the SELECT study continued treatment for another year in the SELECTION study [ClinicalTrials.gov identifier: NCT00870740] [Giovannoni et al. 2014; Kappos et al. 2015]. The primary aim of the SELECTION study was to assess the safety and immunogenicity of extended treatment with DAC HYP and the impact of washout on disease activity. Patients who received placebo in the SELECT study were randomly assigned (1:1) to receive 150 mg (n = 86) or 300 mg (n = 84) of subcutaneous DAC HYP every 4 weeks for 52 weeks in this extension study. Patients who had been on active treatment with DAC HYP for the past 52 weeks of the SELECT study were randomized to either continue with their present dose (n = 172) or to washout for 24 weeks and reinitiate their prior dose (n = 175). Overall, the adverse events (AEs) and immunogenicity were not increased in the second year of continuous treatment with DAC HYP or during treatment washout and reinitiation. One patient in the washout and reinitiation group (300 mg DAC HYP) died because of autoimmune hepatitis; a contributory role of DAC HYP could not be excluded. The reduction of disease activity achieved in the first year of treatment was maintained in patients continuing treatment without washout. The 24-week washout prior to reinitiation of treatment with DAC HYP led to the return of clinical, imaging and laboratory characteristics to pretreatment values without evidence of rebound of disease activity above the pretreatment period. Treatment response in the second year after reinitiation of DAC HYP was not different from the initial year of treatment.
Patients who completed the SELECTION study had an option to continue in the SELECTED study [ClinicalTrials.gov identifier: NCT01051349]. The study enrolled 90% of eligible patients (n = 410), who will continue in open-label treatment with 150 mg of DAC HYP every 4 weeks for up to 6 years. An interim intent-to-treat analysis performed in January 2014 (median number of DAC doses administered over life = 48, range 13–74) has shown that 104 (25%) patients in SELECTED had discontinued treatment (48 due to AEs). Overall, the incidence of AEs, serious AEs and treatment-related study discontinuations did not increase over the SELECTED study [Gold et al. 2016]. The adjusted ARR was 0.15 [95% confidence interval (CI) 0.10–0.21] by weeks 121–144 of treatment with DAC (n = 398) and the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93–1.72) by year 3 in comparison to 1.95 (1.60–2.37) in year 1 of treatment [Gold et al. 2016]. Selection bias inherent to open-label studies needs to be considered when interpreting these results.
Post hoc analysis of brain MRI scans obtained in a subgroup of patients in the SELECT study every 4 weeks between weeks 4 and 24 and then at weeks 36 and 52 revealed that treatment with DAC HYP significantly reduced the number of T1 black holes at week 52 that evolved from new gadolinium-enhanced lesions [Radue et al. 2016]. This observation suggests that inflammatory lesions that occurred during DAC HYP treatment were less destructive than lesions occurring in patients treated with placebo.
Brain atrophy results from post hoc analysis of SELECT and SELECTION studies have been presented as a poster at the 2014 American Academy of Neurology meeting. Greater decrease in the whole brain volume over the first 6 months of study in patients treated with 150 mg of DAC HYP was −0.41% versus −0.32% in the placebo group, consistent with pseudo atrophy that resolved by month 12 [Radue et al. 2014]. An interim analysis of the SELECTED study has shown that the mean annualized brain volume change was −0.77% in year 1 (n = 383) and decreased to −0.57% in year 2 (n = 362) and to −0.32% in year 3 (n = 293) of treatment with DAC [Gold et al. 2016].
