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Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies

Multiple Sclerosis and Related Disorders, Volume 9, September 2016, Pages 36 - 46

Abstract

Background

Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication.

Objective

Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies.

Methods

Patients treated with at least one dose of subcutaneous daclizumab 150 mg or 300 mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint.

Results

This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment.

Conclusion

This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time.

Highlights

  • Daclizumab safety was evaluated in an integrated analysis of six RRMS trials.
  • Most AEs were mild or moderate in severity.
  • A risk for potentially immune-mediated SAEs in liver, skin, and GI organ systems.
  • AEs occurred throughout treatment with no evidence of accumulated toxicity.
  • Most AEs resolved spontaneously or with standard medical therapies.

Abbreviations: AE - adverse event, ALT - alanine aminotransferase, AST - aspartate aminotransferase, DRESS - drug reaction with eosinophilia and systematic symptoms, DSMB - data safety monitoring board, GGT - gamma-glutamyl transferase, GI - gastrointestinal, IL-2 - interleukin 2, IM - intramuscular, MedDRA - Medical Dictionary for Regulatory Activities, MS - multiple sclerosis, RRMS - relapsing-remitting multiple sclerosis, SAE - serious adverse event, SMQ - Standardised MedDRA Query, SOC - System Organ Class, ULN - upper limit of normal..

Keywords: Daclizumab, Relapsing-remitting multiple sclerosis, Safety, Tolerability, Clinical study.

1. Introduction

Multiple sclerosis (MS) is a neuroinflammatory disorder characterised by auto-reactive T cell destruction of myelin and axons, resulting in long-term accumulation of disability (Compston and Coles, 2008). Interleukin 2 (IL-2) plays a dual role in regulating the balance between immune tolerance and autoimmunity (Cheng et al, 2011 and Malek, 2008), and abnormalities in the IL-2 signalling pathway have been identified as a key driver in MS pathogenesis (Wiendl and Gross, 2013).

Daclizumab high-yield process (daclizumab)2 is a humanised monoclonal antibody that binds to the IL-2 receptor alpha subunit (CD25) and modulates IL-2 signalling leading to reductions in pro-inflammatory activated T cells and expansion of CD56bright natural killer cells (Bielekova et al, 2006, Bielekova et al, 2009, and Elkins et al, 2015). Daclizumab showed greater efficacy in reducing clinical and radiologic MS disease activity outcomes versus placebo and intramuscular (IM) interferon beta-1a in multicentre, randomised, double-blind studies of patients with relapsing-remitting MS (RRMS) (Gold et al, 2013 and Kappos et al, 2015). There was an increased incidence of infections and cutaneous adverse events (AEs) relative to placebo and IM interferon beta-1a, as well as a higher incidence of hepatic AEs versus IM interferon beta-1a in these studies (Gold et al, 2013 and Kappos et al, 2015).

Here, we report patient-level safety data from an integrated analysis of the SELECT, DECIDE, and OBSERVE studies, and their respective extensions, over a maximum treatment period of 6.5 years.

2. Materials and methods

2.1. Analysis population and study designs

Adult patients with RRMS who received at least one dose of daclizumab in the pivotal SELECT study (ClinicalTrials.gov identifier NCT00390221) (Gold et al., 2013), phase 3 DECIDE study (NCT01064401) (Kappos et al., 2015), and ongoing phase 3 immunogenicity study OBSERVE (NCT01462318), or their respective extension studies (for SELECT: SELECTION [NCT00870740] (Giovannoni et al., 2014), SELECTED [NCT01051349] (Gold et al., 2015); for DECIDE: EXTEND [NCT01797965]) were included in this pooled analysis (Fig. 1). This included patients initially exposed to placebo in SELECT who went on to participate in SELECTION and SELECTED, and patients initially exposed to IM interferon beta-1a in DECIDE who subsequently received daclizumab 150 mg in EXTEND. Only patients in SELECT and SELECTION received daclizumab 300 mg. SELECT, SELECTION, and DECIDE study designs and results have been reported (Gold et al, 2013, Kappos et al, 2015, and Giovannoni et al, 2014).

Fig. 1

Fig. 1

Flow of patients through the daclizumab clinical studies. Values in bold font indicate stages of first exposure to daclizumab and thus inclusion in the integrated safety set (N=2236). The placebo-controlled SELECT study evaluated the safety and efficacy of daclizumab 150 mg or 300 mg administered subcutaneously every 4 weeks (Gold et al., 2013). Eligible recipients of daclizumab 150 mg or 300 mg and placebo who completed SELECT could enrol in the double-blind, 1-year extension study SELECTION (Giovannoni et al., 2014). Patients treated with placebo in SELECT were randomised to initiate treatment with either daclizumab 150 mg or 300 mg in SELECTION (Giovannoni et al., 2014), while patients who received daclizumab were randomised to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks (Giovannoni et al., 2014). Eligible patients who completed SELECTION were permitted to receive treatment with daclizumab for up to 6.5 years in the ongoing SELECTED study. DECIDE was designed to compare subcutaneous daclizumab 150 mg once every 4 weeks with intramuscular interferon beta-1a 30 mcg once weekly for 96–144 weeks (Kappos et al., 2015). OBSERVE enrolled de novo patients with relapsing-remitting multiple sclerosis who received daclizumab 150 mg every 4 weeks administered with prefilled syringe for up to 4 years (during which time there was a 20-week washout period starting at week 24). Eligible patients from SELECTED, DECIDE and OBSERVE were allowed to enrol in the ongoing 5-year EXTEND study that has the primary objective of assessing adverse events among patients who: (1) received daclizumab monotherapy in DECIDE, SELECTED, or OBSERVE; and (2) those who switched to daclizumab after treatment with intramuscular interferon beta-1a in DECIDE.

 

All study designs were approved by institutional review boards at participating sites and conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice (ICH, 2001) and the Declaration of Helsinki and its amendments (Rits, 1964). All patients provided written informed consent before participation.

