Drug Safety Evaluation
A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis 1.
Introduction
2.
Clinical trials in MS
3.
Safety
4.
Biomarkers of DAC treatment
Emanuele D’Amico, Silvia Messina, Cinzia Caserta & Francesco Patti† †
Universita´degli Studi di Catania, Dipartimento di Neurologia, Catania, Italy
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
response: going towards a personalized treatment in MS? 5.
Conclusions
6.
Expert opinion
Introduction: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS). Areas covered: In this review, we will focus on newly emerging DAC-highyield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety. Expert opinion: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing-remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/ risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice. Keywords: daclizumab, mAb, multiple sclerosis, safety Expert Opin. Drug Saf. (2015) 14(7):1157-1168
1.
Introduction
Daclizumab (DAC) (Box 1) is a humanized mAb of IgG1 subtype that binds to the high-affinity IL-2 receptor (IL-2R) a-chain (CD25) [1,2]. IL-2 is most well characterized as a T-cell growth factor due to its mitogenic effect on T cells, promoting the expansion of activated T cells in vitro through the high-affinity IL-2 receptor [3]. DAC was designed as a therapy that selectively inhibits T-cell activation and received regulatory approval as add-on therapy to standard immunomodulatory regimen for the prevention of acute allograft rejection in renal transplantation. Later, it was presented as a putative therapy for T-cell-mediated autoimmune diseases such as inflammatory uveitis and multiple sclerosis (MS) (see in review [4]). Three forms of DAC have been tested in humans so far: intravenously (iv.) administered DAC (Zenapax) was tested and previously approved for treatment after renal transplantation (it has been discontinued for the US market since 2009); subcutaneously (sc.) administered DAC (Penzberg, produced in Penzberg, Germany) has been used in the CHOICE trial (see below) and sc. DAC-high-yield process (HYP) has been tested in three Phase I studies, and in the SELECT trial (see below) [5]. All three forms show similar biological effects concerning CD25 binding and IL-2 blockade. All DAC doses tested in the CHOICE and in the SELECT trial supersaturate CD25 receptors by a factor of more than 10. The three DAC formulations are manufactured differently and differ in their glycosylation pattern. Therefore, MS DAC trials performed with different formulations should be compared with caution [5]. 10.1517/14740338.2015.1032937 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1157
E. D’Amico et al.
Box 1. Drug summary Drug name (generic)
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action
Daclizumab high-yield process (DAC-HYP) III Relapsing-remitting-multiple sclerosis
Daclizumab blocks the activity of IL-2, a chemical messenger in the immune system, and interferes with the growth of lymphocytes Route of administration Daclizumab is given as an injection under the skin every 4 weeks Chemical structure C6332H9808N1678O1989S42 Pivotal trial(s) The DAC-HYP development program includes the completed pivotal, placebo-controlled, doubleblind SELECT study Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
The past two decades have seen major advances in the treatment of MS due to the better understanding of the immune pathogenesis of the disease and that has resulted in new therapies capable of reducing disease activity (see in review, [6]). With the advent of mAbs technology, several humanized and fully human mAbs were developed to target specific key molecules and immune cell subpopulations involved in the immune cascade that is believed to lead to inflammation, demyelination and axonal loss in MS [5]. In this review, we will discuss the available efficacy and safety data from clinical trials of DAC and DAC-HYP therapy in MS, after a detailed description of its mechanism of action. Moreover, we will discuss the DAC’s putative place in the treatment of MS. Mechanism of action of DAC DAC is a humanized mAb directed against the CD25 subunit of the high-affinity IL-2 receptor. It is a competitive inhibitor of the high-affinity IL-2R, which is expressed predominantly on activated lymphocytes [7]. The high-affinity IL-2R consists of three chains: a non-signaling a-chain (CD25), a signaling b-chain (CD122) and a signaling g-chain (CD132). The achain (CD25) that forms the high-affinity IL-2R together with the b and g chains is expressed at low levels in resting T cells and it is rapidly upregulated in activated T cells. It is also constitutively expressed at high levels on FoxP3+ regulatory T cells (Tregs), which are dependent on IL-2 for their homeostasis [8]. Approximately 30% of human peripheral blood B cells express CD25; and B cells expressing CD25 display a mature phenotype and have a better proliferative and antigen-presenting capacity. Moreover, CD25 is expressed on macrophages that have been found histologically to be activated in MS [7]. In the National Institutes of Health 1.1
1158
(NIH)/National Institutes of Neurological Disorders and Stroke’s laboratories (NINDS), T cells were isolated and stimulated in the presence of in vivo (cells obtained from patients treated with DAC) achievable concentrations of DAC with significant inhibition of Tregs [9,10]. Moreover, DAC inhibited apoptosis of effector T cells in vivo [11] and in vitro [12]. These results are puzzling, because this apparent discrepancy between the expected and the findings, suggesting that immune mechanisms in which DAC is involved may not result from the direct inhibition of T-cell proliferation but from additional effects on the human immune system [4]. The first evidence that supported this hypothesis derived from the ability of DAC to expand the lymphocytic cells that did not express B-cell receptor; and these cells were represented by natural killer (NK) cells [13]. However, it was observed that DAC therapy selectively expands only minor populations of blood NK cells, characterized by a high expression of CD56 surface marker [9]. These CD56bright NK cells have been labeled as ‘immunoregulatory’ because they are selectively expanded during pregnancy (participating in mediating tolerance of the mother’s immune system) and, because they entirely lack granzyme B (in comparison to the more prevalent CD56dim NK cells); therefore, they were considered non-cytotoxic [14,15]. However, the analysis of their function was limited due to their low frequencies in the peripheral blood (i.e., 5 -- 10% of NK cells, which represent ~ 1% of lymphocytes), and the lack of an analogous cell type in the NK cells of rodents that lack the CD56dim. Because DAC expanded CD56bright NK cells in the peripheral blood more than 400% [16], the DAC-treated MS patients provided a unique opportunity to study the immunoregulatory functions of these cells in detail. It was found that CD56bright NK cells are relatively enriched in the cerebrospinal fluid (CSF) as compared with peripheral blood and their CSF levels significantly increased 6.5 months after initiation of DAC treatment [17]. Experimental evidence indicates that only 0.1% of blood concentrations of DAC gain access to the CNS when the blood--brain barrier is intact and this concentration (a peak concentration of 10 ng/ml) is insufficient to block activated T cell [18]. This means that either the inflammatory process was abrogated or alternatively the T cells that became activated in CNS tissue during DAC therapy were either killed by CD56bright NK cells or did not migrate out of the CNS tissue back to the CSF compartment [17]. As further supporting evidence for inhibition of the intrathecal inflammatory process in DAC-treated MS patients, NINDS group observed that 6.5 months after the initiation of DAC, CSF levels of cytokine IL-12p40, produced by activated macrophages, microglia and dendritic cells, were decreased by 50 -- 60% [17]. In the NIH/NINDS laboratories, a strong correlation between in vivo expansion of CD56bright NK cells and inhibition of focal brain inflammatory activity measured by contrast-enhancing lesions (CELs) was observed suggesting that immunoregulation of T-cell responses by CD56bright NK cells may represent a
Expert Opin. Drug Saf. (2015) 14(7)
Daclizumab HYP
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
decisive mechanism of action of DAC in MS [9]. This observation indicated that the level of expansion of CD56bright NK cells and the decrease in ratios of T cells (as target cells) to CD56bright NK cells (as effector cells) could represent a useful biomarker indicative of therapeutic response to DAC therapy, as it differentiated full responders from partial responders in MS cohort [16]. In this regard, interesting data are coming from SELECT study (see below) where among DAC-HYP-treated subjects, a higher number of CD56bright NK counts at week 4 and week 8 predicted fewer new T2 lesions at MRI between weeks 24 and 52 of treatment (p < 0.009 for both) [19]. Pharmacokinetic Dose and dosing frequencies of DAC-HYP were evaluated in early open-label Phase II studies in MS (see below). Data coming from Phase I studies in healthy volunteers described a two-compartment model’s pharmacokinetic with a firstorder absorption and linear elimination at doses ‡ 100 mg. A typical 70 kg individual is estimated to have serum DAC-HYP clearance of 10 ml/h and a steady-state volume of distribution of 6.4 l. DAC-HYP sc. bioavailability (100 -- 300 mg doses) was > 80% and the mean absorption time was 4.6 days [20]. Body weight explained only 20% of DAC pharmacokinetic variability. Sex, age, race or presence of antibodies was not found to correlate with DAC clearance. Effective half-life with monthly administration was estimated to be 21 -- 25 days. Thus, DAC has shown a slow clearance and a linear pharmacokinetics (doses ‡ 100 mg), high sc. bioavailability and half-life suitable for monthly administration. With monthly sc. administration, DAC Cmax to Ctrough ratio is predicted to be ~ 2.5 and steady-state accumulation ratio is predicted to be ~ 1.9) [20]. 1.2
2.