Since DAC HYP was being developed in the context of multiple treatment options approved for relapsing MS, an active control phase III study was designed to prove superior efficacy of DAC HYP to one of the first-line treatments [Kappos et al. 2015]. The DECIDE study [ClinicalTrials.gov identifier: NCT01064401] is an international phase III, randomized, double-blind clinical trial of 96 weeks of monotherapy with DAC HYP 150 mg versus interferon β 1a (Avonex, Biogen, Cambridge, MA, USA) in MS. A total of 1841 patients enrolled in the study had relapsing MS with a mean duration of symptoms of almost 7 years [standard deviation (SD) 6.3], mean EDSS score of 2.5, an ARR of 12 months prior to the baseline 1.5 (SD 0.7) and were randomized in the double dummy design to weekly administration of 30 mg of intramuscular interferon β 1a (n = 922) or 150 mg of DAC HYP (n = 919) administered subcutaneously every 4 weeks. Fifty-nine percent of study participants were treatment naïve. Some patients continued treatment for up to 144 weeks, waiting until the last enrolled patient in the study completed the planned week 96. The primary endpoint, the adjusted ARR over the duration of the treatment (up to 144 weeks), was 45% lower in the DAC HYP group than in the interferon group (0.22 versus 0.39, p < 0.001). The number of new/enlarging lesions on T2-weighted images at week 96 was 54% lower in the DAC HYP group than in the interferon group (p < 0.001). The estimated percentage of patients meeting criteria of disability progression on EDSS confirmed at 3 months [Kappos et al. 2015] was 16% in the DAC HYP group and 20% in the interferon group (p = 0.158) According to the statistical plan, as this second-order secondary endpoint was not significant, all lower-order secondary endpoints lost significance in a preplanned analysis despite their favorable results. The proportion of patients who were relapse free at week 144 of the study was 67% in the DAC HYP group and 51% in the interferon group. Clinically meaningful worsening on the Multiple Sclerosis Impact Scale (MSIS-29) physical subscale was observed in 19% of the DAC HYP group and 23% of the interferon group.
The amount of inflammatory activity in the brain, measured by gadolinium, was reported among tertiary exploratory outcomes. The total number of gadolinium-enhanced lesions at week 96 was significantly lower in the DAC HYP group than in the interferon group (0.4 versus 1.0, odds ratio 0.25, p < 0.001) [Kappos et al. 2015].
Patients, who completed the DECIDE study had an option to continue treatment in the EXTEND study [ClinicalTrials.gov identifier: NCT01797965]. This phase III, open-label, long-term extension study is designed to evaluate the safety and efficacy of 150 mg of subcutaneous DAC HYP every 4 weeks in up to 1600 patients, and is estimated to be complete by August 2019.
Treatment with subcutaneous injections of DAC HYP have been well tolerated. The side effects of treatment with DAC in MS studies occurred mostly in four categories: hepatopathy, skin abnormalities, lymphadenopathy and infections.
Elevation of liver function tests (LFTs) one to three times the upper limit of normal (ULN) have occurred in similar numbers in placebo, low-dose and high-dose treatment groups of the SELECT study, however more patients treated with DAC (4%) had an increase in LFTs above five times the ULN than patients on placebo (1%) [Gold et al. 2013]. Similarly, in the second year of treatment (SELECTION study), the elevation above five times the ULN occurred in 2% of patients (n = 11). Ten of these patients resumed treatment without recurrence of hepatopathy. One patient died because of a diagnosis of autoimmune hepatitis that was made late in the disease course, and a contributory role of 300 mg of DAC HYP could not be excluded [Giovannoni et al. 2014]. In the DECIDE study, the elevation of LFTs above five times the ULN occurred in 3% of patients treated with interferon β 1a (mostly in the first year) and in 6% of patients treated with DAC HYP (evenly distributed throughout the 144 weeks of study) [Kappos et al. 2015]. Occurrence of these side effects resulted in a black box warning on approval of DAC HYP by the FDA.
A variety of skin side effects have been reported during the clinical development of DAC. The skin abnormalities have been characterized as eczema, urticaria, contact dermatitis, folliculitis, erythema nodosum, pityriasis rosea, exfoliative dermatitis, seborrheic dermatitis, alopecia, pruritus and psoriasis. The lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates [Cortese et al. 2016]. Most of these abnormalities have resolved after topical steroid treatment or spontaneously. Mild to moderate skin reactions occurred in about 20% of patients treated with DAC HYP in the SELECT study, and serious skin reactions were reported in less than 1% of DAC HYP treated subjects. In the DECIDE study, cutaneous events were reported in 37% of patients treated with DAC HYP (5% discontinued) and in 19% of patients treated with interferon β (1% discontinued) [Krueger et al. 2016].