2.2. Assessments

During the controlled studies, clinic visits were scheduled every 4 weeks for receipt of daclizumab and safety and tolerability assessments; during the extension studies, visits were scheduled every 4 to 12 weeks. Patients who discontinued study treatment were encouraged to remain in the studies and complete all follow-up assessments as scheduled, with at least 6 months of safety follow-up.

Safety and tolerability were measured by AE monitoring, physical and neurological exams, vital signs, clinical lab evaluations (haematology, blood chemistry, thyroid function panel, and urinalysis), and injection site assessments. The study investigators rated the intensity of each AE (mild, moderate, or severe) and categorised the relationship between each AE and study drug. Serious AEs (SAEs) were those that were life-threatening, resulted in death, inpatient hospitalisation/prolongation of a hospitalisation, persistent or significant disability/incapacity, or required medical or surgical intervention. MS relapses were reported as an AE. All AEs were categorised according to the Medical Dictionary for Regulatory Activities (MedDRA; version 16.1).

An independent data safety monitoring board (DSMB; comprised of expert neurologists, statisticians, hepatologists, infectious disease specialists, rheumatologists/immunologists, and gastroenterologists) monitored safety for the duration of each blinded study and received monthly SAE reports. In response to an event of liver failure due to autoimmune hepatitis in SELECTION, ongoing study protocols were updated to include liver enzyme monitoring every 4 weeks during treatment, and to provide additional guidelines for dose interruption or permanent discontinuation of study treatment. An independent hepatic adjudication committee blinded to treatment evaluated hepatic events that met the criteria of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3×upper level of normal (ULN) and total bilirubin >2×ULN and provided a causality assessment and whether the case met Hy's Law criteria (Temple, 2006). A blinded, independent expert dermatologist periodically reviewed clinically significant cutaneous AEs (i.e. cases of special interest and SAEs) in DECIDE and the three ongoing studies and provided regular reports to the DSMB.

2.3. Statistical considerations

The integrated analysis included patient-level safety data from the six daclizumab RRMS studies, including three completed studies and three ongoing studies. For the ongoing studies (OBSERVE, SELECTED, and EXTEND), available data through 14 November 2014 were included. All patients randomised to daclizumab and who received at least one dose of study treatment were included in the analysis.

The integrated safety data was analysed in two pooled dose groups and overall. Patients randomised to daclizumab 300 mg in SELECT or SELECTION were analysed in the daclizumab 300-mg group; all others were included in the daclizumab 150-mg group. Although patients who received daclizumab 300 mg in SELECTION were switched to daclizumab 150 mg in SELECTED, these patients remained attributed to the 300-mg group in this integrated analysis.

Direct comparisons between dose groups were not performed because of inherent differences in the populations with respect to study design across the clinical studies. These differences relate to the small proportion of patients who received daclizumab 300 mg relative to those who received the 150-mg dose, a greater overall exposure time among the patients in the 300-mg group, and geographic differences.

All AEs that occurred while exposed to daclizumab (i.e. treatment-emergent AEs) were included in analyses. Based on the pharmacodynamic effects, exposure to daclizumab was considered to extend from the time of the first dose through 180 days after the last dosing date.

The primary safety analyses focused on incidence of AEs and SAEs, by MedDRA classification, severity and relationship to study drug, and time interval. Data from extension studies were treated as if the parent study and its extension were a single long-term study; hence, a patient experiencing the same event in more than one study was counted only once in summary of incidence in the integrated analysis. Categories of AEs of special interest were determined based on potential mechanism of action, therapeutic class, or prior clinical experience with daclizumab. AEs belonging to each special interest group were defined by hierarchical MedDRA terms or Standardised or Customised MedDRA Queries. In analyses of event severity or relationship to drug, a patient was counted only once under the worst severity or strongest relationship, with no imputation for missing data.

Where appropriate, the Kaplan-Meier product limit method was used to estimate time to event and the proportion of patients with an event. Other safety endpoints included incidence of abnormalities and changes in quantitative safety assessments such as laboratory parameters, vital signs, and electrocardiograms. For evaluating changes, the date of first dose of daclizumab was used as the reference date.

3. Results

3.1. Patients

At total of 2236 patients received at least one dose of either daclizumab 150 mg (n=1943) or 300 mg (n=293) in the parent and extension studies (Fig. 1; Table 1). Patients in the analysis population were predominantly female (66%), white (92%), and <40 years of age (60%) with a mean (median) disease duration of 4.9 (3.0) years and mean (median) Expanded Disability Status Scale score of 2.6 (2.5). Fifty-seven percent of patients had received no prior MS treatment.

Table 1

Baseline demographics, clinical characteristics, and concomitant medication use in the 2236 patients with relapsing-remitting MS who received at least one dose of daclizumab.

 

Parameter Daclizumab 150 mg (n=1943) Daclizumab 300 mga (n=293) Total (N=2236)
Mean (SD) age, years 37.1 (9.4) 35.9 (8.5) 37.0 (9.3)
  Age <40 years, n (%) 1149 (59) 198 (68) 1347 (60)
Female, n (%) 1297 (67) 188 (64) 1485 (66)
White, n (%) 1780 (92) 282 (96) 2062 (92)
Mean (SD) BMI, kg/m2 24.9 (5.1) 23.7 (4.4) 24.7 (5.0)
Mean (SD) EDSS score 2.6 (1.3) 2.7 (1.2) 2.6 (1.3)
  Median EDSS score 2.5 2.5 2.5
Mean (SD) time since diagnosis, years 5.1 (5.0) 3.9 (4.2) 4.9 (4.9)
  Median time since diagnosis, years 3.0 3.0 3.0
Mean (SD) no. of relapses in prior year 1.1 (0.9) 1.1 (0.8) 1.1 (0.9)
Prior treatment for MS, n (%) 878 (45) 89 (30) 967 (43)

a Patients randomised to daclizumab 300 mg in SELECT or SELECTION. Those who participated in SELECTED were switched to daclizumab 150 mg at start of SELECTED but remain analysed in the 300-mg group.

