Daclizumab beta is a humanised IgG1 monoclonal antibody that binds to CD25 (IL-2Rα), and prevents IL-2 binding to CD25. Daclizumab beta modulates IL-2 signalling by blocking CD25-dependent, high-affinity IL-2 receptor signalling, resulting in higher levels of IL-2 available for signalling through the intermediate-affinity IL-2 receptor. Key effects of this IL-2 pathway modulation potentially related to the therapeutic effects of daclizumab beta in MS include selective antagonism of activated T-cell responses, and expansion of immunoregulatory CD56bright natural killer (NK) cells, which have been shown to selectively decrease activated T-cells. Together, these immunomodulatory effects of daclizumab beta are believed to reduce CNS pathology in MS and thereby reduce the occurrence of relapses and disability progression.
In clinical studies, the pharmacodynamic effects of daclizumab 150 mg administered subcutaneously every 4 weeks were consistent with modulation of IL-2 signalling as evidenced by the rapid and sustained saturation of the target CD25 receptors on circulating T-cells and a sustained approximately 2-fold increase in serum IL-2 concentration. In addition, an increase in CD56bright NK cells and a decrease in regulatory T-cells (defined as CD4+ CD127lowFoxP3+ T-cells) was observed within 2 weeks after the first dose, with a sustained 5-fold increase in CD56bright NK cells above baseline and an approximately 60% decrease in regulatory T-cells in the treatment phase, with a return to baseline levels approximately 20-24 weeks after the last dose. During daclizumab 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 on average ≤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 daclizumab (150mg). Total lymphocyte counts <0.8x109 cells/L ([Common Terminology Criteria for Adverse Events – CTCAE] Grade 2; at least one measurement) occurred in 4% of placebo-treated and 5% of daclizumab-treated patients in the SELECT study, and 9% of the interferon beta-1a (intramuscular)-treated and 8% of daclizumab-treated patients in the DECIDE study. Total NK cell counts increased approximately 1.5-fold as a result of the change in CD56bright NK cells.
Daclizumab beta pharmacokinetics are well described by a two-compartment model with first-order absorption and elimination.
Following subcutaneous administration of daclizumab beta, the median time to reach maximum serum concentrations (Tmax) ranged from 5 to 7 days. The absolute bioavailability of daclizumab beta 150 mg subcutaneously administered was approximately 90% based on a cross-study population pharmacokinetic analysis of subcutaneous and intravenous dosing.
Following subcutaneous administration of daclizumab beta 150 mg every 4 weeks, steady-state serum daclizumab beta concentrations were achieved by the 4th dose and daclizumab beta accumulated to a level approximately 2.5-fold compared to a single dose. At steady state, daclizumab beta mean maximum serum concentration (Cmax), minimum serum concentration (Cmin) and area under the serum concentration-time curve over the dosing interval (AUCtau) values were approximately 30 micrograms/mL, 15 micrograms/mL and 640 day*micrograms/mL, respectively, with inter-patient variability (% CV) of approximately 40%.
Based on the cross-study population pharmacokinetic analysis, the steady-state volume of distribution of daclizumab beta is 6.34 L in a patient with a body weight of 68 kg (approximate median of evaluated patients). This small volume of distribution indicates that daclizumab beta is primarily confined to the vascular and interstitial spaces.
The exact metabolic pathway for daclizumab beta has not been characterised. As an IgG1 monoclonal antibody, daclizumab beta is expected to undergo catabolism to peptides and amino acids in the same manner as endogenous IgG. Daclizumab beta is not expected to undergo metabolism by hepatic enzymes such as CYP isoenzymes.
As an IgG1 monoclonal antibody, daclizumab beta is not expected to undergo renal elimination.
Based on the cross-study population pharmacokinetic analysis, the clearance of daclizumab beta is 0.212 L/day with a terminal half-life value of approximately 21 days. Daclizumab beta clearance in patients who developed neutralising antibodies was, on average, 19% higher.
Consistent with results from individual studies, a cross-study population pharmacokinetic analysis indicated that daclizumab beta exposure is more than dose-proportional in the 50 mg to 100 mg subcutaneous dose range and is dose proportional in the 100 mg to 300 mg subcutaneous dose range.
Within the studied regimens of daclizumab beta 150 mg and 300 mg administered subcutaneous every 4 weeks in MS patients, there was no clear relationship between daclizumab beta exposure and clinical efficacy endpoints (ARR, T2 lesions and Gd-enhancing lesions) or safety endpoints of interest (serious infection status, moderate or severe cutaneous adverse reaction, and AST/ALT >5 times the ULN).
No studies were conducted to evaluate daclizumab beta pharmacokinetics in patients with renal or hepatic impairment. Daclizumab beta is not expected to undergo renal elimination or metabolism by hepatic enzymes.
Based on the cross-study population pharmacokinetic analysis, body weight accounted for less than 40% of the inter-patient variability in daclizumab beta clearance. No meaningful differences in clinical efficacy or safety were observed among the subgroups of MS patients by weight quartile in the DECIDE study.
Based on the cross-study population pharmacokinetic analysis, daclizumab beta pharmacokinetics were not influenced by age (range: 18 to 66 years; n=1670) or gender (n = 567 males and 1103 females).
No pharmacokinetic differences were observed between Japanese and Caucasian healthy volunteers.
Preclinical safety studies were conducted in cynomolgus monkeys due to species specificity of daclizumab beta binding only to human or primate CD25.
Carcinogenicity studies with daclizumab beta have not been conducted. In two 9 month studies in monkeys there were no pre-neoplastic or neoplastic tissue observed.
Genotoxicity studies have not been conducted.
Daclizumab beta did not affect reproductive capacity in female and male cynomolgus monkeys (AUC in females and males up to 85 and 100 times higher than the exposure at the clinical dose respectively). There was no effect on foetal development and no evidence of teratogenicity. Daclizumab beta had no effect on peri- and post-natal development from birth to up to 6 months in the offspring. Exposures (AUC) in these studies ranged from 55 to 140 times that observed with the clinical dose. Daclizumab beta was detected in the milk of 11/14 lactating monkeys at levels that were <0.122% of the maternal serum levels, with no adverse reactions observed in the off-spring.
In two 9 month studies conducted in cynomolgus monkeys daclizumab beta was subcutaneously administered at bi-weekly doses of 10-200 mg/kg. Chronic administration of daclizumab beta at all doses increased the incidence of skin findings (compared to those observed in control animals). These findings (dry, red raised patchy areas of the skin, as compared to controls, that correlated microscopically with acanthosis/hyperkeratosis and subacute to chronic inflammation) were characterised predominantly as mild to moderate, with one case assessed as severe.
A dose dependent increase in incidence of microglial aggregates above background was observed in the brain and spinal cord of monkeys treated with ≥35 mg/kg, (AUC 27 times higher than the clinical dose). Following a recovery period of up to 12 weeks, there was evidence of reversibility. Microglial aggregates in monkeys did not increase in incidence or severity with increased duration of dosing and were not associated with neuronal damage or neurobehavioral effects. A small subset of microglial aggregates were associated with microhaemorrhage but with no evident functional sequelae in monkeys.
In vitro investigative studies suggest that microglial aggregates are not due to a direct effect of daclizumab beta on microglial cells but are likely to be attributable to an increase in local IL-2 bioavailability.
The clinical relevance of microglial aggregates is unknown, however no deleterious neurologic effects attributed to the microscopic change have been observed in monkeys.
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