Clinical trials in MS
DAC was created in the Waldmann Laboratory at the NIH/ National Cancer Institute and, took regulatory approval as adjunctive therapy for the prevention of allograft rejection in patients undergoing renal transplantation as iv. form containing 5 mg/ml (Zenapax, referred to as DAC Nutley) [21,22]. The other two forms of DAC have been later developed: DAC-Penzberg (suitable for iv. or sc. administration at 100 mg/ml); and sc. DAC-HYP (formulated at 100 or 150 mg/ml) and used in recent clinical trials (see below). Following the positive experience in the treatment of uveitis, the Cellular Immunology Section, NIH/NINDS and the Department of Neurology, University of Utah at Salt Lake City began to explore the use of DAC-Zepanax also in patients with active relapsing-remitting (RR)-MS. That was tested in earlier smaller Phase II trials, and then in larger Phase II and Phase III trials (Table 1). In 1999, NIH/NINDS started an open-label crossover Phase I/II clinical trial (the Zenapax to Treat Multiple Sclerosis study; Clinicaltrials.gov identifier: NCT00001934) [13].
This study enrolled 11 RR-MS or secondary progressive (SP)-MS patients who failed treatment with IFN-b and showed CELs on baseline MRI. Patients were treated with iv. DAC at 1 mg/kg/dose (in regimen of combination therapy, i.e., IFN-b plus DAC) 2 weeks apart for the first two doses and every 4 weeks thereafter for a total of seven infusions. Compared with baseline, DAC therapy resulted in a 78% decrease in new CELs and 70% decrease in total CELs (primary outcome measures) on a 6.5-month period, even if the reduction in the occurrence of MRI lesions was already evident after 1.5 -- 2 months. All secondary outcome measures improved, some non-significantly (the changes in T2 lesion volume, black holes volume, Expanded Disability Status Scale [EDSS] and timed 25-foot walk) and others significantly (73% reduction in the volume of CELs, 81% reduction in exacerbation rate and improvement in Scripps Neurological Rating Scale [NRS] and 9-hole peg test). Treatment was generally well-tolerated with the description of increase in the number of mild infections and transient elevation of liver function tests in the main adverse effects (AEs) [13]. The same protocol was shared with the University of Utah, and 19 RR-MS or SP-MS patients were treated with iv. DAC for 5 -- 25 (average 13.6) months using the same NINDS’ protocol [23,24]. Then, dose was adjusted to 0.8 -- 1.9 mg/kg based on clinical response. A total of 10 patients had clinical improvement and 9 patients were stabilized, with an average reduction of 1.5 points on the EDSS during the treatment period (p < 0.0004). Annualized relapse rate (ARR) dropped by 74% from 1.23 to 0.32 and, the number of CELs was significantly reduced (p < 0.05) during treatment. Patients with shorter disease duration and more active disease at baseline responded better to DAC treatment [24]. AEs included paresthesias in six patients, rash in four and mild leukopenia without lymphopenia, transient elevation in liver enzymes and upper respiratory tract infection (one each) [24]. Later, at NIH/NINDS a total of 15 RR-MS and SP-MS patients, who experienced one or more relapses or sustained increase in disability in preceding 12 months on standard IFN-b treatments, and had at least two CELs during 3 monthly baseline brain MRI, were enrolled [16]. Patients were treated with iv. DAC 1 mg/kg every 2 weeks for the first two doses and every 4 weeks thereafter in combination with IFN-b (months 0 -- 5.5) and as monotherapy (months 6.5 -- 15.5). DAC monotherapy was efficacious in 9 of 13 MS patients who completed the trial and, combination therapy with IFN-b was needed according to the protocol in additional four patients to control disease activity. Overall, 72% inhibition of new (p = 0.002) and 77% inhibition of total CELs (p < 0.001) by DAC were observed. All clinical measures of disability improved (for EDSS p < 0.001, for Scripps NRS p < 0.001 and for multiple sclerosis functional composite [MSFC] p = 0.002). Two patients developed systemic immune responses 1 -- 2 months after withdrawal of IFN-b, characterized by mouth ulcers, photosensitivity
Expert Opin. Drug Saf. (2015) 14(7)
1159
E. D’Amico et al.
Table 1. Daclizumab efficacy in clinical trials. Ref.
Population
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Open-label studies [13] RR-MS/SPMS (n = 11)
Treatment arms and duration of study
Clinical response
Radiological response
IFN-b + DAC (30 weeks)
# Exacerbation rate " Scripps NRS score No change in EDSS score # EDSS score
# 78% new CELs # 70% total CELs
[23]
RR-MS/SPMS (n = 19)
DAC (n = 16), IFN-b + DAC, then DAC alone (n = 2), methylprenisolone + DAC (n = 1) (5 -- 25 months) IFN-b + DAC, then DAC alone (16 months)
[16]
RR-MS/SPMS (n = 15)
[17]
RR-MS (n = 16)
DAC (54 weeks)
[24]
RR-MS (n = 9)
IFN-b + DAC, then DAC alone (28 months)
Randomized, double-blind comparator studies RR-MS/SPIFN-b + placebo DAC-CHOICE MS (n = 230) IFN-b + low-dose DAC TRIAL IFN-b + high-dose DAC (24 weeks) [25]
[26]
DAC-HYP SELECT trial
RR-MS (n = 621)
Placebo Low-dose DAC-HYP
High-dose DAC-HYP (52 weeks) [27]
DAC-HYP SELECTION trial
RR-MS (n = 517)
" " # " " # # " #
MSFC score Scripps NRS score EDSS score MSFC score Scripps NRS score EDSS score Relapse rate Scripps NRS score EDSS score
High-dose DAC-HYP (52 weeks)
# 77% new CELs # 88% new CELs # > 75% new CELs # > 75% total CELs
No change in relapse rate, EDSS score or MSFC3 score No change in relapse rate, EDSS score or MSFC3 score
# 25% new or enlarged CELs # 72% new or enlarged CELs
# # # #
# 85% new or enlarged CELs
Relapse rate Disability progression MSIS-29 physical score Relapse rate
# Relapse rate # Disability progression
Low-dose DAC-HYP
/
# 88% new or enlarged CELs # 73% new or enlarged T2 lesions # 88% new or enlarged CELs
CEL: Contrast-enhancing lesions; DAC: Daclizumab; EDSS: Expanded Disability Status Scale; HYP: High-yield process; MSFC: Multiple sclerosis functional composite; MSIS-29: Multiple Sclerosis Impact Scale-29; NRS: Neurological Rating Scale; RR-MS: Relapsing-remitting-multiple sclerosis; SP-MS: Secondary progressive-multiple sclerosis.