BMI, body mass index; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis.

The median number (range) of doses of daclizumab was 27 (1−85). The maximum exposure to daclizumab in this safety population was approximately 6.5 years, which included 1259 (56%) and 888 (40%) patients exposed for ≥96 weeks and ≥144 weeks, respectively. The median (range) time of exposure was 29.9 (0−81) months with a total of 5214 patient-years of exposure to daclizumab (4187 patient-years in the daclizumab 150-mg group and 1027 patient-years in the daclizumab 300-mg group).

3.2. Incidence of AEs

The overall cumulative incidence of any AE in the total daclizumab group was 84%. Most AEs were mild or moderate in severity; 12% of patients experienced a severe AE. Forty-one percent of patients had an AE considered related to study drug (Table 2).

Table 2

AE experience in the daclizumab population.

 

Parameter, n (%) Daclizumab 150 mg (n=1943) Daclizumab 300 mg (n=293) Total (N=2236)
Any AE 1628 (84) 259 (88) 1887 (84)
       
AEs by severitya
  Mild 483 (25) 63 (22) 546 (24)
  Moderate 922 (47) 158 (54) 1080 (48)
  Severe 223 (11) 38 (13) 261 (12)
SAE 433 (22) 106 (36) 539 (24)
  Other than MS relapse 290 (15) 64 (22) 354 (16)
Treatment-related AE 773 (40) 138 (47) 911 (41)
Dose interruption due to AE 296 (15) 78 (27) 374 (17)
Discontinuing treatment due to AE 268 (14) 52 (18) 320 (14)
  Excluding MS relapse 249 (13) 50 (17) 299 (13)
Withdrawal from study due to AE 160 (8) 43 (15) 203 (9)
  Excluding MS relapse 147 (8) 41 (14) 188 (8)
Death 4 (<1) 1 (<1) 5 (<1)
       
AEs occurring in ≥10% of patients in overall population
  MS relapse 570 (29) 113 (39) 683 (31)
  Nasopharyngitis 384 (20) 64 (22) 448 (20)
  Upper respiratory tract infection 293 (15) 45 (15) 338 (15)
  Headache 258 (13) 37 (13) 295 (13)
  Urinary tract infection 194 (10) 24 (8) 218 (10)
       
SAEs occurring in >5 patients in overall population
  MS relapse 189 (10) 55 (19) 244 (11)
  Pneumonia 14 (<1) 1 (<1) 15 (<1)
  Urinary tract infection 13 (<1) 1 (<1) 14 (<1)
  Lymphadenopathy 9 (<1) 3 (1) 12 (<1)
  Depression 7 (<1) 0 7 (<1)
  Lymphadenitis 7 (<1) 0 7 (<1)
  Ulcerative colitis 5 (<1) 1 (<1) 6 (<1)
  Fall 6 (<1) 0 6 (<1)
       
Treatment-related AEs occurring in ≥5% of patients in overall population
  Injection site pain 112 (6) 3 (1) 115 (5)
  ALT increased 88 (5) 20 (7) 108 (5)
       
AEs leading to treatment discontinuation in ≥10 patients
  ALT increased 29 (1) 9 (3) 38 (2)
  Liver function test abnormal 27 (1) 1 (<1) 28 (1)
  MS relapse 20 (1) 2 (<1) 22 (<1)
  AST increased 15 (<1) 4 (1) 19 (<1)
  Hepatic enzyme increased 12 (<1) 2 (<1) 14 (<1)
  Lymphadenopathy 11 (<1) 2 (<1) 13 (<1)
  Rash maculo-papular 12 (<1) 1 (<1) 13 (<1)
  Dermatitis allergic 7 (<1) 3 (1) 10 (<1)
Anaphylaxis SMQ 1 (<1) 2 (<1) 3 (<1)
  Circulatory collapse 1 (<1) 2 (<1) 3 (<1)
Hypersensitivity SMQ 433 (22) 92 (31) 525 (23)
  Hypersensitivity SMQ SAE 29 (1) 9 (3) 38 (2)

a Patients experiencing more than one AE were counted in the row based on maximum severity.

AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; MS, multiple sclerosis; SAE, serious adverse event; SMQ, Standardised Medical Dictionary for Regulatory Activities Query.

The incidence of any AE when evaluated by 6-month intervals in all daclizumab-exposed patients remained stable over time (Fig. 2). There was no increase in the incidence of AEs in the MedDRA System Organ Classes (SOC) of hepatobiliary disorders, skin and subcutaneous tissue disorders, infections and infestations, gastrointestinal disorders, or investigations over time.

Fig. 2

Fig. 2

Incidence of any treatment-emergent adverse event by 24-week time intervals in all daclizumab-treated patients. Results represent the incidence of adverse events over 24-week intervals in the daclizumab total group reported by Medical Dictionary for Regulatory Activities System Organ Class. SOC, System Organ Class.

 

The cumulative incidences of AEs leading to discontinuation of study treatment and withdrawal from study were 14% and 9% (representing 15% of patients overall) and remained stable over time, ranging from 4–6% per year and 3–6% per year, respectively. The cumulative incidence of any SAE was 24% (16% excluding MS relapse).

Five deaths were reported among the 2236 daclizumab-treated patients (cumulative incidence 0.2%), and in two cases, a contributory role for daclizumab was not excluded. In SELECT, one patient in the daclizumab 150 mg arm, who was improving after experiencing serious rash, died due to ischaemic colitis that occurred as a local complication of a psoas abscess (Gold et al., 2013). In SELECTION, one patient in the daclizumab 300-mg/washout/300-mg re-initiation group died of liver failure due to autoimmune hepatitis; in this case, the diagnosis was delayed and treatment for autoimmune hepatitis was not initiated until the hepatic injury was advanced (Giovannoni et al., 2014). The three deaths considered unrelated to daclizumab 150 mg included two cases of acute exacerbation of MS involving brain stem lesions and death due to resulting complications and one case of subdural haematoma resulting from a fall.

