Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T regs ) and B cells (CD38+B regs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.
NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56 dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.
Patients treated with daratumumab monotherapy (n=199) and combination therapy (n=1051) were evaluated for anti-therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the monotherapy patients and 2 of the 1051 combination therapy patients tested positive for anti-daratumumab antibodies; 1 of the combination therapy patients developed transient neutralising antibodies against daratumumab. However, the employed assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development might not have been reliably determined.
The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg.
In the 1 to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, Cmax increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Four population PK analyses were performed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma; Analysis 1 (n=223) in patients receiving daratumumab monotherapy while Analysis 2 (n=694), Analysis 3 (n=352) and Analysis 4 (n=355) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Analysis 2 included 694 patients (n=326 for lenalidomide-dexamethasone; n=246 for bortezomib-dexamethasone; n=99 for pomalidomide- dexamethasone; n=11 for bortezomib-melphalan-prednisone; and n=12 for bortezomib-thalidomide- dexamethasone), Analysis 3 included 352 patients (bortezomib-melphalan-prednisone) and Analysis 4 included 355 patients (lenalidomide-dexamethasone).
Based on the population PK analysis of daratumumab monotherapy (Analysis 1), daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21 st infusion), and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.
Three additional population PK analyses (Analysis 2, Analysis 3 and Analysis 4) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 15-23 days.
Based on the four population PK analyses (Analyses 1-4) body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Simulation of daratumumab pharmacokinetics was conducted for all recommended dosing schedules in 1,309 patients with multiple myeloma. The simulation results confirmed that the split and single dosing for the first dose provide similar PK, with the exception of the PK profile in the first day of the treatment.
Based on four individual population PK analyses (1-4) in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-4), age (range: 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=518) and older (aged ≥65 to <75 years n=761; aged ≥75 years, n=334) patients.
Gender did not affect exposure of daratumumab to a clinically relevant degree in the population PK analyses.
No formal studies of daratumumab in patients with renal impairment have been conducted. Four individual population PK analyses were performed based on pre-existing renal function data in patients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-4), and included a total of 441 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 621 with mild renal impairment (CRCL <90 and ≥60 mL/min), 523 with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 27 with severe renal impairment or end stage renal disease (CRCL<30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.
No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.
Four individual population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-4), and included a total of 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST >ULN) and 8 patients with moderate (TB >1.5 x to 3.0 x ULN; n=7), or severe (TB >3.0 x ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.
Based on four individual population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies (Analyses 1-4), the exposure to daratumumab was similar between white (n=1371) and non-white subjects (n=242).
Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.
No animal studies have been performed to establish the carcinogenic potential of daratumumab.
No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development.
No animal studies have been performed to determine potential effects on fertility in males or females.
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