Odronextamab

Odronextamab is a human IgG4-based bispecific antibody that binds to CD20, a B-cell surface antigen present on normal and malignant B cells and CD3, a T-cell antigen associated with the T-cell receptor complex. Simultaneous engagement of both arms of odronextamab results in formation of a synapse between the T cell and the CD20-expressing cell, resulting in T-cell activation and generation of polyclonal cytotoxic T-cell response, which result in redirected lysis of the targeted cells, including malignant B cells.

Pharmacodynamic effects

Circulating B-cell count

Following administration of the recommended doses of odronextamab, median circulating B cells decreased to undetectable levels (<1 cells/microliter) by Week 4 (Cycle 2, Day 1, after the first 80-mg 19 dose for r/r FL or 160-mg dose for r/r DLBCL) administered in patients who had detectable B cells at baseline. The B-cell depletion was sustained while patients remained on treatment.

Cytokine concentration

Concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) in serum were measured. Transient elevation of circulating cytokines was observed at dose levels of 0.2 mg and above. After administration of the recommended step-up dosing regimen of odronextamab, the highest elevation of systemic cytokine concentrations was observed within 24 hours after each intravenous infusion in Cycle 1, typically observed in the first two weeks. The elevated cytokine concentrations generally returned to baseline prior to the next infusion during the step-up dosing period (Cycle 1). Limited cytokine release was observed following subsequent doses.

Immunogenicity

During treatment in Study 1625 and Study 1333, anti-odronextamab antibodies (ADA) were detected in 1.5% (6/400) of patients. No neutralizing antibodies were observed. No evidence of ADA impact on pharmacokinetics or safety was observed, however, data are still limited.

Pharmacokinetics (PK) of odronextamab was characterized in patients with B-cell non-Hodgkin lymphoma (B-NHL) over a dose range from 0.03 mg to 320 mg following intravenous infusion. During the step-up dosing period, the disposition of odronextamab is concentration-and time-dependent. As dose levels increase with continued treatment to ≥80 mg, the PK profile of odronextamab becomes linear and dose-proportional at steady-state. The exposure parameters at doses ≥80 mg were approximately dose-proportional (see table). PK was similar across the B-NHL patient populations evaluated.

Predicted exposure parameters of recommended dose for odronextamab:

^a Values are median and 5^th and 95^th percentiles from a simulation of 507 subjects with B-NHL.
^b AUC_τ for the specified dosing interval.

Distribution

The estimated geometric mean (CV%) of volume of distribution at steady-state (Vd_ss) of odronextamab is 9.34 L (CV% 48.5).

Biotransformation

Odronextamab is expected to be metabolized into small peptides by catabolic pathways.

Elimination

Odronextamab elimination is mediated by two parallel processes, a linear, non-saturable catabolic process and a nonlinear, saturable target-mediated pathway, with higher clearance at lower doses.

Following administration of the last dose of 160 mg once every 2 weeks at steady-state, the time to reach a lower limit of quantification (LLOQ, 0.00313 mg/L) was 19 weeks, and the time to reach 1% of the median C_max of 160 mg once every 2 weeks dose was 12 weeks.

Following administration of the last dose of 320 mg once every 2 weeks at steady-state, the time to reach the LLOQ (0.00313 mg/L) was 24 weeks, and the time to reach 1% of the median C_max of 320 mg once every 2 weeks dose was 16 weeks.

Special populations

No clinically relevant differences in exposure to odronextamab were observed based on age (22 to 89 years; N=507), sex, race [white (N=316), Asian (N=129), or Black (N=7)], body weight, renal impairment, or mild to moderate hepatic impairment.

Renal impairment

The population pharmacokinetics analysis of odronextamab showed that creatinine clearance (CrCL) does not affect the pharmacokinetics of odronextamab. No clinically relevant differences in exposure to odronextamab were observed in patients with normal renal function and with mild (N=178; CrCL ≥60 to <90 mL/min), moderate (N=110; CrCL ≥30 to <60 mL/min), and severe (N=4; CrCL ≥15 to <30 mL/min) renal impairment.

Hepatic impairment

No clinically relevant differences in exposure to odronextamab were observed in patients with normal hepatic function and with mild (N=78; total bilirubin > ULN to 1.5 x ULN or AST > ULN) and moderate (N=5; total bilirubin > 1.5 to 3 x ULN and any AST) hepatic impairment. The effects of severe (total bilirubin > 3 to 10 x ULN and any AST) hepatic impairment on the PK of odronextamab are unknown.

No carcinogenicity or genotoxicity studies have been conducted with odronextamab.

No specific studies have been conducted to evaluate potential effects of odronextamab on fertility. No adverse effects on male or female reproductive organs and no effects on semen analysis or menstrual cyclicity were observed in a 16-week repeat-dose toxicology study in cynomolgus monkeys.

No developmental toxicity studies in animals have been conducted with odronextamab. Based on its mechanism of action, odronextamab may cause foetal B-cell lymphocytopenia that may be harmful to the foetus and transient CRS that may be harmful to pregnancy maintenance.