3.3. Type of AEs

The most common AEs (cumulative incidence ≥10%) by Preferred Term were MS relapse, nasopharyngitis, upper respiratory tract infection, headache, and urinary tract infection (Table 2). Treatment-related AEs with a cumulative incidence of ≥5% were injection site pain and increased ALT (Table 2). Severe AEs were most common in the SOCs of nervous systems disorders (3%), infections and infestations (2%), skin and subcutaneous tissue disorders (2%), and investigations (2%). By Preferred Term, no SAE was reported in ≥1% of patients other than MS relapse. Nervous system disorders (which included MS relapse in 22 patients), skin and subcutaneous tissue disorders, and investigations were the three most common reasons for treatment discontinuation due to an AE based on MedDRA SOC.

3.4. Hepatic AEs

The cumulative incidence of hepatic AEs and SAEs as identified using the Standardised MedDRA Query (SMQ) of drug-related hepatic disorders was 16% and 1%, respectively (Table 3). Five percent of patients discontinued treatment due to a hepatic AE. Median time to a hepatic AE was 1.3 years of therapy and most hepatic AEs resolved during study follow-up (86% of events) with a median duration of 29 days.

Table 3

Treatment-emergent hepatic AE experience with daclizumab.

 

Parameter Daclizumab 150 mg (n=1943) Daclizumab 300 mg (n=293) Total (N=2236)
Hepatic AE, n (%)a
  Any AE 285 (15) 68 (23) 353 (16)
  Any severe AE 32 (2) 5 (2) 37 (2)
  Any SAE 17 (<1) 7 (2) 24 (1)
  Patients discontinuing treatment due to AE 92 (5) 19 (6) 111 (5)
Median (IQR) time to first hepatic event, days 450 (225–786) 617 (282–1299) 478 (229–862)
AEs that resolved, n (%)b 495 (85) 138 (91) 633 (86)
  Median (IQR) duration of resolved AEs, days 29.0 (22.0–58.0) 29.0 (23.0–83.0) 29.0 (23.0–59.0)
     
Hepatic AEs occurring in ≥3% of patients in overall population, n (%)c
  Investigations 260 (13) 60 (20) 320 (14)
    ALT increased 138 (7) 42 (14) 180 (8)
    AST increased 101 (5) 34 (12) 135 (6)
    Liver function test abnormal 65 (3) 5 (2) 70 (3)
    GGT increased 57 (3) 11 (4) 68 (3)
     
Serious hepatic AEs occurring in ≥3 patients in overall population, n (%)c
  Hepatobiliary disorders 12 (<1) 5 (2) 17 (<1)
    Hepatitis toxic 4 (<1) 0 4 (<1)
    Autoimmune hepatitis 1 (<1) 2 (<1) 3 (<1)
    Jaundice 1 (<1) 2 (<1) 3 (<1)
 Investigations 6 (<1) 2 (<1) 8 (<1)
   Hepatic enzyme increased 3 (<1) 1 (<1) 4 (<1)
   ALT increased 3 (<1) 0 3 (<1)
   AST increased 3 (<1) 0 3 (<1)
       
Laboratory abnormalities
   ALT or AST, n (%)
     ≥3×ULN 182 (9) 43 (15) 225 (10)
     >5×ULN 113 (6) 22 (8) 135 (6)
     >10×ULN 52 (3) 11 (4) 63 (3)
   ALT/AST ≥3×ULN and total bilirubin ≥2×ULN, n (%) 11 (<1) 4 (1) 15 (<1)
   Hy's Law, nd 2 1 3

a Hepatic AEs identified based on Standardised Medical Dictionary for Regulatory Activities (MEdDRA) Query of drug-related hepatic disorders.

b AEs that resolved during study follow-up. Percentages are based on total number of hepatic AEs identified based on Standardised MedDRA Query in each group: daclizumab 150 mg n=581; daclizumab 300 mg n=152; total daclizumab n=733.

c Categorised by MedDRA System Organ Class and Preferred Term.

d Per US Food and Drug Administration criteria (U. S. Department of Health and Human Services, 2009). Clinical assessment of causality based on the structured approach (Rockey et al., 2010). There were two cases in the daclizumab 150-mg treatment group and one case in the daclizumab 300-mg treatment group with a causality score of probable.

AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma-glutamyl transferase; IQR, interquartile range; SAE, serious adverse event; ULN, upper limit of normal.

Elevated ALT and AST levels were observed in 35% and 28% of patients without baseline elevations, respectively. ALT or AST elevations of ≥3×ULN, >5×ULN, and >10×ULN were observed in 10%, 6%, and 3% of patients, respectively, most of which were asymptomatic episodes (Table 3). In the first 3 years of treatment, the incidence of ALT or AST elevations ≥3×ULN ranged from 2–3% per 6-month interval. Following the case of fatal autoimmune hepatitis in SELECTION (Giovannoni et al., 2014), ongoing study protocols were updated to include monitoring of liver enzymes every 4 weeks and guidelines for suspension and permanent discontinuation of study treatment in patients with elevated liver enzymes. Most patients (121/137; 88%) who had a serum transaminase level >5×ULN recovered while on study (defined as simultaneous ALT and AST ≤1.5×ULN), with a median duration of 105 days. Among patients treated with daclizumab after recovery, 86% had no recurrence of these AEs and no Hy's Law (Temple, 2006) cases occurred among patients who had resumed treatment after a suspension as a result of elevated serum transaminases.

Fifteen patients had concurrent elevations in liver transaminases ≥3×ULN and total bilirubin ≥2×ULN while on study (Table 3); additionally, three other cases were reported (two patients while hospitalized and one patient beyond the daclizumab exposure period). Three cases were considered by the independent hepatic adjudication committee to meet the criteria for Hy's Law based on a causality assessment of probable or higher. One case occurred in a patient who had initiated treatment with carbamazepine/valproate and another case occurred in a patient who had resumed daclizumab treatment after a pre-planned 6-month washout period and developed autoimmune hepatitis and died approximately 4 months after the liver enzyme abnormalities were first detected. In this case, the treatment for autoimmune hepatitis was not instituted until after the liver injury was already advanced. The third case occurred in a patient with a viral illness, fever, who received amoxicillin.

