Zinbryta - Scientific Information
|Form:||Liquid solution, Subcutaneous (SC)|
|Ingredients:||Daclizumab, Sodium succinate, Anhydrous, Succinic acid, Sodium chloride, Polysorbate 80, Water for injection|
Daclizumab is a humanized monoclonal antibody that binds to the alpha subunit of the interleukin-2 receptor (IL-2Rα, CD25). Daclizumab is composed of two humanized gamma-1 heavy chains and two humanized kappa light chains and has a molecular weight of approximately 144 kilodaltons (kDa).
ZINBRYTA injection is supplied as a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for subcutaneous use in a single-dose prefilled syringe. Each 1 mL prefilled syringe contains 150 mg daclizumab; polysorbate 80, USP (0.3 mg); sodium chloride (5.84 mg); sodium succinate, anhydrous (5.94 mg); succinic acid (0.35 mg); and Water for Injection, USP. The pH is 6.0.
Mechanism of Action
The precise mechanism by which daclizumab exerts therapeutic effects in multiple sclerosis is unknown but is presumed to involve modulation of IL-2 mediated activation of lymphocytes through binding to CD25, a subunit of the high-affinity IL-2 receptor.
During ZINBRYTA treatment, mean cell counts for the major immune subsets (T, B, and NK cells) remained within normal ranges. Total lymphocyte, T and B cell counts decreased less than 10% from baseline during the first year of treatment. Total lymphocyte counts returned to baseline levels approximately 8-12 weeks after the last dose of ZINBRYTA (150 mg).
The pharmacokinetics of ZINBRYTA are similar for healthy volunteers and patients with multiple sclerosis (MS).
Following a single subcutaneous injection of ZINBRYTA, the maximum concentration occurred between 5 and 7 days. At steady state, daclizumab mean maximum serum concentration (Cmax) was 30 μg/mL, minimum serum concentration (Cmin) was 15 μg/mL, and area under the serum concentration-time curve over the dosing interval (AUCtau) values were approximately 640 μg-days per mL. The absolute bioavailability of 150 mg subcutaneous daclizumab was approximately 90%.
After administration of ZINBRYTA 150 mg subcutaneously every 4 weeks, serum daclizumab concentrations reached steady state by the fourth dose. Daclizumab accumulated to a level approximately 2.5-fold compared with a single dose.
The coefficient of variation between individual patients was approximately 35-40% for exposure (Cmax and AUC) and 27-51% for clearance and volume of distribution.
In multiple sclerosis patients taking 150 mg subcutaneous doses of ZINBRYTA every 4 weeks, the estimated steady-state volume of distribution of daclizumab was approximately 6.34 liters.
Metabolism and Elimination
Because it is a protein, daclizumab is expected to undergo catabolism to peptides and amino acids in the same manner as endogenous IgG proteins without renal elimination. The estimated clearance of daclizumab is 0.212 liters per day with an elimination half-life of 21 days. Daclizumab clearance in patients who developed neutralizing antibodies was 19% higher [see Adverse Reactions (Immunogenicity)].
Clinical studies did not identify significant differences in pharmacokinetic parameters between Japanese and Caucasian healthy volunteers. Covariate analyses did not identify significant differences in pharmacokinetic parameters based on gender, age, or weight for patients with relapsing forms of multiple sclerosis.
Drug Interaction Studies
ZINBRYTA 150 mg administered subcutaneously every 4 weeks for 12 weeks in patients with multiple sclerosis did not significantly affect the systemic exposure of concomitantly administered oral midazolam (CYP3A substrate), warfarin (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), omeprazole (CYP2C19 substrate), or caffeine (CYP1A2 substrate).
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of ZINBRYTA has not been assessed.
Genetic toxicology studies of ZINBRYTA have not been conducted.
Impairment of Fertility
ZINBRYTA (0, 10, 50, or 200 mg/kg) administered biweekly by subcutaneous injection to monkeys had no adverse effect on male (sperm motility, concentration, and morphology or testosterone levels) or female (estrus cycle length or estradiol/progesterone patterns) fertility endpoints. At the highest dose tested, plasma exposures (AUC) in males and females were 100 and 85 times, respectively, that at the recommended human dose (RHD) of 150 mg.
Animal Toxicology and/or Pharmacology
There was a dose-dependent increase in microglial aggregates in the brain and spinal cord of monkeys at subcutaneous doses greater than 10 mg/kg administered biweekly for up to 39 weeks. Microglial aggregates were, in some animals, associated with microhemorrhage; however, no evidence of neuronal injury was observed. There was evidence of reversibility by 12 weeks after the last dose.
The efficacy of ZINBRYTA was demonstrated in two randomized, double-blind, controlled studies (Study 1 and Study 2). Both studies evaluated 150 mg of subcutaneous ZINBRYTA taken once every four weeks in patients with relapsing multiple sclerosis (RMS).
