Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B cells and to CD3 on T cells. The activity of epcoritamab is dependent upon simultaneous engagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamab that induces specific T-cell activation and T-cell-mediated killing of CD20-expressing cells.
Epcoritamab Fc region is silenced to prevent target-independent immune effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).
Epcoritamab induced rapid and sustained depletion of circulating B-cells (defined as CD19 B-cell counts ≤10 cell/μl) in the subjects who have detectable B cells at treatment initiation. There were 21% subjects (n=33) with DLBCL and 50% subjects (n=56) with FL who had detectable circulating B-cells at treatment initiation. Transient reduction in circulating T cells was observed immediately after each dose in Cycle 1 and followed by T cell expansion in subsequent cycles.
In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 2-step step-up dose schedule in patients with LBCL, transient and modest elevations of circulating levels of selected cytokines (IFN-γ, TNFα, IL-6, IL-2, and IL-10) occurred mostly after the first full dose (48 mg), with peak levels between 1 to 4 days post dose. Cytokine levels returned to baseline prior to the next full dose, however elevations of cytokines could also be observed after Cycle 1. In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 3-step step-up dose schedule in patients with FL, median IL-6 levels associated with CRS risk remained consistently low after each dose in Cycle 1 and beyond, particularly after the first full dose, compared to patients who received the 2-step step-up dose.
The population pharmacokinetics following subcutaneous administration of epcoritamab was described by a two-compartment model with first order subcutaneous absorption and target-mediated drug elimination. The moderate to high pharmacokinetic variability for epcoritamab was observed and characterised by inter-individual variability (IIV) ranging from 25.7% to 137.5% coefficient of variation (CV) for epcoritamab PK parameters.
In patients with LBCL in study GCT3013-01, based on individually estimated exposures using population pharmacokinetic modelling, following the recommended 2-step step-up dose schedule SC dose of epcoritamab 48 mg, the geometric mean (% CV) Cmax of epcoritamab is 10.8 mcg/ml (41.7%) and AUC0-7d is 68.9 day*mcg/ml (45.1%) at the end of the weekly dosing schedule. The Ctrough at Week 12 is 8.4 (53.3%) mcg/ml.The geometric mean (% CV) Cmax of epcoritamab is 7.52 mcg/ml (41.1%) and AUC0-14d is 82.6 day*mcg/ml (49.3%) at the end of q2w schedule. The Ctrough for q2W schedule is 4.1 (73.9%) mcg/ml.The geometric mean (% CV) Cmax of epcoritamab is 4.76 mcg/ml (51.6%) and AUC0-28d is 74.3 day*mcg/ml (69.5%) at steady state during the q4w schedule. The Ctrough for q4W schedule is 1.2 (130%) mcg/ml.
Exposure parameters of epcoritamab in patients with FL were consistent with the exposure parameters seen in the patients with LBCL. Epcoritamab exposures are similar between FL subjects who received the 3-step step-up dose schedule and 2-step step-up dose schedule except for transiently lower trough concentrations, as expected, at Cycle 1 Day 15 after the second intermediate dose (3 mg) with 3-step step-up dose schedule compared first full 48 mg dose with 2-step step-up dose schedule.
The peak concentrations occurred around 3-4 days (Tmax) in patients with LBCL receiving the 48 mg full dose.
The geometric mean (% CV) central volume of distribution is 8.27 l (27.5%) and apparent steady-state volume of distribution is 25.6 l (81.8%) based on population PK modelling.
The metabolic pathway of epcoritamab has not been directly studied. Like other protein therapeutics, epcoritamab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Epcoritamab is expected to undergo saturable target mediated clearance. The geometric mean (% CV) clearance (l/day) is 0.441 (27.8%). The half-life of epcoritamab is concentration dependent. The population PK model-derived geometric mean half-life of full dose epcoritamab (48 mg) ranged from 22 to 25 days based on frequency of dosing.
No clinically important effects on the pharmacokinetics of epcoritamab (Cycle 1 AUC within approximately 36%) were observed based on age (20 to 89 years), sex, or race/ethnicity (white, Asian, and other), mild to moderate renal impairment creatinine clearance (CLcr ≥30 ml/min to CLcr <90 ml/min), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight. No patients with severe to end-stage renal disease (CLcr <30 ml/min) or severe hepatic impairment (total bilirubin >3 times ULN and any AST) have been studied. There is very limited data in moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST, N=1). Therefore, the pharmacokinetics of epcoritamab is unknown in these populations.
Like other therapeutic proteins, body weight (39 to 172 kg) has a statistically significant effect on the pharmacokinetics of epcoritamab. Based on exposure-response analysis and clinical data, considering the exposures in patients at either low body weight (e.g., 46 kg) or high body weight (e.g., 105 kg) and across body weight categories (<65 kg, 65 - <85, ≥85), the effect on exposures is not clinically relevant.
The pharmacokinetics of epcoritamab in paediatric patients has not been established.
No reproductive or developmental toxicity studies in animals have been conducted with epcoritamab. Effects generally consistent with the pharmacologic mechanism of action of epcoritamab were observed in cynomolgus monkeys. These findings included dose-related adverse clinical signs (including vomiting, decreased activity, and mortality at high doses) and cytokine release, reversible hematologic alterations, reversible B-cell depletion in peripheral blood, and reversible decreased lymphoid cellularity in secondary lymphoid tissues.
Mutagenicity studies have not been conducted with epcoritamab.
Carcinogenicity studies have not been conducted with epcoritamab.
Animal fertility studies have not been conducted with epcoritamab, however, epcoritamab did not cause toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses up to 1 mg/kg/week in intravenous general toxicity study of 5-week duration. The AUC exposures (time-averaged over 7 days) at the high dose in cynomolgus monkeys were similar to those in patients (AUC0-7d) receiving the recommended dose.
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