3.5. Cutaneous AEs

Approximately one-third of daclizumab-treated patients had a cutaneous AE, which manifested primarily as rash, eczema, and allergic dermatitis (Table 4). Median time to a moderate to severe cutaneous AE was 1.3 years and most AEs (79%) resolved during study follow-up with a median duration of 47.5 days.

Table 4

Treatment-emergent cutaneous AE experience with daclizumab.a

 

Parameter Daclizumab 150 mg (n=1943) Daclizumab 300 mg (n=293) Total (N=2236)
Cutaneous AE, n (%)
  Any AE 617 (32) 120 (41) 737 (33)
  Any moderate or severe AE 278 (14) 51 (17) 329 (15)
  Any SAE 34 (2) 10 (3) 44 (2)
  Patients discontinuing treatment due to an AE 74 (4) 14 (5) 88 (4)
Median (IQR) time to first moderate or severe cutaneous AE, days 443 (224–785) 572 (211–908) 468 (224–810)
Moderate or severe AEs that resolved, n (%)b 306 (77) 76 (89) 382 (79)
  Moderate or severe AEs resolved without steroids, n (%)c 83 (81) 15 (100) 98 (84)
  Moderate or severe AEs resolved with topical steroids only, n (%)d 133 (77) 47 (90) 180 (80)
  Moderate or severe AEs resolved with systemic steroids, n (%)e 90 (74) 14 (78) 104 (74)
Median (IQR) duration of resolved moderate or severe AEs, days 46.0 (19.0–125.0) 61.0 (16.5–109.5) 47.5 (18.0–118.0)
       
Cutaneous AEs occurring in ≥3% of patients in overall population, n (%)
  Rash 126 (6) 31 (11) 157 (7)
  Eczema 68 (3) 12 (4) 80 (4)
  Dermatitis allergic 56 (3) 21 (7) 77 (3)
  Erythema 61 (3) 13 (4) 74 (3)
       
Serious cutaneous AEs in ≥3 patients in overall population, n (%)
  Dermatitis 3 (<1) 0 3 (<1)
  Drug eruption 2 (<1) 1 (<1) 3 (<1)
  Eczema 2 (<1) 1 (<1) 3 (<1)
  Erythema nodosum 2 (<1) 1 (<1) 3 (<1)
  Psoriasis 2 (<1) 1 (<1) 3 (<1)
  Toxic skin eruption 2 (<1) 1 (<1) 3 (<1)
  Urticaria 2 (<1) 1 (<1) 3 (<1)
SAE in the SMQ of severe cutaneous adverse reactions, n (%) 7 (<1) 2 (<1) 9 (<1)
  Toxic skin eruption 2 (<1) 1 (<1) 3 (<1)
  Dermatitis exfoliative 1 (<1) 1 (<1) 2 (<1)
  DRESSf 2 (<1) 0 2 (<1)
  Erythema multiforme 1 (<1) 0 1 (<1)
  Stevens-Johnson syndromef 1 (<1) 0 1 (<1)

a Based on the Medical Dictionary for Regulatory Activities System Organ Class skin and subcutaneous tissue disorders.

b AEs that resolved during study follow-up. Percentages are based on total number of moderate or severe cutaneous AEs reported in each group: daclizumab 150 mg n=397; daclizumab 300 mg n=85; total daclizumab n=482.

c AEs that resolved during study follow-up. Percentages are based on total number of moderate or severe cutaneous AEs not treated with steroids in each group: daclizumab 150 mg n=102; daclizumab 300 mg n=15; total daclizumab n=117.

d AEs that resolved during study follow-up. Percentages are based on total number of moderate or severe cutaneous AEs treated with topical steroids in each group: daclizumab 150 mg n=173; daclizumab 300 mg n=52; total daclizumab n=225.

e AEs that resolved during study follow-up. Percentages are based on total number of moderate or severe cutaneous AEs treated with systemic steroids or systemic and topical steroids in each group: daclizumab 150 mg n=122; daclizumab 300 mg n=18; total daclizumab n=140.

f Cases were not consistent with the diagnosis of DRESS and Stevens-Johnson syndrome after medical review by a central dermatologist who considered the two DRESS cases and one Stevens-Johnson syndrome case most likely to be delayed-type drug hypersensitivity rashes.

AE, adverse event; DRESS, drug reaction with eosinophilia and systemic symptoms; IQR, interquartile range; SAE, serious adverse event; SMQ, Standardised Medical Dictionary for Regulatory Activities Query.

The cumulative incidence of cutaneous SAEs was 2% in daclizumab-treated patients (Table 4). Nine patients had a SAE under SMQ severe cutaneous adverse reactions, including toxic skin eruption (n=3), drug reaction with eosinophilia and systematic symptoms (DRESS), and exfoliative dermatitis (each n=2) (Table 4). After medical review by the central dermatologist, an initial diagnosis of Stevens-Johnson syndrome in one patient was not confirmed, and the case was consistent with cutaneous drug hypersensitivity with oral erosions; similarly, the two cases of DRESS were considered consistent with delayed-type hypersensitivity reactions. Both cases reported as DRESS were treated with plasma exchange after not responding to topical and low-dose systemic corticosteroids. One patient improved following treatment with one course of plasma exchange and concomitant corticosteroids, whereas the other patient worsened despite receiving six courses of plasma exchange, but responded to high-dose systemic corticosteroids.

3.6. Infections

The cumulative incidence of any infection and serious infection was 59% and 4%, respectively (Table 5). The median time to onset of the first infection was 162 days. The vast majority of infections resolved during study follow-up (97%) with a median duration of 8 days. The most common serious infections were upper and lower respiratory tract infections and urinary tract infections. The cumulative incidence of any potential opportunistic infections was 2%, primarily due to non-invasive Candida infections.

