Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin that selectively binds to CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs including the skin, resulting in depletion of the target cells. CCR4 is expressed on the surface of some cancer cells including T cell malignancies, such as MF and SS in which CCR4 expression is inherent.
The pharmacokinetics (PK) of mogamulizumab was evaluated in adult patients with T-cell leukaemia-lymphoma (ATL) and CTCL over a dose range of 0.01 to 1 mg/kg administered as multiple doses of mogamulizumab every week or every 2 weeks, and included the recommended 1.0 mg/kg dose and regimen (days 1, 8, 15 and 22 for the first 28-day cycle and on Days 1 and 15 for subsequent 28-day cycles). The population PK analysis included 444 patients receiving mogamulizumab in six clinical trials. The exposure to mogamulizumab increased proportionally with dose over the dose range of 0.1 to 1.0 mg/kg.
Mogamulizumab is dosed via intravenous route and therefore is immediately and completely bioavailable.
Based on a population PK analysis, the geometric mean [% coefficient of variation (CV%)] central volume of distribution (Vc) was 3.57 L (20.1%).
The metabolic pathway of mogamulizumab has not been characterised. Mogamulizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Based on a population PK analysis, the geometric mean (% coefficient of variation [CV%]) clearance (CL) is 12.0 mL/h (83.7%) and geometric mean elimination half-life (t1/2) is 17 days (65.5%).
Mogamulizumab exhibits linear PK from the dose in a dose range of 0.01 mg/kg to 1 mg/kg. Based on a population PK analysis, the steady-state concentrations of mogamulizumab were reached after 12 weeks of repeated dosing when administered using the recommended regimen, and systemic accumulation was 1.7-fold. On a power model analysis, no deviation from dose proportionality was evident.
The effect of renal impairment on the clearance of mogamulizumab was evaluated by a population PK analysis in patients with mild (creatinine clearance [CrCL] between 60 and 89; n=157), moderate (CrCL between 59 and 30; n=80), or severe renal impairment (CrCL less than 30 mL/min; n=2). No clinically important differences in the clearance of mogamulizumab were found between patients with mild to severe renal impairment and patients with normal renal function.
The effect of hepatic impairment on the clearance of mogamulizumab was evaluated by a population PK analysis in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=80) or moderate (TB greater than 1.5 to 3 times ULN and any AST; n=3) hepatic impairment. No clinically important differences in the clearance of mogamulizumab were found between patients with mild to moderate hepatic impairment and patients with normal hepatic function. Mogamulizumab has not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any AST).
The effects of various covariates on the PKs of mogamulizumab were assessed in population PK analyses. The following factors had no clinically important effect on the CL of mogamulizumab: age (range: 22 to 101 years), sex, ethnicity (other than Japanese, limited data are available in other ethnic populations), renal impairment, mild or moderate hepatic impairment, disease subtype (mycosis fungoides (MF) or Sézary Syndrome (SS)), degree of CCR4 expression or ECOG status, although it should be noted that patients with ECOG PS ≥2 were excluded from the clinical trials.
Exposure-Response analysis indicated that efficacy was not correlated with mogamulizumab exposure in the pivotal study. Efficacy, as measured by improvement in PFS based on investigator assessment, was not associated with increasing mogamulizumab exposure.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity. Carcinogenicity or genotoxicity studies have not been conducted with mogamulizumab. No specific studies have been conducted to evaluate potential effects on fertility.
No mogamulizumab-related toxic effects in the male and female reproductive organs were observed in repeat-dose toxicology studies in sexually mature monkeys up to 26 weeks.
In an animal reproductive and developmental toxicity study, administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for embryo-foetal lethality, teratogenicity, or foetal growth retardation. In general, IgG molecules are known to cross the placental barrier and mogamulizumab concentrations in foetus plasma were detected. Pharmacological activity of mogamulizumab was noted in foetuses as was evident from a decrease in CCR4 expressing lymphocytes.
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