rash that required corticosteroid therapy for resolution and did not complete the trial. Other AEs included lymphopenia (1), generalized lymphadenopathy (1) and transient elevation of bilirubin (1) and liver enzymes (1) [16]. Interesting data coming from the immunological substudy was that further expansion of CD56bright NK cells and contraction of CD4+ and CD8+ T cells occurred with DAC monotherapy after cessation of IFN-b, and that could be considered as biomarker discriminating between full and partial DAC responders [16]. These non-controlled, non-randomized, small studies showed consistent results indicating a potential benefit for DAC as a monotherapy, especially in RR-MS and early SP-MS patients for up to 27.5 months. One study also suggested synergistic effects of IFN-b and DAC, the need for combination treatment with IFN-b or a higher dose of DAC for optimal response in some patients and a possible biomarker for response to DAC [16]. These studies paved the way for additional larger controlled studies investigating the 1160
possible role of DAC in treatment-naive MS patients as well as add-on therapy or in comparison with a standard therapy with IFN-b treatment. That was accomplished in two multicenter Phase II trials sponsored by the pharmaceutical industry: the CHOICE study (the Study of Subcutaneous DAC in Patients With Active, Relapsing Forms of Multiple Sclerosis) [25], which investigated IFN-b/DAC combination therapy and the Phase II SELECT trial (the Safety and Efficacy Study of DAC-HYP to Treat RR-MS trial), which investigated DACHYP monotherapy (Figure 1). This last study used a new form of DAC called DAC-HYP, which has a different N-linked glycosylation profile than do previous versions of DAC; and that results in decreased antibody-dependent cellular cytotoxicity activity in biological assays, which is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific
Expert Opin. Drug Saf. (2015) 14(7)
Daclizumab HYP
Safety and efficacy of specific therapies in multiple sclerosis
Alemtuzumab Natalizumab Triple risk Mitoxantrone
Natalizumab JCV- /No ISS Rituximab,
Ocrelizumab
Cyclophosphamide Daclizumab CDNK56+ Fingolimod BG 12
Efficacy
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Daclizumab CDNK56-
Interferons glatiramer and teriflunomide in CIS Teriflunomide
New drugs Phase I, Phase II studies
Interferons Glatiramer
Azathioprine Laquinimod
Safety
Figure 1. Safety and efficacy of specific therapies in multiple sclerosis. Daclizumab constitutes a new avenue in the research and treatment of MS. It has shown effects on both the innate and adaptive immune systems in MS, involving expansion of CD56bright natural killer cells, inhibition of T-cell activation. Whether approved, its place in the MS treatment will be determined by its ability to merge high safety and efficacy profiles. The differences in terms of efficacy and safety based on the presence or not of a marked expansion in CD56bright cells led to consider this biomarker as mirror of daclizumab’s use in MS. MS: Multiple sclerosis.
Abs. DAC-HYP was produced in an NS0 (murine myeloma) cell line that has been adapted to grow in a serum-free, cholesterol-free and other animal product-free media. Moreover, DAC-HYP was developed for sc. administration (once every 4 weeks) in contrast to iv. administration of DAC. The pharmacokinetics of DAC-HYP was assessed using 938 measureable serum concentrations from 70 subjects who received active treatment [20]. The CHOICE study (Clinicaltrials.gov identifier: NCT00109161) enrolled 230 among RR-MS (92%) and SP-MS (8%) patients with active disease, defined as having at least one relapse, or CEL(s) on MRI in the previous year despite receiving IFN-b treatment [25]. Patients were randomized to receive add-on sc. DAC (DAC-Penzberg) 2 mg/kg every 2 weeks (IFN-b/high-dose DAC group), DAC 1 mg/kg every 4 weeks (IFN-b/low-dose DAC-Penzberg group) or placebo (IFN-b/placebo group) for 24 weeks. The adjusted mean number of new or enlarged CELs (primary end point) was reduced by 72% in the high-dose arm (p = 0.004) and by 25% in the low-dose arm (p = 0.51). Mean number of new or enlarged T2 lesions was reduced by
68% (ordinal logistic regression, p = 0.007) and 35% (ordinal logistic regression, p = 0.60) and the mean increase in total volume of new or enlarged CELs was slightly significant (p = 0.046) and non-significantly lower in the high- and low-dose arms, respectively. MS lesion activity returned to about the baseline level in all groups 2 -- 3 months after treatment discontinuation. DAC-Penzberg was well tolerated and common AEs, including infections, were generally equally distributed across treatment groups. However, serious AEs were more common in the DAC-Penzberg groups (13%) than in the placebo group (5%). More patients in the DAC groups had a variety of cutaneous events, including injection site irritation and rash. There were no opportunistic infections or deaths. The number of CD56bright NK cells was seven to eight times higher in both DAC-Penzberg groups than in IFN-b/placebo group. This was associated with fewer new CELs and provided support to the theory that expansion of CD56bright NK cells might mediate some of the effects of DAC-Penzberg on reducing MS lesion activity [25]. The CHOICE trial was short in duration (6 months) and it was also not powered to detect any significant clinical benefit.
Expert Opin. Drug Saf. (2015) 14(7)
1161
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
E. D’Amico et al.
However, this study was consistent with the four previous smaller trials and showed again the significant reduction of inflammatory activity in active MS patients. In February 2008, enrolment began to the SELECT trial [26]. This was a large-scale Phase IIb double-blind, placebo-controlled study to evaluate the safety and efficacy of DAC-HYP in subjects with RR-MS. It randomized 621 subjects in a 1:1:1 ratio to receive sc. placebo, 150 mg or 300 mg DAC-HYP every 4 weeks for 1 year. To be eligible, patients had to have EDSS score £ 5.0, at least one clinical relapse in the preceding year plus MRI evidence of MS and/ or a MRI scan with CEL(s) within 6 weeks prior to randomization. Primary end point was the ARR; secondary end points included the number of new or enlarged CELs at weeks 8 -- 24 in a MRI substudy (n = 309 MRI scans performed at weeks 8, 12, 16, 20, 24), new T2 lesions on MRI at week 52, the proportion of patients relapsing within 1 year and change in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Score (a quality of life measure) over 1 year. Confirmed disability progression, as measured as EDSS score at week 52 was a tertiary end point. Most patients (93%) completed study treatment, representing a high adherence rate. At 1 year, DAC treatment (150 and 300 mg) resulted in a significantly lower ARR versus placebo (0.21, 0.23 vs 0.46; a reduction of 54%, p < 0.0001 and 50%, p = 0.00015, respectively); a higher proportion of relapse-free patients versus placebo (81%, p < 0.0001 and 80%, p = 0.00032 vs 64%); reductions in the mean number of new CELs between weeks 8 -- 24 (n = 309; 1.5, 1.0 vs 4.8; a reduction of 69 and 78%, respectively, p < 0.0001 for both doses) and in the mean number of new or newly enlarging T2 lesions (2.4, 1.7 vs 8.1; a reduction of 70 and 79%, respectively p < 0.0001 for both doses). After 1 year, 13% of the placebo patients had a 3-month sustained disability progression, which was reduced in the DAC 150 mg group to 6% (--57%, p = 0.021 and in the DAC 300 mg group to 8% [--43%, p = 0.091]). AEs related to DAC included an increase in serious infections (2%, including one case each of appendicitis, gastroenteritis, hepatitis B, peritonsillar abscess, sinusitis, urinary tract infection, Yersinia and ‘viral’ infections), serious cutaneous events (1%), elevations in liver enzymes (> 5 upper limit of normal) (4%) and potential immune-mediated events (1%, autoimmune thyroiditis, Crohn’s disease, hypersensitivity and lymphadenopathy; all in the DAC 300 mg group). Four malignancies were detected during the trial, including two cases of melanoma in the DAC 300 mg group (both of them were treated with local excision with no reported recurrence). One patient who was recovering from a serious rash died due to a complication of a psoas abscess [26]. A marked expansion in CD56bright cells was associated with lower numbers of new MRI T2 lesions and fewer clinical relapses [19]. Neutralizing antibodies to DAC-HYP were detected in six (2%) patients in the DAC-HYP groups at week 24, and in only two (< 1%) at week 52; they were largely transient and no impact on safety or efficacy was detected. 1162
