Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX29

Mechanism of action

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.

Pharmacodynamic effects

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

Clinical efficacy and safety

The efficacy of TALVEY monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multicentre study, MonumenTAL-1. The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who received T cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T cell redirection therapy, an allogeneic stem cell transplant within the past 6 months, autologous stem cell transplant within 3 months, stroke or seizure within the past 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, plasma cell leukaemia, POEMS syndrome, primary light chain amyloidosis, and active or documented history of autoimmune disease, with the exception of vitiligo, resolved childhood atopic dermatitis, and prior Grave’s disease that was euthyroid based on clinical symptoms and laboratory testing.
Patients received TALVEY 0.4 mg/kg subcutaneously weekly, following two step-up doses (0.01 and 0.06 mg/kg) in the first week of therapy, or TALVEY 0.8 mg/kg subcutaneously biweekly (every 2 weeks), following three step-up doses (0.01, 0.06 and 0.3 mg/kg), until disease progression or unacceptable toxicity. Patients were hospitalised for monitoring for at least 48 hours after each TALVEY dose during the step-up phase.

Of 143 patients treated with TALVEY 0.4 mg/kg weekly who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 46 to 86) years, 55% were male, 90% were White, and 8% were Black or African American. Patients had received a median of 5 (range: 2 to 13) prior therapies, and 78% of patients had received prior autologous stem cell transplantation (ASCT).
Ninety-four percent (94%) of patients were refractory to their last therapy, and 74% were refractory to a PI, immunomodulatory agent, and anti-CD38 antibody. Of the 132 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 31% of patients. Twenty-three percent (23%) of patients had extramedullary plasmacytomas.

Of 145 patients treated with TALVEY 0.8 mg/kg biweekly (every 2 weeks) who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 38 to 84) years, 57% were male, 86% were White, and 6% were Black or African American. Patients had received a median of 5 (range: 2 to 17) prior therapies, and 79% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-four percent (94%) of patients were refractory to their last therapy, and 69% were refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. Of the 128 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 29% of patients. Twenty-six percent (26%) of patients had extramedullary plasmacytomas.

Efficacy results were based on an overall response rate as determined by the Independent Review Committee assessment using IMWG criteria. The median duration of follow-up among patients receiving TALVEY 0.4 mg/kg weekly was 18.8 months; an estimated 51.5% of responders maintained response for at least 9 months.

Table 8:      Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY 0.4 mg/kg weekly
0.4 mg/kg weeklya
(N=143)
Overall response rate (ORR=sCR+CR+VGPR+PR)                               106 (74.1%) 95% CI (%)                                                                (66.1, 81.1) Stringent complete response (sCR)                                         23.8% Complete response (CR)                                                     9.8% Very good partial response (VGPR)                                         25.9% Partial response (PR)                                                     14.7% Duration of response (DOR)
Number of responders                                                        106 Median DOR (95% CI) (months)                                         9.5 (6.7, 13.3) Time to first response
Number of responders                                                        106 Median (range) (months)                                              1.2 (0.2, 10.9) MRD negativity ratea
MRD negativity rate in all treated patients, n (%)                     44 (30.8%) 95% CI (%)                                                         (23.3, 39.0) MRD negativity rateb in patients achieving CR or sCR
Number of patients with CR or better                                  N=48 MRD negativity rate, n (%)                                         26 (54.2%) 95% CI (%)                                                         (39.2, 68.6) CI=confidence interval; MRD=minimal residual disease;
a
MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at any timepoint after initial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
b
Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.


The median duration of follow-up among patients receiving TALVEY 0.8 mg/kg biweekly was 12.7 months; an estimated 76.3% of responders maintained response for at least 9 months.