Study 1: Active-Controlled Trial in RMS
Study 1 compared ZINBRYTA to 30 mcg weekly intramuscular doses of AVONEX in 1841 patients. The study included RMS patients who had either: 1) at least 2 relapses during the prior 3 years and at least one relapse in the year prior to randomization; or 2) one or more clinical relapses and one or more new T1 gadolinium (Gd)-enhancing or T2 hyperintense MRI lesions within the prior 2 years with at least one of these events in the prior 12 months. Patients with progressive forms of multiple sclerosis or an Expanded Disability Status Scale (EDSS) score greater than 5 were excluded. Treatment continued for up to 144 weeks until the last enrolled patient completed 96 weeks of treatment. Clinical assessments were to occur every 12 weeks and after relapse events. MRI scans were performed at Week 24 and Week 96.
The primary outcome measure of Study 1 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients relapsed, the proportion of patients who experienced confirmed disability progression, and the number of new or newly enlarging T2 hyperintense lesions. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks.
In Study 1, randomization assigned 919 patients to ZINBRYTA and 922 patients to AVONEX; 71% of ZINBRYTA- and 70% of AVONEX -treated patients completed at least 96 weeks of treatment with the assigned drug. At baseline, the mean age of patients was 36 years, the mean disease duration since diagnosis was 4.2 years, the mean EDSS score was 2.5, and the mean number of relapses in the prior year was 1.6. At baseline, 68% of patients were female, 46% of patients had MRI scans with T1 Gd-enhancing lesions and 41% of patients had previously taken one or more non-steroid treatments for MS.
ZINBRYTA had a statistically significant effect on the annualized relapse rate and on the number of new or newly enlarging T2 hyperintense lesions. There was no statistically significant effect on 12-week confirmed disability progression.
Results for Study 1 are shown in Table 1 and Figure 1, below.
150 mg SQ
Every 4 Weeks
30 mcg IM
|Annualized relapse rate
Proportion Relapse Free
|Proportion with 12-week confirmed disability progression||16%||20%||0.16|
|Mean number of new or newly enlarging T2 hyperintense lesions
1 Values refer to results up to144 weeks
2 MRI analysis used evaluable dataset and values reflect results at 96 weeksFigure 1: Study 1 Percentage of Relaps e-Free Patients
In a subgroup analysis of Study 1, a reduction was observed compared with AVONEX on annualized relapse rate across patient subgroups (based on gender, age, prior multiple sclerosis disease modifying therapy, and disease activity levels).
Study 2: Placebo-Controlled Trial in RMS
Study 2 compared ZINBRYTA to placebo in 412 patients. The study included RMS patients who had experienced at least one relapse in the year prior to randomization or who had one or more T1 Gd-enhancing MRI lesions within 6 weeks of randomization. Patients with progressive forms of multiple sclerosis or an EDSS score greater than 5 were excluded. Treatment duration was 52 weeks. Clinical assessments were to occur every 12 weeks and after relapse events. MRI scans were performed at weeks 24, 36, and 52 in all patients and every 4 weeks in a subset of patients.
The primary outcome measure of Study 2 was the annualized relapse rate (ARR) at Week 52. Additional outcome measures included new T1 Gd-enhancing lesions between Week 8 and Week 24, the proportion of patients relapsed, the proportion of patients who experienced 12-week confirmed disability progression (as defined in Study 1) and the number of new or newly enlarging T2 hyperintense lesions.
In Study 2, randomization assigned 208 patients to receive ZINBRYTA (150 mg) and 204 patients to receive placebo; 91% of ZINBRYTA patients and 91% of placebo patients completed treatment. At baseline, the mean age of patients was 36 years, the mean disease duration since diagnosis was 4.3 years, the mean EDSS score was 2.8, and the mean number of relapses in the prior year was 1.4. At baseline, 65% of patients were female, 48% of patients had MRI scans with T1 Gd-enhancing lesions and 21% of patients had previously taken one or more non-steroid treatments for MS.
ZINBRYTA had a statistically significant effect on the annualized relapse rate, the proportion of patients relapse free, the number of new T1 Gd -enhancing lesions, and the number of new or newly enlarging T2 hyperintense lesions. The results for Study 2 are shown in Table 2.
|ZINBRYTA 150 mg SQ Every 4 Weeks N=208||Placebo N=204||p-value|
|Annualized relapse rate
Proportion Relapse Free
|Proportion with 12-week confirmed disability progression3
Relative risk reduction
|Mean number of new or newly enlarging
T2 hyperintense lesions1
|Mean number of new T1 Gd-enhancing
1 Values refer to results at 52 weeks
2 MRI analyses used evaluable dataset for each endpoint; T1 Gd-enhancing: MRI intensive population, between 8-24 weeks
3 The proportion of patients with 12-week confirmed disability progression was an exploratory measure in Study 2. As the proportion of patients with 12-week confirmed disability was used as a key secondary outcome in Study 1, and is one of the main outcome measures in MS studies, the disability progression results are presented for Study 2. The nominal p value for that comparison, p=0.02, is not adjusted for multiple comparisons.