To assess the efficacy of DAC-HYP in a second year of treatment and the effect of treatment washout and re-initiation on disease activity, the SELECTION extension study (ClinicalTrials.gov, number NCT00870740) was performed with the primary aim to assess the safety and immunogenicity of extended treatment with DAC-HYP [27]. This multicenter, randomized, double-blind, 52-week extension trial was done in 74 centers in Europe between 13 February 2009 and 3 October 2012. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 or 300 mg sc. DAC-HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received DAC-HYP were randomly assigned (1:1) to two groups for 20 weeks. The first group (washout and re-initiation group) continued to receive DAC-HYP at the same dosage after a wash-out period. The second group (continuous treatment group) did not experienced a wash-out period. Both groups were treated for 20 weeks more [27]. Patients received their last dose in SELECT at week 48; the first dose of the assigned regimen in SELECTION was given at week 52 of SELECT. Therefore, patients in the washout and re-initiation group did not receive DAC for 24 weeks (from week 48 to week 72). The primary objective of the trial was to assess safety and immunogenicity of DAC-HYP. The secondary objective was to assess the durability of the DAC-HYP treatment effect on disease activity. Efficacy was defined by relapse activity (ARR and the proportion of patients who relapsed), confirmed disability progression (‡ 1.0 point increase in EDSS score from a baseline score of ‡ 1.0, or a 1.5 point increase from a baseline score of 0 that was sustained for 12 weeks) and MRI end points (new CELs, new or newly enlarging T2 hyperintense lesions, total volume of T2 hyperintense lesions, volume of new T1 hypointense lesions, total volume of T1 hypointense lesions and whole brain volume). CD56bright NK cell counts were included as a pharmacodynamic end point to assess the effect of treatment washout. At 52 weeks, 517 (91%) of 567 patients completed the SELECT and entered the SELECTION. All patients who underwent randomization in SELECTION received at least one dose of the assigned drug and so were included in the safety population. Overall, frequencies of AEs and serious AEs were similar between the treatment initiation and continuous treatment groups. No new safety signals were observed in the SELECTION trial, with the exception of three cases of immune-mediated severe AEs, including one patient who died because of autoimmune hepatitis and liver failure. The incidence of serious infections (2 vs 2%) and serious cutaneous events (1.1 vs 1.0%) was similar in SELECTION versus SELECT; taking into account the heterogeneity of study arms in each of the two studies. Six patients (1%) had serious cutaneous events: in the 150 mg treatment initiation group, one patient had drug eruption and one had eczema; in the 150 mg washout and re-initiation group, one patient had pityriasis rubra pilaris; and in the 300 mg continuous treatment group, one patient had drug eruption and eczema, one had exfoliative dermatitis and one
Expert Opin. Drug Saf. (2015) 14(7)
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Daclizumab HYP
had urticaria. One patient in the treatment initiation group who was given 300 mg DAC-HYP developed breast cancer, which the investigators did not consider to be related to treatment. The number of CD56bright NK cells that increased during the SELECT trial plateaued during the second year in the continuous treatment arms of the SELECTION trial, but gradually decreased to the baseline level during the 24-week washout period [27]. A reciprocal effect on FoxP3+-Tregs was observed [28]. Overall, the findings of SELECTION are consistent with the safety and efficacy profile of DAC-HYP monotherapy reported previously for 1 year of treatment, and show that effects are maintained through the second year of treatment [27]. Ongoing clinical trials Four additional clinical trials are currently ongoing with DAC-HYP in RR-MS: the SELECTED study (ClinicalTrials.gov identifier: NCT01051349) is a Phase II, multicenter, open-label, extension study to evaluate the long-term safety and efficacy of SC DAC 150 mg (DAC-HYP) monotherapy once a month in subjects with MS who have completed 52 weeks’ treatment in the SELECTION study. The estimate study completion date is 2018. The OBSERVE study (ClinicalTrials.gov identifier: NCT01462318) is a Phase III single arm, open-label study to investigate the immunogenicity, pharmacokinetics and pharmacodynamics of DAC-HYP administered by prefilled syringes. Approximately 150 subjects will be enrolled and treated with DAC-HYP 150 mg sc. for up to a 24-week treatment period and then enter a 20-week washout period for monthly assessment of immunogenicity, pharmacokinetics, pharmacodynamics, safety and tolerability. The DECIDE study (Efficacy and Safety of Daclizumab High-Yield Process Versus IFN-b1a in Patients With Relapsing-Remitting Multiple Sclerosis) (ClinicalTrials.gov identifier: NCT01064401) is a Phase III, multicenter, randomized, double-blind, double dummy, parallel group, active-control study to determine the superiority of monthly DAC-HYP 150 mg monotherapy compared with Avonex (IFN-b1a) in reducing the ARR in ~ 1800 subjects with RR-MS over a 96- to 144-week treatment period. The primary end point is ARR; secondary end points include the number of new or newly enlarging T2 hyperintense lesions on brain MRI, change in the MSFC score, 3-month sustained disability progression, change in the MSIS-29 physical score and the proportion of relapse-free subjects. On June 2014, Biogen Idec (NASDAQ:BIIB) and AbbVie (NYSE:ABBV) announced positive top-line results from the Phase III DECIDE clinical trial. DAC-HYP was superior on the study’s primary end point, demonstrating a statistically significant 45% reduction in ARR compared with IFN-b1a (p < 0.0001). 2.1
DAC-HYP showed superiority on the first secondary end point, number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54% reduction relative to IFN-b1a (p < 0.0001). On the second secondary end point, DAC-HYP reduced the risk of 3 months confirmed disability progression as measured by the EDSS by 16% over IFN-b1a, which was not statistically significant (p = 0.16). Using a pre-specified sensitivity analysis that accounted for 67 patients who did not have a confirmatory disability assessment, DAC-HYP showed a 21% reduction in the risk of sustained disability progression (p = 0.047). Subjects completing the DECIDE study were given the opportunity to enter an open-label extension trial with DAC-HYP (EXTEND study) (ClinicalTrials.gov identifier: NCT01797965). This study will primarily assess the long-term safety and tolerability of DAC-HYP monotherapy, and secondarily the immunogenicity of DAC-HYP, clinical and MRI outcomes, safety, tolerability and efficacy of switching from long-term treatment with IFN-b1a to DAC-HYP, as well as pharmacodynamics parameters that may be associated with treatment response. Other clinical experiences Pediatric use of DAC was described in a case series performed in two comprehensive pediatric MS centers [29]. In this small retrospective analysis, seven patients aged 12.8 -- 17.2 years were treated with iv. DAC 1 mg/kg for 12 -- 40 months (in five of them DAC was combined with IFN). Mean ARR was reduced from 2.6 to 0.62, EDSS stabilized in five patients and improved in another two patients, and the median number of CELs decreased from 3 (range 0 -- 11) to 0 (range 0 -- 2) on the last available MRI following a median of 10.5 months (range 6 -- 27 months) of DAC treatment. However, four of the seven patients had relapses and new CELs during DAC treatment. The treatment was well-tolerated, and AEs were usually mild and included headaches on the day of infusions (1), leukopenia (2), anaemia (3) and elevation of liver enzymes (1) that improved after halving the concomitant IFN-b dose [29]. A very recent retrospective analysis of frequent MRI scans performed on 70 patients at the NIH/NINDS showed that iv. DAC therapy was associated with a significant reduction in the meaningful measure of the rate of brain atrophy compared with other therapies (3.72 vs 5.17 ml/year, p < 0.001) [30]. 2.2
3.
Safety
Overall, DAC-HYP therapy has been well tolerated in the clinical trials performed so far (Table 2). The safety and tolerability of monthly iv. DAC 1 mg/kg have also been evaluated in 55 MS patients who received the drug off-label in a single center [31]. Among 36 patients who reported any AEs, the most common were fatigue (8), gastrointestinal upset (4), rash (3) and generalized weakness (3) [31]. Common infections including viral meningitis, lymphadenopathy,
Expert Opin. Drug Saf. (2015) 14(7)
1163
1164
Expert Opin. Drug Saf. (2015) 14(7)
100 5 (pooled) 50 1 ND ND 0
97
1
39
0
ND
ND 0
IFN-b + DAC 1 mg/kg (n = 78)
ND 0
ND
1
37
95
IFN-b + DAC 2 mg/kg (n = 75)
1 0
A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis 1.