The incidence of infections increased overall, but not dramatically, in patients treated with DAC HYP. Serious infections reported in the CHOICE study (2%) included appendicitis, gastroenteritis, hepatitis B, peritonsillar abscess, sinusitis, urinary tract infection, cytomegalovirus and Yersinia infection. One patient, who was recovering from a serious rash, died due to a complication of a psoas abscess [Wynn et al. 2010]. In the DECIDE study, infections were reported in 65% of patients on DAC HYP and in 57% of patients in the interferon group, and included mostly nasopharyngitis, upper respiratory tract infections and urinary tract infections. Serious infections occurred in 4% of patients on DAC HYP and in 2% of patients on interferon, and included urinary tract infection, pneumonia, appendicitis, cellulitis and viral infection. The incidence of herpes virus infection was similar in both treatment groups (8% and 7% respectively). There were no opportunistic infections [Kappos et al. 2015].
An occurrence of lymphadenopathy was noted in one out of 147 patients treated with DAC HYP in the SELECT study [Gold et al. 2013] and serious lymphadenopathy was reported in two patients in the SELECTED study [Gold et al. 2016]. In the DECIDE study, there were five reported cases of lymphadenopathy (as serious AEs) in patients treated with DAC HYP (1%) that led to discontinuation of treatment [Kappos et al. 2015]. A case of lymphadenopathy has been described in detail in a patient with MS treated off label with Zenapax for 42 months. Lymph node biopsy demonstrated lymphocytic infiltrate with CD56 expressing cells and the lymphadenopathy resolved with discontinuation of therapy. There was no evidence of lymphoma [Oh et al. 2014].
Six patients (1%) reported serious gastrointestinal events by interim analysis of the SELECTED study, including three cases of ulcerative colitis and one case each of colitis, Crohn’s disease and hemorrhagic enterocolitis [Gold et al. 2016].
Other types of immune-mediated or autoimmune conditions that were observed in two or more DAC HYP treated patients include type I diabetes, celiac disease, autoimmune thyroiditis, immune hemolytic anemia, thrombocytopenia, pancreatitis, glomerulonephritis, sarcoidosis, rheumatoid arthritis, thyroiditis and sialadenitis [Zinbryta, 2016]. There was one case of small-vessel CNS vasculitis described in a patient treated with DAC (Zenapax) off label after completion of the phase II study at NIH (21 doses) [Ohayon et al. 2013]. A report of patients treated off label with Zenapax at Johns Hopkins has revealed the occurrence of diffuse rash, alopecia and diffuse lymphadenopathy (reversible upon discontinuation of treatment) [Oh et al. 2014].
An explanation for the development of these autoimmune conditions during treatment with DAC is not known, however it has been pointed out that CD25 is highly expressed not only on effector T cells but also on regulatory T cells [Boyman and Sprent, 2012]. The loss or dysfunction of CD4+CD25+ regulatory T cells has been implicated in the pathogenesis of a number of autoimmune conditions, including systemic lupus erythematosis and psoriasis [Oh et al. 2009].
There were three malignancies reported in the DAC HYP group in the SELECT study (two melanomas and one cervix carcinoma) that were deemed unrelated to treatment. One patient in the SELECTION study developed breast carcinoma. Less than 1% of patients on interferon and 1% of patients on DAC HYP developed a malignant condition in the DECIDE study.
In 2016, the FDA and the European Medicines Agency approved DAC HYP as Zinbryta 150 mg prefilled syringes for subcutaneous administration every 4 weeks for the treatment of patients with MS. A risk evaluation and mitigation strategy program installed for Zinbryta is a necessary provision for any new immunomodulatory medication that may lead to severe or unexpected side effects. The position of DAC in clinical practice will evolve over the next few years owing to the limited knowledge of the long-term safety of this treatment approach. Nevertheless, a drug with a novel targeted MOA, significant efficacy, good tolerability and relatively convenient administration may become a significant addition to the armamentarium of treatments for MS.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research is supported by the Czech Ministry of Education project PRVOUK-P26/LF1/4.
Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Jana Lizrova Preiningerova, Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Praha 2, Praha, 121 08, Czech Republic.
Marta Vachova, Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, Faculty of Medicine and General University Hospital in Prague, Praha, Czech Republic.