Table 5

Treatment-emergent infectious AE experience with daclizumab.a

 

Parameter Daclizumab 150 mg (n=1943) Daclizumab 300 mg (n=293) Total (N=2236)
Infections, n (%)
  Any AE 1120 (58) 199 (68) 1319 (59)
  Any SAE 85 (4) 14 (5) 99 (4)
  Any potential opportunistic infection 38 (2) 2 (<1) 40 (2)
  Any serious potential opportunistic infection 3 (<1) 0 3 (<1)
Median (range) time to first infection, days 161.5 (1.0–2019.0) 172.0 (2.0–2217.0) 162.0 (1.0–2217.0)
Infections that resolved, n (%)b 3895 (97) 796 (99) 4691 (97)
  Median (IQR) duration of resolved infections, days 8.0 (5.0–14.0) 8.0 (5.0–14.0) 8.0 (5.0–14.0)
     
Infections occurring in ≥10% of patients in overall population, n (%)
  Nasopharyngitis 384 (20) 64 (22) 448 (20)
  Upper respiratory tract infection 293 (15) 45 (15) 338 (15)
  Urinary tract infection 194 (10) 24 (8) 218 (10)
     
Serious infections occurring in ≥5 patients in overall population, n (%)
  Pneumonia 14 (<1) 1 (<1) 15 (<1)
  Urinary tract infection 13 (<1) 1 (<1) 14 (<1)
  Bronchitis 1 (<1) 4 (1) 5 (<1)
     
Potential opportunistic infections in ≥3 patients in overall population, n (%)c
  Oral candidiasis 12 (<1) 1 (<1) 13 (<1)
  Vulvovaginal candidiasis 12 (<1) 0 12 (<1)
  Pulmonary tuberculosis 3 (<1) 0 3 (<1)
       
Potential serious opportunistic infections, n (%)c
  Mycobacterium abscessus infection 1 (<1) 0 1 (<1)
  Cytomegalovirus infection 1 (<1) 0 1 (<1)
  Pulmonary tuberculosis 1 (<1) 0 1 (<1)

a Infections identified based on Medical Dictionary for Regulatory (MedDRA) Activities System Organ Class of infections and infestations.

b AEs that resolved during study follow-up. Percentages are based on total number of infections reported in each group: daclizumab 150 mg n=4013; daclizumab 300 mg n=807; total daclizumab n=4820.

c Potential opportunistic infections identified based on a Customised MedDRA Query.

AE, adverse event; IQR, interquartile range; SAE, serious adverse event.

3.7. Gastrointestinal AEs

The cumulative incidence of any gastrointestinal AE was 25%; the most common event was diarrhoea (7%; Table 6). Almost all diarrhoea AEs resolved during study follow-up (96%) over a median of 5 days. The incidence of potentially inflammatory gastrointestinal AEs, including inflammatory bowel disease or inflammatory bowel–like presentations, was 1%, of which 0.6% (n=13) were serious. Serious cases tended to be late onset, occurring after approximately 1 to 3.5 years of daclizumab exposure. Most events resolved or were stable with no flares following treatment for the events.

Table 6

Treatment-emergent GI AE experience with daclizumab.a

 

Parameter, n (%) Daclizumab 150 mg (n=1943) Daclizumab 300 mg (n=293) Total (N=2236)
GI AEs, n (%)
 Any AE 491 (25) 69 (24) 560 (25)
 Any SAE 29 (1) 6 (2) 35 (2)
       
GI AEs occurring in ≥3% of patients in overall population, n (%)
 Diarrhoea 132 (7) 21 (7) 153 (7)
 Nausea 68 (3) 10 (3) 78 (3)
 Constipation 56 (3) 8 (3) 64 (3)
 Vomiting 51 (3) 7 (2) 58 (3)
       
GI SAEs occurring in ≥3 patients in overall population, n (%)
 Colitis ulcerative 5 (<1) 1 (<1) 6 (<1)
 Diarrhoea 3 (<1) 0 3 (<1)
Potential inflammatory GI AEs, n (%)b 19 (<1) 7 (2) 26 (1)
Potential inflammatory GI SAEs, n (%)b 9 (<1) 4 (1) 13 (<1)
 Ulcerative colitis 5 (<1) 1 (<1) 6 (<1)
 Colitis 1 (<1) 1 (<1) 2 (<1)
 Crohn's disease 0 2 (<1) 2 (<1)
 Ischaemic colitis 1 (<1)c 0 1 (<1)
 Microscopic colitis 1 (<1) 0 1 (<1)
 Haemorrhagic enterocolitis 1 (<1) 0 1 (<1)

a GI AEs identified based on Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class.

b Potential inflammatory GI AEs identified based on MedDRA High Level Term (primary or secondary pathway) of colitis (excluding infective).

c Occurred secondary to a psoas abscess.

AE, adverse event; GI, gastrointestinal; SAE, serious adverse event.

3.8. Laboratory abnormalities and vital signs

With the exception of liver enzyme abnormalities, no clinically significant changes in haematological parameters (white blood cell, lymphocyte, or neutrophil counts), kidney function, and urinalysis were observed. The cumulative incidence of lymphopenia (below 0.8×109 cells/L) and leukopenia (below 3.0×109 cells/L) was low (7% and 4%, respectively). The majority of lymphopenia cases reported as AEs were mild in severity, and no severe sustained lymphopenia was observed. There were no clinically significant changes in vital signs, QTc interval, or any other electrocardiogram parameter.