Introduction
2.
Clinical trials in MS
3.
Safety
4.
Biomarkers of DAC treatment
Emanuele D’Amico, Silvia Messina, Cinzia Caserta & Francesco Patti† †
Universita´degli Studi di Catania, Dipartimento di Neurologia, Catania, Italy
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
response: going towards a personalized treatment in MS? 5.
Conclusions
6.
Expert opinion
Introduction: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS). Areas covered: In this review, we will focus on newly emerging DAC-highyield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety. Expert opinion: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing-remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/ risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice. Keywords: daclizumab, mAb, multiple sclerosis, safety Expert Opin. Drug Saf. (2015) 14(7):1157-1168
1.
Introduction
Daclizumab (DAC) (Box 1) is a humanized mAb of IgG1 subtype that binds to the high-affinity IL-2 receptor (IL-2R) a-chain (CD25) [1,2]. IL-2 is most well characterized as a T-cell growth factor due to its mitogenic effect on T cells, promoting the expansion of activated T cells in vitro through the high-affinity IL-2 receptor [3]. DAC was designed as a therapy that selectively inhibits T-cell activation and received regulatory approval as add-on therapy to standard immunomodulatory regimen for the prevention of acute allograft rejection in renal transplantation. Later, it was presented as a putative therapy for T-cell-mediated autoimmune diseases such as inflammatory uveitis and multiple sclerosis (MS) (see in review [4]). Three forms of DAC have been tested in humans so far: intravenously (iv.) administered DAC (Zenapax) was tested and previously approved for treatment after renal transplantation (it has been discontinued for the US market since 2009); subcutaneously (sc.) administered DAC (Penzberg, produced in Penzberg, Germany) has been used in the CHOICE trial (see below) and sc. DAC-high-yield process (HYP) has been tested in three Phase I studies, and in the SELECT trial (see below) [5]. All three forms show similar biological effects concerning CD25 binding and IL-2 blockade. All DAC doses tested in the CHOICE and in the SELECT trial supersaturate CD25 receptors by a factor of more than 10. The three DAC formulations are manufactured differently and differ in their glycosylation pattern. Therefore, MS DAC trials performed with different formulations should be compared with caution [5]. 10.1517/14740338.2015.1032937 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1157
E. D’Amico et al.
Box 1. Drug summary Drug name (generic)
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action
Daclizumab high-yield process (DAC-HYP) III Relapsing-remitting-multiple sclerosis
Daclizumab blocks the activity of IL-2, a chemical messenger in the immune system, and interferes with the growth of lymphocytes Route of administration Daclizumab is given as an injection under the skin every 4 weeks Chemical structure C6332H9808N1678O1989S42 Pivotal trial(s) The DAC-HYP development program includes the completed pivotal, placebo-controlled, doubleblind SELECT study Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
The past two decades have seen major advances in the treatment of MS due to the better understanding of the immune pathogenesis of the disease and that has resulted in new therapies capable of reducing disease activity (see in review, [6]). With the advent of mAbs technology, several humanized and fully human mAbs were developed to target specific key molecules and immune cell subpopulations involved in the immune cascade that is believed to lead to inflammation, demyelination and axonal loss in MS [5]. In this review, we will discuss the available efficacy and safety data from clinical trials of DAC and DAC-HYP therapy in MS, after a detailed description of its mechanism of action. Moreover, we will discuss the DAC’s putative place in the treatment of MS. Mechanism of action of DAC DAC is a humanized mAb directed against the CD25 subunit of the high-affinity IL-2 receptor. It is a competitive inhibitor of the high-affinity IL-2R, which is expressed predominantly on activated lymphocytes [7]. The high-affinity IL-2R consists of three chains: a non-signaling a-chain (CD25), a signaling b-chain (CD122) and a signaling g-chain (CD132). The achain (CD25) that forms the high-affinity IL-2R together with the b and g chains is expressed at low levels in resting T cells and it is rapidly upregulated in activated T cells. It is also constitutively expressed at high levels on FoxP3+ regulatory T cells (Tregs), which are dependent on IL-2 for their homeostasis [8]. Approximately 30% of human peripheral blood B cells express CD25; and B cells expressing CD25 display a mature phenotype and have a better proliferative and antigen-presenting capacity. Moreover, CD25 is expressed on macrophages that have been found histologically to be activated in MS [7]. In the National Institutes of Health 1.1
1158
(NIH)/National Institutes of Neurological Disorders and Stroke’s laboratories (NINDS), T cells were isolated and stimulated in the presence of in vivo (cells obtained from patients treated with DAC) achievable concentrations of DAC with significant inhibition of Tregs [9,10]. Moreover, DAC inhibited apoptosis of effector T cells in vivo [11] and in vitro [12]. These results are puzzling, because this apparent discrepancy between the expected and the findings, suggesting that immune mechanisms in which DAC is involved may not result from the direct inhibition of T-cell proliferation but from additional effects on the human immune system [4]. The first evidence that supported this hypothesis derived from the ability of DAC to expand the lymphocytic cells that did not express B-cell receptor; and these cells were represented by natural killer (NK) cells [13]. However, it was observed that DAC therapy selectively expands only minor populations of blood NK cells, characterized by a high expression of CD56 surface marker [9]. These CD56bright NK cells have been labeled as ‘immunoregulatory’ because they are selectively expanded during pregnancy (participating in mediating tolerance of the mother’s immune system) and, because they entirely lack granzyme B (in comparison to the more prevalent CD56dim NK cells); therefore, they were considered non-cytotoxic [14,15]. However, the analysis of their function was limited due to their low frequencies in the peripheral blood (i.e., 5 -- 10% of NK cells, which represent ~ 1% of lymphocytes), and the lack of an analogous cell type in the NK cells of rodents that lack the CD56dim. Because DAC expanded CD56bright NK cells in the peripheral blood more than 400% [16], the DAC-treated MS patients provided a unique opportunity to study the immunoregulatory functions of these cells in detail. It was found that CD56bright NK cells are relatively enriched in the cerebrospinal fluid (CSF) as compared with peripheral blood and their CSF levels significantly increased 6.5 months after initiation of DAC treatment [17]. Experimental evidence indicates that only 0.1% of blood concentrations of DAC gain access to the CNS when the blood--brain barrier is intact and this concentration (a peak concentration of 10 ng/ml) is insufficient to block activated T cell [18]. This means that either the inflammatory process was abrogated or alternatively the T cells that became activated in CNS tissue during DAC therapy were either killed by CD56bright NK cells or did not migrate out of the CNS tissue back to the CSF compartment [17]. As further supporting evidence for inhibition of the intrathecal inflammatory process in DAC-treated MS patients, NINDS group observed that 6.5 months after the initiation of DAC, CSF levels of cytokine IL-12p40, produced by activated macrophages, microglia and dendritic cells, were decreased by 50 -- 60% [17]. In the NIH/NINDS laboratories, a strong correlation between in vivo expansion of CD56bright NK cells and inhibition of focal brain inflammatory activity measured by contrast-enhancing lesions (CELs) was observed suggesting that immunoregulation of T-cell responses by CD56bright NK cells may represent a
Expert Opin. Drug Saf. (2015) 14(7)
Daclizumab HYP
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
decisive mechanism of action of DAC in MS [9]. This observation indicated that the level of expansion of CD56bright NK cells and the decrease in ratios of T cells (as target cells) to CD56bright NK cells (as effector cells) could represent a useful biomarker indicative of therapeutic response to DAC therapy, as it differentiated full responders from partial responders in MS cohort [16]. In this regard, interesting data are coming from SELECT study (see below) where among DAC-HYP-treated subjects, a higher number of CD56bright NK counts at week 4 and week 8 predicted fewer new T2 lesions at MRI between weeks 24 and 52 of treatment (p < 0.009 for both) [19]. Pharmacokinetic Dose and dosing frequencies of DAC-HYP were evaluated in early open-label Phase II studies in MS (see below). Data coming from Phase I studies in healthy volunteers described a two-compartment model’s pharmacokinetic with a firstorder absorption and linear elimination at doses ‡ 100 mg. A typical 70 kg individual is estimated to have serum DAC-HYP clearance of 10 ml/h and a steady-state volume of distribution of 6.4 l. DAC-HYP sc. bioavailability (100 -- 300 mg doses) was > 80% and the mean absorption time was 4.6 days [20]. Body weight explained only 20% of DAC pharmacokinetic variability. Sex, age, race or presence of antibodies was not found to correlate with DAC clearance. Effective half-life with monthly administration was estimated to be 21 -- 25 days. Thus, DAC has shown a slow clearance and a linear pharmacokinetics (doses ‡ 100 mg), high sc. bioavailability and half-life suitable for monthly administration. With monthly sc. administration, DAC Cmax to Ctrough ratio is predicted to be ~ 2.5 and steady-state accumulation ratio is predicted to be ~ 1.9) [20]. 1.2
2.
