Belantamab mafodotin is a humanised IgG1 kappa monoclonal antibody conjugated with a cytotoxic agent, mcMMAF. Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised. Once inside the tumour cell, the cytotoxic agent (cys-mcMMAF) is released disrupting the microtubule network, leading to cell cycle arrest and apoptosis. The antibody also enhances recruitment and activation of immune effector cells, killing tumour cells by antibody-dependent cellular cytotoxicity and phagocytosis. Apoptosis induced by belantamab mafodotin is accompanied by markers of immunogenic cell death, which may contribute to an adaptive immune response to tumour cells.
Belantamab mafodotin or cys-mcMMAF had no meaningful QTc prolongation (>10 ms) at doses of up to 3.4 mg/kg once every 3 weeks.
Anti-drug antibodies (ADA) were rarely detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
Maximum concentration for belantamab mafodotin ADC occurred at or shortly after the end of infusion while cys-mcMMAF concentrations peaked ~24 hours after dosing.
The followed table describes the pharmacokinetics of belantamab mafodotin for 2.5 mg/kg doses on cycle 1 Day 1 at the end of the first 3-week interval.
Belantamab mafodotin pharmacokinetics at the end of the first 3-week intervala:
| AUCb | Cavg21 | Cmax | Ctau | |
|---|---|---|---|---|
| ADC (%) | 3 950 mcg•h/mL (30.6) | 7.83 mcg/mL (30.6) | 43.7 mcg/mL (22.1) | 2.03 mcg/mL (62.5) |
| cys-mcMMAF (%) | 94.2 ng•h/mL (42.3) | 0.243 ng/mL (42.4) | 0.976 ng/mL (45.3) | – |
ADC = antibody drug conjugate; AUC = Area under the curve; Cavg21 = belantamab mafodotin average concentration over 21 days; Cmax = maximum plasma concentration; Ctau = concentration at the end of a dosing interval.
a Data presented as geometric mean (%CV), based on population PK models.
b AUC for ADC is AUC(0-21days) and AUC(0-7days) for cys-mcMMAF.
Accumulation of belantamab mafodotin (ADC) was minimal to moderate (the ratio from cycle 3 to cycle 1 was 1.13 for Cmax and 1.58 for AUC) and accumulation of cys-mcMMAF was negligible as observed in clinical trials with a every 3 weeks dosing regimen.
In vitro, cys-mcMMAF exhibited low protein binding, (70% unbound at a concentration of 5 ng/mL) in human plasma in a concentration-dependent manner.
Based on the population PK analysis, the geometric mean (geometric CV%) for steady-state volume of distribution of belantamab mafodotin was 10.8 L (22%).
The monoclonal antibody portion of belantamab mafodotin is expected to undergo proteolysis to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Cys-mcMMAF had limited metabolic clearance in human hepatic S9 fraction incubation studies.
In vitro studies demonstrated that cys-mcMMAF is not an inhibitor, an inducer, or a sensitive substrate of cytochrome P450 enzymes, but is a substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and a possible substrate of P-glycoprotein (P-gp). Clinically relevant drug-drug interactions with inhibitors or inducers of these enzymes and transporters are not expected.
Based on the population PK analysis from patients treated with belantamab mafodotin monotherapy or in combination with other medicinal products, the geometric mean (geometric CV%) belantamab mafodotin (ADC) initial systemic clearance (CL) was 0.901 L/day (40%), and the elimination half- life was 13 days (26%). Following treatment, steady-state CL was 0.605 L/day (43%) or approximately 33% lower than initial systemic CL with an elimination half-life of 17 days (31%).
The fraction of intact cys-mcMMAF excreted in urine was not substantial (approximately 18% of the dose) after cycle 1 dose, with no evidence of other MMAF-related metabolites.
Belantamab mafodotin exhibits dose-proportional pharmacokinetics over the recommended dose range with a reduction in clearance over time.
Based on a population of patients aged 32 to 89 years, age was not a significant covariate in population pharmacokinetics analyses.
In patients with severe renal impairment (eGFR 15-29 mL/min, n=8), belantamab mafodotin Cmax decreased by 23% and AUC(0-tau) decreased by 16% compared with patients with normal renal function or mild renal impairment (eGFR ≥ 60 mL/min, n=8). For cys-mcMMAF, Cmax and AUC(0-168h) decreased by 56% and 44%, respectively compared to patients with normal renal function or mild renal impairment. Renal function (eGFR 12-150 mL/min) was not a significant covariate in population pharmacokinetic analyses that included patients with normal renal function, mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe renal impairment (eGFR < 30 mL/min not requiring dialysis). No impact on belantamab mafodotin PK was observed for patients with end stage renal disease (eGFR < 15 mL/min requiring dialysis, n=5).
Belantamab mafodotin is not expected to be removed via dialysis due to its molecular size. While free cys-mcMMAF may be removed via dialysis, cys-mcMMAF systemic exposure is very low and has not been shown to be associated with efficacy or safety based on exposure-response analysis.
No formal studies have been conducted in patients with hepatic impairment. Hepatic function as per the National Cancer Institute Organ Dysfunction Working Group classification, was not a significant covariate in population pharmacokinetic analyses that included patients with normal hepatic function, mild (total bilirubin > ULN to ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN with AST > ULN) or moderate hepatic impairment (total bilirubin > 1.5 x ULN to ≤ 3 × ULN and any AST). Limited data are available for patients with moderate (n=5) or severe hepatic impairment (n=1, total bilirubin > 3 × ULN and any AST) in the population pharmacokinetic analyses.
Body weight (37 to 170 kg) was a significant covariate in population pharmacokinetic analyses, but this effect will be adjusted by the weight-proportional dosing regimen.
In non-clinical trials, the principal adverse findings (directly related to belantamab mafodotin) in the rat and monkey, at similar exposures to the recommended clinical dose of 2.5 mg/kg, were elevated liver enzymes sometimes associated with hepatocellular necrosis at ≥10 and ≥3 mg/kg, respectively, and increases in alveolar macrophages associated with eosinophilic material in the lungs at ≥3 mg/kg (rat only). Most findings in animals were related to the cytotoxic drug conjugate, the histopathological changes observed in the testes and lungs, were not reversible in rats.
Single cell necrosis in the corneal epithelium and/or increased mitoses of corneal epithelial cells was observed in rat and rabbit. Inflammation of the corneal stroma correlating with superficial haze and vascularisation was observed in rabbits. Belantamab mafodotin was taken up into cells throughout the body by a mechanism unrelated to BCMA receptor expression on the cell membrane.
Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes, consistent with the pharmacological effect of cys-mcMMAF-mediated disruption of microtubules causing aneuploidy.
No carcinogenicity or definitive genotoxicity studies have been conducted with belantamab mafodotin.
No animal studies have been performed to evaluate the potential effects of belantamab mafodotin on reproduction or development. The mechanism of action is to kill rapidly dividing cells which would affect a developing embryo which has rapidly dividing cells. There is also a potential risk of heritable changes via aneuploidy in female germ cells.
Effects on male and female reproductive organs have been observed in animals at doses of ≥10 mg/kg, which is approximately 4 times the exposure of the clinical dose. Luteinised nonovulatory follicles were seen in the ovaries of rats after 3 weekly doses. Findings in male reproductive organs that were adverse and progressed following repeat dosing in rat, included marked degeneration/atrophy of seminiferous tubules that generally did not reverse following dosing cessation.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.