Linvoseltamab

Linvoseltamab is a human IgG4-based bispecific antibody that binds to cluster of differentiation 3 (CD3), a T-cell antigen associated with the T-cell receptor complex, and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. Simultaneous engagement of both arms of linvoseltamab results in formation of a synapse between the T-cell and the BCMA-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 multiple myeloma B-lineage cells. This effect occurs without regard to T-cell receptor specificity or reliance on major histocompatibility complex (MHC) Class I molecules on the surface of antigen-presenting cells.

Transient elevation of circulating cytokines (IL-2, IL-6, and IFN-γ) was primarily observed during the step-up dose regimen and the first full 200 mg dose. The highest elevation of cytokines was generally observed 4 hours after each infusion and generally returned to baseline prior to the next dose. Limited cytokine release was observed following subsequent doses.

Immunogenicity

During treatment in LINKER-MM1 (evaluated through 30 months), the overall incidence of treatment-emergent anti-linvoseltamab antibodies was 1.0% (2/192) in patients treated with linvoseltamab. No evidence of anti-drug antibody impact on pharmacokinetics or safety was observed; however, data are still limited.

Pharmacokinetics of linvoseltamab was characterized in patients with relapsed or refractory multiple myeloma over a dose range of 1 mg to 800 mg following intravenous infusion. The C_max, C_trough, and AUC_τ of linvoseltamab at the end of weekly, every other week dosing regimens and at steady state on every 4 week dosing regimen are presented at the 200 mg dose level in Table 1.

Table 1. Geometric mean (CV%) of model-based exposure parameters of recommended dose for linvoseltamab:

^a AUC_τ for the specified dosing interval.

Distribution

Based on the population pharmacokinetic model, the estimated geometric mean (CV%) of volume of distribution at steady-state (Vd_ss) of linvoseltamab is 7.05 L (33.6%).

Biotransformation

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

Elimination

The elimination of linvoseltamab is mediated by two parallel processes, a linear, non-saturable catabolic process, and a nonlinear, saturable target-mediated pathway.

Based on the population pharmacokinetic model, the time to reach lower limit of quantification (LLOQ) (0.078 mg/L) following the last dose of 200 mg weekly, every other week, and every 4 weeks is presented in Table 2.

Table 2. Elimination of recommended dose for linvoseltamab:

^a Values are median [5^th and 95^th percentile]

Special populations

Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure (such as C_trough, AUC_τ) to linvoseltamab based on age (37 to 91 years; N=282), sex, and race [White (N=205), Asian (N=18), or Black (N=44)].

Renal impairment

No formal studies of linvoseltamab in patients with renal impairment have been conducted.

Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure to linvoseltamab between patients with normal renal function (N=78; CrCL ≥ 90 mL/min) and with mild (N=116; CrCL ≥ 60 to < 90 mL/min), moderate (N=76; CrCL ≥ 30 to < 60 mL/min), and severe (N=11; CrCL ≥ 15 to < 30 mL/min) renal impairment.

Hepatic impairment

No formal studies of linvoseltamab in patients with hepatic impairment have been conducted.

Results of population pharmacokinetic analyses indicate no clinically relevant differences in exposure to linvoseltamab between patients with normal (N=255) and with mild hepatic function (N=27; total bilirubin > ULN to 1.5 × ULN or AST > ULN). The effects of moderate (total bilirubin > 1.5 to 3 × ULN, any AST) and severe (total bilirubin > 3 to 10 × ULN, any AST) hepatic impairment on the PK of linvoseltamab are unknown.

No carcinogenicity or genotoxicity studies have been conducted with linvoseltamab.

No specific studies have been conducted to evaluate potential effects of linvoseltamab on fertility.

No developmental toxicity studies in animals have been conducted with linvoseltamab. Human IgG is known to cross the placenta; therefore, linvoseltamab has the potential to be transmitted from the mother to the developing foetus. Based on its mechanism of action, linvoseltamab may cause foetal B-cell and plasma cell lymphocytopenia that may be harmful to the foetus and transient CRS that may be harmful to pregnancy maintenance.