Clinical trials in MS
DAC was created in the Waldmann Laboratory at the NIH/ National Cancer Institute and, took regulatory approval as adjunctive therapy for the prevention of allograft rejection in patients undergoing renal transplantation as iv. form containing 5 mg/ml (Zenapax, referred to as DAC Nutley) [21,22]. The other two forms of DAC have been later developed: DAC-Penzberg (suitable for iv. or sc. administration at 100 mg/ml); and sc. DAC-HYP (formulated at 100 or 150 mg/ml) and used in recent clinical trials (see below). Following the positive experience in the treatment of uveitis, the Cellular Immunology Section, NIH/NINDS and the Department of Neurology, University of Utah at Salt Lake City began to explore the use of DAC-Zepanax also in patients with active relapsing-remitting (RR)-MS. That was tested in earlier smaller Phase II trials, and then in larger Phase II and Phase III trials (Table 1). In 1999, NIH/NINDS started an open-label crossover Phase I/II clinical trial (the Zenapax to Treat Multiple Sclerosis study; Clinicaltrials.gov identifier: NCT00001934) [13].
This study enrolled 11 RR-MS or secondary progressive (SP)-MS patients who failed treatment with IFN-b and showed CELs on baseline MRI. Patients were treated with iv. DAC at 1 mg/kg/dose (in regimen of combination therapy, i.e., IFN-b plus DAC) 2 weeks apart for the first two doses and every 4 weeks thereafter for a total of seven infusions. Compared with baseline, DAC therapy resulted in a 78% decrease in new CELs and 70% decrease in total CELs (primary outcome measures) on a 6.5-month period, even if the reduction in the occurrence of MRI lesions was already evident after 1.5 -- 2 months. All secondary outcome measures improved, some non-significantly (the changes in T2 lesion volume, black holes volume, Expanded Disability Status Scale [EDSS] and timed 25-foot walk) and others significantly (73% reduction in the volume of CELs, 81% reduction in exacerbation rate and improvement in Scripps Neurological Rating Scale [NRS] and 9-hole peg test). Treatment was generally well-tolerated with the description of increase in the number of mild infections and transient elevation of liver function tests in the main adverse effects (AEs) [13]. The same protocol was shared with the University of Utah, and 19 RR-MS or SP-MS patients were treated with iv. DAC for 5 -- 25 (average 13.6) months using the same NINDS’ protocol [23,24]. Then, dose was adjusted to 0.8 -- 1.9 mg/kg based on clinical response. A total of 10 patients had clinical improvement and 9 patients were stabilized, with an average reduction of 1.5 points on the EDSS during the treatment period (p < 0.0004). Annualized relapse rate (ARR) dropped by 74% from 1.23 to 0.32 and, the number of CELs was significantly reduced (p < 0.05) during treatment. Patients with shorter disease duration and more active disease at baseline responded better to DAC treatment [24]. AEs included paresthesias in six patients, rash in four and mild leukopenia without lymphopenia, transient elevation in liver enzymes and upper respiratory tract infection (one each) [24]. Later, at NIH/NINDS a total of 15 RR-MS and SP-MS patients, who experienced one or more relapses or sustained increase in disability in preceding 12 months on standard IFN-b treatments, and had at least two CELs during 3 monthly baseline brain MRI, were enrolled [16]. Patients were treated with iv. DAC 1 mg/kg every 2 weeks for the first two doses and every 4 weeks thereafter in combination with IFN-b (months 0 -- 5.5) and as monotherapy (months 6.5 -- 15.5). DAC monotherapy was efficacious in 9 of 13 MS patients who completed the trial and, combination therapy with IFN-b was needed according to the protocol in additional four patients to control disease activity. Overall, 72% inhibition of new (p = 0.002) and 77% inhibition of total CELs (p < 0.001) by DAC were observed. All clinical measures of disability improved (for EDSS p < 0.001, for Scripps NRS p < 0.001 and for multiple sclerosis functional composite [MSFC] p = 0.002). Two patients developed systemic immune responses 1 -- 2 months after withdrawal of IFN-b, characterized by mouth ulcers, photosensitivity
Expert Opin. Drug Saf. (2015) 14(7)
1159
E. D’Amico et al.
Table 1. Daclizumab efficacy in clinical trials. Ref.
Population
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Open-label studies [13] RR-MS/SPMS (n = 11)
Treatment arms and duration of study
Clinical response
Radiological response
IFN-b + DAC (30 weeks)
# Exacerbation rate " Scripps NRS score No change in EDSS score # EDSS score
# 78% new CELs # 70% total CELs
[23]
RR-MS/SPMS (n = 19)
DAC (n = 16), IFN-b + DAC, then DAC alone (n = 2), methylprenisolone + DAC (n = 1) (5 -- 25 months) IFN-b + DAC, then DAC alone (16 months)
[16]
RR-MS/SPMS (n = 15)
[17]
RR-MS (n = 16)
DAC (54 weeks)
[24]
RR-MS (n = 9)
IFN-b + DAC, then DAC alone (28 months)
Randomized, double-blind comparator studies RR-MS/SPIFN-b + placebo DAC-CHOICE MS (n = 230) IFN-b + low-dose DAC TRIAL IFN-b + high-dose DAC (24 weeks) [25]
[26]
DAC-HYP SELECT trial
RR-MS (n = 621)
Placebo Low-dose DAC-HYP
High-dose DAC-HYP (52 weeks) [27]
DAC-HYP SELECTION trial
RR-MS (n = 517)
" " # " " # # " #
MSFC score Scripps NRS score EDSS score MSFC score Scripps NRS score EDSS score Relapse rate Scripps NRS score EDSS score
High-dose DAC-HYP (52 weeks)
# 77% new CELs # 88% new CELs # > 75% new CELs # > 75% total CELs
No change in relapse rate, EDSS score or MSFC3 score No change in relapse rate, EDSS score or MSFC3 score
# 25% new or enlarged CELs # 72% new or enlarged CELs
# # # #
# 85% new or enlarged CELs
Relapse rate Disability progression MSIS-29 physical score Relapse rate
# Relapse rate # Disability progression
Low-dose DAC-HYP
/
# 88% new or enlarged CELs # 73% new or enlarged T2 lesions # 88% new or enlarged CELs
CEL: Contrast-enhancing lesions; DAC: Daclizumab; EDSS: Expanded Disability Status Scale; HYP: High-yield process; MSFC: Multiple sclerosis functional composite; MSIS-29: Multiple Sclerosis Impact Scale-29; NRS: Neurological Rating Scale; RR-MS: Relapsing-remitting-multiple sclerosis; SP-MS: Secondary progressive-multiple sclerosis.
