Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T-cells and B-cell maturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells. Binding of elranatamab to BCMA on tumour cells and CD3 on T-cells is independent of native T-cell receptor (TCR) specificity or reliance on major histocompatibility (MHC) Class 1 molecules. Elranatamab activated T-cells, led to proinflammatory cytokine release, and resulted in multiple myeloma cell lysis.
During treatment with elranatamab at the recommended dose, anti-drug antibodies (ADA) were detected in 8.3% participants. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed; however, data are still limited.
Pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) for unbound elranatamab unless otherwise specified. The Cmax and AUCtau of elranatamab after the first subcutaneous dose increased in a dose proportional manner over the evaluated dose range via subcutaneous administration (~6 to 76 mg). The median accumulation ratio after 24 weeks of weekly dosing relative to the first subcutaneous dose of elranatamab 76 mg for Cmax and AUCtau was 6.6-fold and 11.2-fold, respectively. The predicted Cavg, Cmax, and Ctrough of elranatamab are presented in Table 8.
Table 8. Predicted pharmacokinetic parameters of elranatamab following the recommended dose:
| Timepoint | Parameters | ||
|---|---|---|---|
| Cavg (mcg/mL) | Cmax (mcg/mL) | Ctrough (mcg/mL) | |
| End of weekly dose (week 24) | 32.7 (49%) | 33.6 (48%) | 31.2 (50%) |
| Steady state (every two weeks dosing)a,b | 18.4 (57%) | 20.1 (55%) | 15.9 (64%) |
a In patients who have achieved a response.
b Steady state exposure of elranatamab every two weeks dose is approximated at week 48.
The predicted mean bioavailability of elranatamab was 56.2% when administered subcutaneously. The median Tmax after elranatamab SC administration across all dose levels ranged from 3 to 7 days.
Based on the population pharmacokinetic model, the predicted mean volume of distribution of unbound elranatamab was 4.78 L, 69% (CV) for the central compartment, and 2.83 L for the peripheral compartment.
The predicted geometric mean half-life of elranatamab is 22, 64% (CV) days at week 24 following doses of 76 mg weekly. Based on the population pharmacokinetic model, the predicted mean elranatamab clearance was 0.324 L/day, 69% (CV).
No clinically relevant differences in the pharmacokinetics of elranatamab were observed based on age (36 to 89 years), sex (167 male, 154 female), race (193 White, 49 Asian, 29 Black), and body weight (37 to 160 kg).
No studies of elranatamab in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m² ≤ eGFR < 90 mL/min/1.73 m²) or moderate renal impairment (30 mL/min/1.73 m² ≤ eGFR < 60 mL/min/1.73 m²) did not significantly influence the pharmacokinetics of elranatamab. Limited data are available from patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).
No studies of elranatamab in patients with hepatic impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin >1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN) did not significantly influence the pharmacokinetics of elranatamab. No data are available in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe (total bilirubin >3.0 × ULN and any AST) hepatic impairment.
No animal studies have been performed to assess the carcinogenic or genotoxic potential of elranatamab.
No animal studies have been performed to evaluate the effects of elranatamab on fertility or reproduction and foetal development.
In a 13-week repeat-dose toxicity study in sexually mature cynomolgus monkeys, there were no notable effects on male and female reproductive organs following subcutaneous doses up to 6 mg/kg/week (approximately 6.5 times the maximum recommended human dose, based on AUC exposure).
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