Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates , ATC code: L01FX24

Mechanism of action

Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells 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. With its dual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ cells, resulting in T cell activation and subsequent lysis and death of BCMA+ cells, which is mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen presenting cells.

Pharmacodynamic effects

Within the first month of treatment, activation of T-cells, redistribution of T-cells, reduction of B-cells and induction of serum cytokines were observed.

Within one month of treatment with teclistamab, the majority of responders had reduction in soluble BCMA, and a greater reduction in soluble BCMA was observed in subjects with deeper responses to teclistamab.

Clinical efficacy and safety

The efficacy of TECVAYLI monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multi-centre, Phase 1/2 study (MajesTEC-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 experienced stroke or seizure within the past 6 months, and patients with Eastern Cooperative Oncology Group performance score (ECOG PS) ≥2, plasma cell leukaemia, known active CNS involvement or exhibited clinical signs of meningeal involvement of multiple myeloma, or active or documented history of autoimmune disease with the exception of vitiligo, Type 1 diabetes and prior autoimmune thyroiditis.

Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg of TECVAYLI administered subcutaneously, followed by the maintenance dose of TECVAYLI 1.5 mg/kg, administered subcutaneously once weekly thereafter, until disease progression or unacceptable toxicity (see section 4.2). The median duration between Step-up Dose 1 and Step-up Dose 2 was 2.9 (Range: 2-7) days. The median duration between Step-up Dose 2 and the initial maintenance dose was 3.1 (Range: 2-9) days. Patients were hospitalised for monitoring for at least 48 hours after administration of each dose of the TECVAYLI Step-up dosing schedule.

The efficacy population included 165 patients. The median age was 64 (Range: 33-84) years with 15% of subjects ≥75 years of age; 58% were male; 81% were White, 13% were Black, 2% were Asian. The International Staging System (ISS) at study entry was 52% in Stage I, 35% in Stage II and 12% in 
Stage III. High-risk cytogenetics (presence of del(17p), t(4;14) or t(14;16)) were present in 26% of patients. Seventeen percent of patients had extramedullary plasmacytomas.

The median time since initial diagnosis of multiple myeloma to enrolment was 6 (Range: 0.8-22.7) years. The median number of prior therapies was 5 (Range: 2-14), with 23% of patients who received 3 prior therapies. Eighty-two percent of patients received prior autologous stem cell transplantation, and 4.8% of patients received prior allogeneic transplantation. Seventy-eight percent of patients were triple-class refractory (refractory to proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody).

Efficacy results were based on overall response rate, as determined by the Independent Review Committee (IRC) assessment, using International Myeloma Working Group (IMWG) 2016 criteria (see Table 7).

Table 7:        Efficacy results for MajesTEC-1
All Treated (N=165)
Overall response rate (ORR: sCR, CR, VGPR, PR) n(%)                                            104 (63.0%) 95% CI (%)                                                                                   (55.2%, 70.4%) Stringent complete response (sCR)                                                             54 (32.7%) Complete response (CR)                                                                        11 (6.7%) Very good partial response (VGPR)                                                             32 (19.4%) Partial response (PR)                                                                          7 (4.2%) Duration of Response (DOR) (months)
Number of Responders                                                                               104 DOR (Months): Median (95% CI)                                                                18.4 (14.9, NE)1 Time to First Response (months)
Number of responders                                                                                104 Median                                                                                              1.2 Range                                                                                            (0.2; 5.5) MRD negativity rate2 in all treated patients, n (%) [N=165]                                     44 (26.7%) 95% CI (%)                                                                                    (20.1%, 34.1%) MRD negativity rate2,3 in patients achieving CR or sCR, n (%)                                   30 (46.2%) [N=65]
95% CI (%)                                                                                    (33.7%, 59.0%) 1
NE=not estimable
2
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.
3
Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.

Results of an updated efficacy analysis after a median follow-up of 30.6 months among responders (n=104) showed a higher proportion of patients with CR (7.3%) and sCR (38.8%) compared with the primary analysis. MRD negativity rates also increased in all treated patients (29.1%) and in patients achieving CR or sCR (51.3%). The median DOR was 24.0 (17.0, NE) months.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose). Ninety percent of steady state exposure was achieved after 12 weekly maintenance doses. The mean accumulation ratio between the first and 13th weekly maintenance dose of teclistamab 1.5 mg/kg was 4.2-fold for Cmax, 4.1-fold for Ctrough, and 5.3-fold for AUCtau.

The Cmax, Ctrough, and AUCtau of teclistamab are presented in Table 8.

Table 8:     Pharmacokinetic parameters of teclistamab for the 13th recommended weekly maintenance dose (1.5 mg/kg) in patients with relapsed or refractory multiple myeloma in MajesTEC-1
Teclistamab
Pharmacokinetic Parameter                                   Geometric Mean (CV%) Cmax (µg/mL)                                                       23.8 (55%) Ctrough (µg/mL)                                                    21.1 (63%) AUCtau (µg·h/mL)                                                  3 838 (57%) Cmax = Maximum serum teclistamab concentration; Ctrough = Serum teclistamab concentration prior to next dose; CV = geometric coefficient of variation; AUCtau = Area under the concentration-time curve over the weekly dosing interval.

Absorption

The mean bioavailability of teclistamab was 72% when administered subcutaneously. The median (range) Tmax of teclistamab after the first and 13th maintenance doses were 139 (19 to 168) hours and 72 (24 to 168) hours, respectively.

Distribution

The mean volume of distribution was 5.63 L (29% coefficient of variation (CV)).
Elimination

Teclistamab clearance decreases over time, with a mean (CV%) maximal reduction from baseline to the 13th maintenance dose of 40.8% (56%). The geometric mean (CV%) clearance is 0.472 L/day (64%) at the 13th maintenance dose. Patients who discontinue teclistamab after the 13th maintenance dose are expected to have a 50% reduction from Cmax in teclistamab concentration at a median (5th to 95th percentile) time of 15 (7 to 33) days after Tmax and a 97% reduction from Cmax in teclistamab concentration at a median time of 69 (32 to 163) days after Tmax.

Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did not impact teclistamab serum concentrations.

Special populations

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

Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did not influence the pharmacokinetics of teclistamab.

Renal impairment

No formal studies of TECVAYLI in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m2 ≤ estimated glomerular filtration rate (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 teclistamab. Limited data are available from patients with severe renal impairment.

Hepatic impairment

No formal studies of TECVAYLI in patients with hepatic impairment have been conducted.
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 teclistamab.
No data are available in patients with moderate and severe hepatic impairment.