rash that required corticosteroid therapy for resolution and did not complete the trial. Other AEs included lymphopenia (1), generalized lymphadenopathy (1) and transient elevation of bilirubin (1) and liver enzymes (1) [16]. Interesting data coming from the immunological substudy was that further expansion of CD56bright NK cells and contraction of CD4+ and CD8+ T cells occurred with DAC monotherapy after cessation of IFN-b, and that could be considered as biomarker discriminating between full and partial DAC responders [16]. These non-controlled, non-randomized, small studies showed consistent results indicating a potential benefit for DAC as a monotherapy, especially in RR-MS and early SP-MS patients for up to 27.5 months. One study also suggested synergistic effects of IFN-b and DAC, the need for combination treatment with IFN-b or a higher dose of DAC for optimal response in some patients and a possible biomarker for response to DAC [16]. These studies paved the way for additional larger controlled studies investigating the 1160
possible role of DAC in treatment-naive MS patients as well as add-on therapy or in comparison with a standard therapy with IFN-b treatment. That was accomplished in two multicenter Phase II trials sponsored by the pharmaceutical industry: the CHOICE study (the Study of Subcutaneous DAC in Patients With Active, Relapsing Forms of Multiple Sclerosis) [25], which investigated IFN-b/DAC combination therapy and the Phase II SELECT trial (the Safety and Efficacy Study of DAC-HYP to Treat RR-MS trial), which investigated DACHYP monotherapy (Figure 1). This last study used a new form of DAC called DAC-HYP, which has a different N-linked glycosylation profile than do previous versions of DAC; and that results in decreased antibody-dependent cellular cytotoxicity activity in biological assays, which is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific
Expert Opin. Drug Saf. (2015) 14(7)
Daclizumab HYP
Safety and efficacy of specific therapies in multiple sclerosis
Alemtuzumab Natalizumab Triple risk Mitoxantrone
Natalizumab JCV- /No ISS Rituximab,
Ocrelizumab
Cyclophosphamide Daclizumab CDNK56+ Fingolimod BG 12
Efficacy
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Daclizumab CDNK56-
Interferons glatiramer and teriflunomide in CIS Teriflunomide
New drugs Phase I, Phase II studies
Interferons Glatiramer
Azathioprine Laquinimod
Safety
Figure 1. Safety and efficacy of specific therapies in multiple sclerosis. Daclizumab constitutes a new avenue in the research and treatment of MS. It has shown effects on both the innate and adaptive immune systems in MS, involving expansion of CD56bright natural killer cells, inhibition of T-cell activation. Whether approved, its place in the MS treatment will be determined by its ability to merge high safety and efficacy profiles. The differences in terms of efficacy and safety based on the presence or not of a marked expansion in CD56bright cells led to consider this biomarker as mirror of daclizumab’s use in MS. MS: Multiple sclerosis.
Abs. DAC-HYP was produced in an NS0 (murine myeloma) cell line that has been adapted to grow in a serum-free, cholesterol-free and other animal product-free media. Moreover, DAC-HYP was developed for sc. administration (once every 4 weeks) in contrast to iv. administration of DAC. The pharmacokinetics of DAC-HYP was assessed using 938 measureable serum concentrations from 70 subjects who received active treatment [20]. The CHOICE study (Clinicaltrials.gov identifier: NCT00109161) enrolled 230 among RR-MS (92%) and SP-MS (8%) patients with active disease, defined as having at least one relapse, or CEL(s) on MRI in the previous year despite receiving IFN-b treatment [25]. Patients were randomized to receive add-on sc. DAC (DAC-Penzberg) 2 mg/kg every 2 weeks (IFN-b/high-dose DAC group), DAC 1 mg/kg every 4 weeks (IFN-b/low-dose DAC-Penzberg group) or placebo (IFN-b/placebo group) for 24 weeks. The adjusted mean number of new or enlarged CELs (primary end point) was reduced by 72% in the high-dose arm (p = 0.004) and by 25% in the low-dose arm (p = 0.51). Mean number of new or enlarged T2 lesions was reduced by
68% (ordinal logistic regression, p = 0.007) and 35% (ordinal logistic regression, p = 0.60) and the mean increase in total volume of new or enlarged CELs was slightly significant (p = 0.046) and non-significantly lower in the high- and low-dose arms, respectively. MS lesion activity returned to about the baseline level in all groups 2 -- 3 months after treatment discontinuation. DAC-Penzberg was well tolerated and common AEs, including infections, were generally equally distributed across treatment groups. However, serious AEs were more common in the DAC-Penzberg groups (13%) than in the placebo group (5%). More patients in the DAC groups had a variety of cutaneous events, including injection site irritation and rash. There were no opportunistic infections or deaths. The number of CD56bright NK cells was seven to eight times higher in both DAC-Penzberg groups than in IFN-b/placebo group. This was associated with fewer new CELs and provided support to the theory that expansion of CD56bright NK cells might mediate some of the effects of DAC-Penzberg on reducing MS lesion activity [25]. The CHOICE trial was short in duration (6 months) and it was also not powered to detect any significant clinical benefit.
Expert Opin. Drug Saf. (2015) 14(7)
1161
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
E. D’Amico et al.
However, this study was consistent with the four previous smaller trials and showed again the significant reduction of inflammatory activity in active MS patients. In February 2008, enrolment began to the SELECT trial [26]. This was a large-scale Phase IIb double-blind, placebo-controlled study to evaluate the safety and efficacy of DAC-HYP in subjects with RR-MS. It randomized 621 subjects in a 1:1:1 ratio to receive sc. placebo, 150 mg or 300 mg DAC-HYP every 4 weeks for 1 year. To be eligible, patients had to have EDSS score £ 5.0, at least one clinical relapse in the preceding year plus MRI evidence of MS and/ or a MRI scan with CEL(s) within 6 weeks prior to randomization. Primary end point was the ARR; secondary end points included the number of new or enlarged CELs at weeks 8 -- 24 in a MRI substudy (n = 309 MRI scans performed at weeks 8, 12, 16, 20, 24), new T2 lesions on MRI at week 52, the proportion of patients relapsing within 1 year and change in Multiple Sclerosis Impact Scale (MSIS)-29 Physical Score (a quality of life measure) over 1 year. Confirmed disability progression, as measured as EDSS score at week 52 was a tertiary end point. Most patients (93%) completed study treatment, representing a high adherence rate. At 1 year, DAC treatment (150 and 300 mg) resulted in a significantly lower ARR versus placebo (0.21, 0.23 vs 0.46; a reduction of 54%, p < 0.0001 and 50%, p = 0.00015, respectively); a higher proportion of relapse-free patients versus placebo (81%, p < 0.0001 and 80%, p = 0.00032 vs 64%); reductions in the mean number of new CELs between weeks 8 -- 24 (n = 309; 1.5, 1.0 vs 4.8; a reduction of 69 and 78%, respectively, p < 0.0001 for both doses) and in the mean number of new or newly enlarging T2 lesions (2.4, 1.7 vs 8.1; a reduction of 70 and 79%, respectively p < 0.0001 for both doses). After 1 year, 13% of the placebo patients had a 3-month sustained disability progression, which was reduced in the DAC 150 mg group to 6% (--57%, p = 0.021 and in the DAC 300 mg group to 8% [--43%, p = 0.091]). AEs related to DAC included an increase in serious infections (2%, including one case each of appendicitis, gastroenteritis, hepatitis B, peritonsillar abscess, sinusitis, urinary tract infection, Yersinia and ‘viral’ infections), serious cutaneous events (1%), elevations in liver enzymes (> 5 upper limit of normal) (4%) and potential immune-mediated events (1%, autoimmune thyroiditis, Crohn’s disease, hypersensitivity and lymphadenopathy; all in the DAC 300 mg group). Four malignancies were detected during the trial, including two cases of melanoma in the DAC 300 mg group (both of them were treated with local excision with no reported recurrence). One patient who was recovering from a serious rash died due to a complication of a psoas abscess [26]. A marked expansion in CD56bright cells was associated with lower numbers of new MRI T2 lesions and fewer clinical relapses [19]. Neutralizing antibodies to DAC-HYP were detected in six (2%) patients in the DAC-HYP groups at week 24, and in only two (< 1%) at week 52; they were largely transient and no impact on safety or efficacy was detected. 1162