3.9. Anaphylaxis and hypersensitivity

The cumulative incidence of anaphylaxis was <1% (Table 2). The only serious case (cumulative incidence 0.04%), circulatory collapse characterised by dizziness, hypotension, and syncope, occurred in the daclizumab 300-mg group after the first dose (third injection of 100 mg each), was not life-threatening, and resolved on the day of onset. The cumulative incidences of any hypersensitivity and serious hypersensitivity were 23% and 2%, respectively (Table 2). Most hypersensitivity AEs were due to skin and subcutaneous disorders (21%). All other hypersensitivity AEs had a cumulative incidence of ≤1%.

3.10. Autoimmune disorders and lymphadenopathy

The cumulative incidence of potential autoimmune disorders was 1.5% and potential autoimmune serious AEs was 0.4%, with no pattern to either of these AE categories. Autoimmune thyroiditis was the most common disorder occurring in six patients. Three of the 10 cases of potential autoimmune SAEs were cases of autoimmune hepatitis, and the remaining seven cases of autoimmune disorders (autoimmune thyroiditis, Basedow's disease, coeliac disease, lupus-like syndrome, myasthaenia gravis, pernicious anaemia, Reiter's syndrome) were reported in one patient each.

Cumulative incidences of lymphadenopathy and lymphadenitis were 5% and 1%, respectively. Most patients were asymptomatic, and lymph node involvement showed no specific pattern (i.e. localised or generalised). In cases in which biopsies were performed, findings generally showed a reactive or inflammatory process or benign, inactive lymph nodes, and there was no evidence of malignancy.

3.11. Malignancies

Nineteen of 2236 patients (0.8%; n=19) had a malignancy. No pattern was observed in the types and rates of malignancies reported.

4. Discussion

The integrated safety data for daclizumab has been well characterised in six clinical studies, providing information on the experience with daclizumab for periods of up to 6.5 years; 2236 patients with RRMS have received daclizumab with >5200 patient-years of exposure. A safety database of this size is sufficient for identifying risks associated with daclizumab therapy, including uncommon risks and risks associated with an incidence as low as 1 per 1000 patient-years; however, it is not large enough to identify rare events.

Consistent with previous reports (Gold et al, 2013 and Kappos et al, 2015; Giovannoni et al., 2014), the most important safety concerns with daclizumab therapy are hepatic AEs and serum transaminase elevations. Most hepatic AEs were asymptomatic, self-limiting, and non-recurring when continuing or re-initiating daclizumab. Most patients with serum transaminase elevations >5×ULN recovered during the study. Among patients who reinitiated daclizumab after recovery from an ALT or AST elevation >5×ULN, most did not experience a recurrence. While most events were self-limited, one case of autoimmune hepatitis resulted in liver failure and death. Serum transaminase monitoring is recommended for managing hepatic risks.

Most cutaneous, infectious, and gastrointestinal AEs observed with daclizumab were mild or moderate in severity, and either self-limiting or generally manageable with standard medical interventions. Further description of the AEs in the controlled clinical studies of daclizumab versus placebo and IM interferon beta-1a is provided in Table 7. In the integrated analysis, most patients with cutaneous AEs continued on daclizumab without any dosage regimen modification. Moderate or severe cutaneous AEs were generally managed with topical or systemic corticosteroids. Serious cutaneous AEs, some of which presented clinically as delayed-type hypersensitivity reactions, were generally managed with high-dose systemic corticosteroids.

Table 7

Treatment-emergent AEs in controlled clinical studies of daclizumab.

 

Parameter, n (%) SELECT study (Gold et al., 2013) 52 weeks DECIDE study (Kappos et al., 2015) 96–144 weeks
Placebo (n=204) Daclizumab 150 mg (n=208) Daclizumab 300 mg (n=209) IM IFN beta-1a (n=922) Daclizumab 150 mg (n=919)
Any AE, n (%) 161 (79) 151 (73) 159 (76) 842 (91) 838 (91)
Any SAE, n (%) 53 (26) 32 (15) 36 (17) 194 (21) 221 (24)
  Other than MS relapse 12 (6) 15 (7) 19 (9) 88 (10) 142 (15)
Discontinuing treatment due to AE 2 (<1) 6 (3) 9 (4) 112 (12) 142 (15)
Death, n (%) 0 1 (<1) 0 4 (<1) 1 (<1)
           
Hepatic event (SMQ), n (%)a
  Any AE 12 (6)b 19 (9)b 18 (9)b 130 (14) 144 (16)
  Any SAE 0b 2 (<1)b 1 (<1)b 4 (<1) 6 (1)
           
Laboratory abnormalities
  ALT or AST, n (%)
    >5×ULN 1 (<1) 9 (4) 8 (4) 31 (3) 59 (6)
  Hy's Law, nc 0b 0b 0b 1 (<1) 1 (<1)
           
Cutaneous AE, n (%)
  Any AE 27 (13) 38 (18) 45 (22) 176 (19) 344 (37)
  Any SAE 0 2 (<1) 3 (<1) 1 (<1) 14 (2)
           
Infections, n (%)
  Any AE 89 (44) 104 (50) 112 (54) 523 (57) 595 (65)
  Any SAE 0 6 (3) 3 (1) 15 (2) 40 (4)
Malignancies 1 (<1) 1 (<1) 2 (<1) 8 (1) 7 (1)

a Hepatic AEs identified based on SMQ of drug-related hepatic disorders.

b Results from the SELECT study were not previously published. Biogen data on file.

c Per US Food and Drug Administration criteria (U.S. Department of Health and Human Services, 2009). Clinical assessment of causality based on the structured approach (Rockey et al., 2010).

AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; IFN, interferon; IM, intramuscular; MS, multiple sclerosis; SAE, serious adverse event; SMQ, Standardized Medical Dictionary for Regulatory Activities Query; ULN, upper limit of normal.

Infections and serious infections were more common with daclizumab than placebo or IM interferon beta-1a (Gold et al, 2013 and Kappos et al, 2015) (Table 7). The Candida infections reported were superficial mucosal infections, which are common in the general population. Invasive or systemic Candida infections were not observed. The types of infections observed were not characteristic of an immunocompromised or immunosuppressed population.

