Talquetamab

Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody directed against GPRC5D and the CD3 receptor on T Cells.

Talquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing T cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent lysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with minimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple myeloma cells particularly.

Within the first month of treatment with talquetamab, activation and redistribution of T cells and induction of serum cytokines were observed.

0.4 mg/kg weekly dose

Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose ranging from 0.005 to 0.8 mg/kg weekly (0.0125 to 2 times the recommended 0.4 mg/kg weekly dose). The mean accumulation ratio between the 1st and 7th weekly dose of talquetamab 0.4 mg/kg was 3.9- and 4.5-fold for C_max and AUC_tau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 7th recommended weekly dose of 0.4 mg/kg are shown in Table 1.

Table 1. Pharmacokinetic parameters of talquetamab following the first and seventh recommended weekly dose (0.4 mg/kg) in patients with relapsed or refractory multiple myeloma in MonumenTAL-1:

T_max = Time to reach the C_max; C_max = Maximum observed serum talquetamab concentration; C_trough = Observed serum talquetamab concentration prior to next dose; AUC_tau = Area under the concentration-time curve over the weekly dosing interval. Data are presented as mean ± standard deviation, except for T_max which is presented as median (minimum-maximum).

0.8 mg/kg biweekly dose

Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose ranging from 0.8 mg/kg to 1.2 mg/kg biweekly (1.0 to 1.5 times the recommended 0.8 mg/kg biweekly dose). The mean accumulation ratio between the 1^st and 5^th biweekly dose of talquetamab 0.8 mg/kg was 2.3- and 2.2-fold for C_max and AUC_tau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 5th recommended biweekly maintenance dose of 0.8 mg/kg are shown in Table 2.

Table 2. Pharmacokinetic parameters of talquetamab following the first and fifth recommended biweekly (every 2 weeks) dose (0.8 mg/kg) in patients with relapsed or refractory multiple myeloma in MonumenTAL-1:

T_max = Time to reach the C_max; C_max = Maximum observed serum talquetamab concentration; C_trough = Observed serum talquetamab concentration prior to next dose; AUC_tau = Area under the concentration-time curve over the Q2W dosing interval. Data are presented as mean ± standard deviation, except for T_max which is presented as median (minimum-maximum).

Absorption

Based on the population pharmacokinetic model, the typical value of the bioavailability of talquetamab was 62% when administered subcutaneously relative to intravenous dosing.

At 0.4 mg/kg weekly dose regimen, the median (range) T_max of talquetamab after the 1^st and 7^th treatment doses were 3 (1 to 8) days and 2 (1 to 6) days, respectively.

At 0.8 mg/kg biweekly (every 2 weeks) dose regimen, the median (range) T_max of talquetamab after the 1^st and 5^th treatment doses were 3 (2 to 14) days and 3 (1 to 8) days, respectively.

Distribution

Based on the population pharmacokinetic model, the typical value of the volume of distribution was 4.3 L (22% CV [coefficient of variation]) for the central compartment, and 5.8 L (83% CV) for the peripheral compartment.

Elimination

Talquetamab exhibited both linear time-independent and time-dependent clearance. Based on the population pharmacokinetic model and the post hoc parameters of participants receiving SC doses (N=392), the median total clearance is 1.64 L/day at initial treatment and 0.80 L/day at steady state. The time-dependent clearance accounted for 48.8% of total clearance at initial treatment and then decreased exponentially to <5% at around Week 16. The concentration-time profile at Week 16 would reach 90% of steady-state concentration for both 0.4 mg/kg weekly and 0.8 mg/kg biweekly regimens. The median terminal phase half-life was 7.56 days at initial treatment, and 12.2 days at steady state.

Special populations

The pharmacokinetic analysis includes 86% White (n=424), 9% Black (n=43), 2.2% Asian (n=11), and 2.8% Others (n=14). Based on population PK analysis, the race or ethnicity, sex and body weight (range: 40 to 143 kg) did not have clinically meaningful effects on the pharmacokinetics of talquetamab.

Paediatric population

The pharmacokinetics of talquetamab in paediatric patients aged 17 years and younger have not been investigated.

Elderly

Results of population pharmacokinetic analyses indicate that age (33 to 86 years) did not influence the pharmacokinetics of talquetamab. Only limited data for patients ≥85 years was available (see Table 3).

Table 3. Proportion of elderly subjects in the pharmacokinetic (PK) studies of talquetamab:

Renal impairment

No formal studies of talquetamab in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild (60 mL/min ≤ absolute glomerular filtration rate (GFR) <90 mL/min) or moderate (30 mL/min ≤ absolute GFR < 60 mL/min) renal impairment did not significantly influence the pharmacokinetics of talquetamab. No data is available in patients with severe renal impairment.

Hepatic impairment

No formal studies of talquetamab in patients with hepatic impairment have been conducted. Using the NCI classification, results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin >1 to 1.5 times upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ ULN and AST > ULN) did not significantly influence the pharmacokinetics of talquetamab. Limited data (n=2) are available in participants with moderate hepatic impairment while no data are available in participants with severe hepatic impairment.

A tool molecule was well tolerated in general toxicity studies in cynomolgus monkeys, but the results of these studies conducted with normal healthy monkeys have limited translatability to multiple myeloma patients.

Carcinogenicity and mutagenicity

No animal studies have been performed to assess the carcinogenic or genotoxic potential of talquetamab.

Reproductive toxicology and fertility

No animal studies have been conducted to evaluate the effects of talquetamab on reproduction and foetal development. No studies have been conducted to evaluate the effects of talquetamab on fertility.