To assess the efficacy of DAC-HYP in a second year of treatment and the effect of treatment washout and re-initiation on disease activity, the SELECTION extension study (ClinicalTrials.gov, number NCT00870740) was performed with the primary aim to assess the safety and immunogenicity of extended treatment with DAC-HYP [27]. This multicenter, randomized, double-blind, 52-week extension trial was done in 74 centers in Europe between 13 February 2009 and 3 October 2012. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 or 300 mg sc. DAC-HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received DAC-HYP were randomly assigned (1:1) to two groups for 20 weeks. The first group (washout and re-initiation group) continued to receive DAC-HYP at the same dosage after a wash-out period. The second group (continuous treatment group) did not experienced a wash-out period. Both groups were treated for 20 weeks more [27]. Patients received their last dose in SELECT at week 48; the first dose of the assigned regimen in SELECTION was given at week 52 of SELECT. Therefore, patients in the washout and re-initiation group did not receive DAC for 24 weeks (from week 48 to week 72). The primary objective of the trial was to assess safety and immunogenicity of DAC-HYP. The secondary objective was to assess the durability of the DAC-HYP treatment effect on disease activity. Efficacy was defined by relapse activity (ARR and the proportion of patients who relapsed), confirmed disability progression (‡ 1.0 point increase in EDSS score from a baseline score of ‡ 1.0, or a 1.5 point increase from a baseline score of 0 that was sustained for 12 weeks) and MRI end points (new CELs, new or newly enlarging T2 hyperintense lesions, total volume of T2 hyperintense lesions, volume of new T1 hypointense lesions, total volume of T1 hypointense lesions and whole brain volume). CD56bright NK cell counts were included as a pharmacodynamic end point to assess the effect of treatment washout. At 52 weeks, 517 (91%) of 567 patients completed the SELECT and entered the SELECTION. All patients who underwent randomization in SELECTION received at least one dose of the assigned drug and so were included in the safety population. Overall, frequencies of AEs and serious AEs were similar between the treatment initiation and continuous treatment groups. No new safety signals were observed in the SELECTION trial, with the exception of three cases of immune-mediated severe AEs, including one patient who died because of autoimmune hepatitis and liver failure. The incidence of serious infections (2 vs 2%) and serious cutaneous events (1.1 vs 1.0%) was similar in SELECTION versus SELECT; taking into account the heterogeneity of study arms in each of the two studies. Six patients (1%) had serious cutaneous events: in the 150 mg treatment initiation group, one patient had drug eruption and one had eczema; in the 150 mg washout and re-initiation group, one patient had pityriasis rubra pilaris; and in the 300 mg continuous treatment group, one patient had drug eruption and eczema, one had exfoliative dermatitis and one
Expert Opin. Drug Saf. (2015) 14(7)
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.
Daclizumab HYP
had urticaria. One patient in the treatment initiation group who was given 300 mg DAC-HYP developed breast cancer, which the investigators did not consider to be related to treatment. The number of CD56bright NK cells that increased during the SELECT trial plateaued during the second year in the continuous treatment arms of the SELECTION trial, but gradually decreased to the baseline level during the 24-week washout period [27]. A reciprocal effect on FoxP3+-Tregs was observed [28]. Overall, the findings of SELECTION are consistent with the safety and efficacy profile of DAC-HYP monotherapy reported previously for 1 year of treatment, and show that effects are maintained through the second year of treatment [27]. Ongoing clinical trials Four additional clinical trials are currently ongoing with DAC-HYP in RR-MS: the SELECTED study (ClinicalTrials.gov identifier: NCT01051349) is a Phase II, multicenter, open-label, extension study to evaluate the long-term safety and efficacy of SC DAC 150 mg (DAC-HYP) monotherapy once a month in subjects with MS who have completed 52 weeks’ treatment in the SELECTION study. The estimate study completion date is 2018. The OBSERVE study (ClinicalTrials.gov identifier: NCT01462318) is a Phase III single arm, open-label study to investigate the immunogenicity, pharmacokinetics and pharmacodynamics of DAC-HYP administered by prefilled syringes. Approximately 150 subjects will be enrolled and treated with DAC-HYP 150 mg sc. for up to a 24-week treatment period and then enter a 20-week washout period for monthly assessment of immunogenicity, pharmacokinetics, pharmacodynamics, safety and tolerability. The DECIDE study (Efficacy and Safety of Daclizumab High-Yield Process Versus IFN-b1a in Patients With Relapsing-Remitting Multiple Sclerosis) (ClinicalTrials.gov identifier: NCT01064401) is a Phase III, multicenter, randomized, double-blind, double dummy, parallel group, active-control study to determine the superiority of monthly DAC-HYP 150 mg monotherapy compared with Avonex (IFN-b1a) in reducing the ARR in ~ 1800 subjects with RR-MS over a 96- to 144-week treatment period. The primary end point is ARR; secondary end points include the number of new or newly enlarging T2 hyperintense lesions on brain MRI, change in the MSFC score, 3-month sustained disability progression, change in the MSIS-29 physical score and the proportion of relapse-free subjects. On June 2014, Biogen Idec (NASDAQ:BIIB) and AbbVie (NYSE:ABBV) announced positive top-line results from the Phase III DECIDE clinical trial. DAC-HYP was superior on the study’s primary end point, demonstrating a statistically significant 45% reduction in ARR compared with IFN-b1a (p < 0.0001). 2.1
DAC-HYP showed superiority on the first secondary end point, number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54% reduction relative to IFN-b1a (p < 0.0001). On the second secondary end point, DAC-HYP reduced the risk of 3 months confirmed disability progression as measured by the EDSS by 16% over IFN-b1a, which was not statistically significant (p = 0.16). Using a pre-specified sensitivity analysis that accounted for 67 patients who did not have a confirmatory disability assessment, DAC-HYP showed a 21% reduction in the risk of sustained disability progression (p = 0.047). Subjects completing the DECIDE study were given the opportunity to enter an open-label extension trial with DAC-HYP (EXTEND study) (ClinicalTrials.gov identifier: NCT01797965). This study will primarily assess the long-term safety and tolerability of DAC-HYP monotherapy, and secondarily the immunogenicity of DAC-HYP, clinical and MRI outcomes, safety, tolerability and efficacy of switching from long-term treatment with IFN-b1a to DAC-HYP, as well as pharmacodynamics parameters that may be associated with treatment response. Other clinical experiences Pediatric use of DAC was described in a case series performed in two comprehensive pediatric MS centers [29]. In this small retrospective analysis, seven patients aged 12.8 -- 17.2 years were treated with iv. DAC 1 mg/kg for 12 -- 40 months (in five of them DAC was combined with IFN). Mean ARR was reduced from 2.6 to 0.62, EDSS stabilized in five patients and improved in another two patients, and the median number of CELs decreased from 3 (range 0 -- 11) to 0 (range 0 -- 2) on the last available MRI following a median of 10.5 months (range 6 -- 27 months) of DAC treatment. However, four of the seven patients had relapses and new CELs during DAC treatment. The treatment was well-tolerated, and AEs were usually mild and included headaches on the day of infusions (1), leukopenia (2), anaemia (3) and elevation of liver enzymes (1) that improved after halving the concomitant IFN-b dose [29]. A very recent retrospective analysis of frequent MRI scans performed on 70 patients at the NIH/NINDS showed that iv. DAC therapy was associated with a significant reduction in the meaningful measure of the rate of brain atrophy compared with other therapies (3.72 vs 5.17 ml/year, p < 0.001) [30]. 2.2
3.
Safety
Overall, DAC-HYP therapy has been well tolerated in the clinical trials performed so far (Table 2). The safety and tolerability of monthly iv. DAC 1 mg/kg have also been evaluated in 55 MS patients who received the drug off-label in a single center [31]. Among 36 patients who reported any AEs, the most common were fatigue (8), gastrointestinal upset (4), rash (3) and generalized weakness (3) [31]. Common infections including viral meningitis, lymphadenopathy,
Expert Opin. Drug Saf. (2015) 14(7)
1163
1164
Expert Opin. Drug Saf. (2015) 14(7)
100 5 (pooled) 50 1 ND ND 0
97
1
39
0
ND
ND 0
IFN-b + DAC 1 mg/kg (n = 78)
ND 0
ND
1
37
95
IFN-b + DAC 2 mg/kg (n = 75)
1 0