Serious gastrointestinal AEs had a late onset, which is inconsistent with a potential acute reaction to daclizumab treatment. Some patients had mild disease, while others had severe disease with dehydration. Most patients had visible inflammation with erythema and ulceration (frank colitis), but there also were cases of lymphocytic inflammation (microscopic colitis). The small intestine was relatively spared from inflammation. In all cases, the acute illness responded to standard medical therapy for inflammatory colitis. In the cases in which daclizumab was interrupted or discontinued, no patients progressed to sequelae of chronic inflammation. In all cases, improvement was reported after daclizumab was stopped and/or treatment for colitis was initiated.

Five deaths occurred during daclizumab exposure. A contributory role of daclizumab could not be excluded in two cases (complication of psoas abscess and autoimmune hepatitis). Overall, no specific patterns of fatalities related to daclizumab therapy could be identified in the clinical program. In the 1-year placebo-controlled SELECT study, there was one death in the daclizumab 150-mg arm and no deaths in the placebo arm (Table 7) (Gold et al., 2013). In the 2- to 3-year DECIDE study, there were two deaths in the daclizumab arm (one that occurred after treatment discontinuation and one after study withdrawal) and five deaths in the IM interferon beta-1a arm (four during treatment; one after study withdrawal; Table 7) (Kappos et al., 2015) Additionally, the cumulative incidences of malignancy (0.8% vs. 4.3%) and autoimmune thyroiditis (0.3% vs. 1.4%) appeared lower than those observed in the general population of patients with MS (Somers et al, 2009 and Marrie et al, 2015).

A key strength of this analysis was the robustness of the safety database, which included representative RRMS patient-level data comprising all reported and adjudicated daclizumab-emergent AEs. Because the safety data were analysed from six separate studies over a cumulative period of up to 6.5 years, there is no valid treatment comparison group for the integrated analysis; however, safety results for the placebo- and active-controlled studies have been reported and a summary of these data is provided Table 7 (Gold et al, 2013 and Kappos et al, 2015). Patients were classified based on daclizumab dose level at treatment initiation and most were receiving concomitant medication. It also is possible that comorbidities emerged over the course of the monitoring period, which spanned >6 years. These factors should be taken into account when evaluating these data.

5. Conclusions

In conclusion, this integrated analysis demonstrates that daclizumab remained well tolerated over a period of up to 6.5 years. Most AEs observed with daclizumab were mild or moderate in severity and managed with standard medical interventions. In the clinical studies, daclizumab demonstrated statistically significant benefits on clinical, radiographic, and patient-reported outcome measures in patients with RRMS (Gold et al, 2013 and Kappos et al, 2015; Giovannoni et al., 2014). The integrated safety data reported here when considered alongside the previously reported efficacy data provide valuable information on the benefit-risk profile of daclizumab in patients with relapsing MS.

Role of funding source

The integrated analysis and the daclizumab clinical studies were funded by Biogen and AbbVie Biotherapeutics Inc. The sponsors designed the integrated analysis on data collected by the investigators of each study. The authors, including representatives of the sponsor, interpreted the data. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this manuscript. Malcolm Darkes (Excel Scientific Solutions, Southport, CT) wrote the first draft based on input from authors, and Elizabeth Cassell (Excel Scientific Solutions, Southport, CT) copyedited and styled the manuscript per journal requirements. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the manuscript. The authors had full editorial control of the manuscript, and provided their final approval of all content, and made the decision to submit the manuscript for publication.

Conflict of interest

G Giovannoni has received research grant support from Bayer HealthCare, Biogen, GW Pharma, Merck Serono, Merz, Novartis, Sanofi-Aventis, and Teva; and personal compensation for participating on advisory boards in relation to clinical study design, trial steering committees, and data and safety monitoring committees from AbbVie Biotherapeutics Inc., Bayer HealthCare, Biogen, Canbex Therapeutics, Eisai, Elan, Five Prime Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon, Teva, UCB, and Vertex Pharmaceuticals; and compensation from Elsevier for his role as co-chief editor on Multiple Sclerosis and Related Disorders.

L Kappos' institution (University Hospital Basel, Basel, Switzerland) received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharmaceutical Co., Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems AG; and grants from Bayer HealthCare, Biogen, Merck, Novartis, Roche, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.

R Gold has received speaker honoraria or research grant support from Bayer HealthCare, Biogen, Merck Serono, Merz Pharma, Novartis, Sanofi-Aventis, and Teva; and compensation for advisory board activities from Biogen, Merck Serono, Novartis, and Teva.

B Khatri has received speaker honoraria and/or consulting compensation from Avanir, Bellevue, Biogen, EMD Serono, Genzyme, Mallinckrodt Pharmaceuticals, Novartis, Pfizer, and Teva.

K Selmaj has received consulting compensation from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; and compensation for speaking from Biogen.

K Umans is an employee of and holds stock/stock options in Biogen and K Umans’ family member holds stock in Sinovac Biotech Ltd.

J Elkins and P McCroskery are employees of and hold stock/stock options in Biogen.

M Sweester was an employee of Biogen at the time of this analysis and holds stock in Biogen and is currently an employee of Alnylam Pharmaceuticals.

SJ Greenberg is an employee of and holds stock in AbbVie Inc.

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Footnotes

a Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK

b Neurology, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland

c Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Gudrunstraße 56, 44791 Bochum, Germany

d Center for Neurological Disorders and The Regional Multiple Sclerosis Center, Wheaton Franciscan Health Care St. Francis Hospital, 3237 S 16th Street, Milwaukee, WI 53215, USA

e Department of Neurology, Medical University of Lodz, ul. Kopcinskiego 22, 90–153 Lodz, Poland

f Biogen, 225 Binney Street, Cambridge, MA 02142, USA

g AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA

Corresponding author.

1 Present address: Alnylam Pharmaceuticals, Inc., 300 Third Street, Cambridge, MA 02142.

2 Daclizumab HYP, approved as Zinbryta™, has a different form and structure than an earlier form of daclizumab (Zenapax).


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