Table 9:      Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY 0.8 mg/kg biweekly (every 2 weeks)
0.8 mg/kg biweekly (every 2 weeks)a
(N=145)
Overall response rate (ORR=sCR+CR+VGPR+PR)                                104 (71.7%) 95% CI (%)                                                                 (63.7, 78.9) Stringent complete response (sCR)                                          29.7% Complete response (CR)                                                     9.0% Very good partial response (VGPR)                                          22.1% Partial response (PR)                                                      11.0% Duration of response (DOR)
Number of responders                                                        104 Median DOR (95% CI) (months)                                          NE (13.0, NE) Time to first response
Number of responders                                                        104 Median (range) (months)                                                                               1.3 (0.2, 9.2) MRD negativity ratea
MRD negativity rate in all treated patients, n (%)                                                    43 (29.7%) 95% CI (%)                                                                                          (22.4, 37.8) MRD negativity rateb in patients achieving CR or sCR
Number of patients with CR or better                                                                   N=56 MRD negativity rate, n (%)                                                                          24 (42.9%) 95% CI (%)                                                                                          (29.7, 56.8) CI=confidence interval; MRD=minimal residual disease; NE=not estimable a
MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at any timepoint after initial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
b
Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.


ORR results were consistent across pre-specified subgroups, including number of prior lines of therapy, refractoriness to prior therapy, and cytogenetic risk at baseline.

Immunogenicity

In MonumenTAL-1, 328 patients treated with subcutaneous talquetamab monotherapy at 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), with or without prior T cell redirection therapy, were evaluated for antibodies to talquetamab. Following treatment 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), 106 of 328 patients (32.3%) developed anti-talquetamab antibodies.
The limited number of anti-talquetamab antibody (ADA) positive subjects and the lack of information of the neutralising ADA, preclude drawing a definite conclusion regarding the effect of the neutralising ADAs on clinical parameters.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
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 Cmax and AUCtau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 7th recommended weekly dose of 0.4 mg/kg are shown in Table 10.

Table 10:     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
Pharmacokinetic parameters                1st dose of 0.4 mg/kg               7th dose of 0.4 mg/kg 2.93 (0.98 - 7.75)                  2.01 (0.94 - 5.97)
Tmax (days)
(n=21)                             (n=13)
1 568 ± 1 185                      3 799 ± 2 411
Cmax (ng/mL)
(n=21)                             (n=13)
178 ± 124                        2 548 ± 1 308
Ctrough (ng/mL)
(n=19)                             (n=13)
178 101 ± 130 802                   607 297 ± 371 399
AUCtau (ng·h/mL)
(n=17)                             (n=10)
Tmax = Time to reach the Cmax; Cmax = Maximum observed serum talquetamab concentration; Ctrough = Observed serum talquetamab concentration prior to next dose; AUCtau = Area under the concentration-time curve over the weekly dosing interval. Data are presented as mean ± standard deviation, except for Tmax 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 1st and 5th biweekly dose of talquetamab 0.8 mg/kg was 2.3- and 2.2-fold for Cmax and AUCtau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 5th recommended biweekly maintenance dose of 0.8 mg/kg are shown in Table 11.

Table 11:     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
Pharmacokinetic parameters                1st dose of 0.8 mg/kg               5th dose of 0.8 mg/kg 2.83 (1.68 - 13.98)                   2.85 (0.96 - 7.82)
Tmax (days)
(n=33)                               (n=19)
2 507 ± 1 568                       4 161 ± 2 021
Cmax (ng/mL)
(n=33)                               (n=19)
597 ± 437                          1 831 ± 841
Ctrough (ng/mL)
(n=32)                               (n=17)
675 764 ± 399 680                   1 021 059 ± 383 417
AUCtau (ng·h/mL)
(n=28)                               (n=17)
Tmax = Time to reach the Cmax; Cmax = Maximum observed serum talquetamab concentration; Ctrough = Observed serum talquetamab concentration prior to next dose; AUCtau = Area under the concentration-time curve over the Q2W dosing interval. Data are presented as mean ± standard deviation, except for Tmax 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) Tmax of talquetamab after the 1st and 7th 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) Tmax of talquetamab after the 1st and 5th 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 TALVEY 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 12).

Table 12:      Proportion of elderly subjects in the pharmacokinetic (PK) studies of talquetamab Age 65-74                  Age 75-84                    Age 85+
(Older subjects number (Older subjects number (Older subjects number
/total number)             /total number)              /total number) PK Studies                          181/492                    73/492                       1/492 
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.