Huybrecht T'jollyn 1, Belén Valenzuela 2, Xavier Woot de Trixhe 1, Pharavee Jaiprasart 3, Victor Villalobos 3, Sherry Wang 4, Hui Tian 5, Nahor Haddish-Berhane 3, Juan-Jose Perez-Ruixo 1, Oliver Ackaert 1
1 Johnson & Johnson (Beerse, Belgium), 2 Johnson & Johnson (Madrid, Spain), 3 Johnson & Johnson (Springhouse, USA), 4 Johnson & Johnson (San Fransisco, USA), 5 Johnson & Johnson (Lexington, USA)
Objective
To support the development of pasritamig, a KLK2×CD3 bispecific T‑cell engager, through model‑informed drug development (MIDD) methodologies, integrating population pharmacokinetics (popPK) and exposure–response (E–R) analyses.
This work aimed to support the selection of the Phase 3 dosing regimen in patients with metastatic castration‑resistant prostate cancer (mCRPC) by leveraging the outcomes from MIDD alongside the proposed mechanism of action informed by translational research.
Methods
Data from 165 mCRPC patients enrolled in a first‑in‑human study evaluating subcutaneous (SC) (0.5–2000 mg) and intravenous (IV) (150–900 mg) pasritamig dosing schedules were analyzed. A popPK model incorporating linear and KLK2‑mediated target‑mediated drug disposition (TMDD) pathways was developed to characterize serum PK and derive individual average free‑drug concentrations (Cavg) over the first 8 weeks of therapy.
Exposure–response (E–R) relationships were quantified using logistic regression for confirmed PSA response (CPSAR), and selected safety endpoints: Grade ≥ 3 anemia and Grade ≥ 2 fatigue. Covariate effects on PK and E–R parameters were evaluated using standard selection procedures and estimation of geometric mean ratios relative to a reference population (for PK parameters).
Pharmacometric analyses (popPK and E-R modeling) and post-hoc processing (exploratory analyses, graphics generation) were performed in NONMEM 7.4.0 (1) and R4.2 (2), respectively.
Results
Pasritamig PK was adequately described by a two‑compartment model with linear and nonlinear (KLK2‑mediated) clearance. Terminal half‑life was 18.3 days, and exposure increased approximately dose‑proportionally. Covariate effects on exposure were limited, with geometric mean ratios falling within the 80–125% interval, suggesting no clinically meaningful PK variability across key subgroups.
A pooled logistic regression analysis, including both SC and IV data, confirmed the significant association between exposure (Cavg) and probability of CPSAR, which approached a plateau at exposures corresponding to 300 mg IV Q6W. Based on the E-R modelling, the odds of CPSAR was estimated to increase with increasing exposures. While the observed response data may suggest a potentially different E-R pattern for IV compared to SC, the available clinical evidence does not allow for a definitive conclusion.
While the incidence on a subject level of fatigue Grade ≥ 2 was found to be numerically higher in the SC arms compared to the IV arms, no significant E-R relationship for safety endpoints anemia (Grade ≥ 3) and fatigue (Grade ≥ 2) with pasritamig exposure could be identified.
Conclusions
Integrated MIDD analyses support 300 mg IV Q6W, following two IV step‑up doses (3.5 mg Day 1; 18 mg Day 8), as the recommended regimen for the phase 3 trial. While the E–R model suggested a modest increase in CPSAR with higher IV doses, clinical results to date have not confirmed this (3). Dosing pasritamig Q6W optimized the antitumor activity of pasritamig, given the reduced T-cell exhaustion and activation-induced T-cell death (4). No dose adjustment was warranted across evaluated patient subgroups based on popPK or E–R findings.
References:
1. NONMEM 7.4.0 Users Guide (1989-2013). Beal SS, LB; Boeckmann, AJ; Bauer, RJ, editor. Icon Development Solutions, Ellicott City, MD.
2. R Core Team. R: A language and environment for statistical computing. R foundation for statistical computing, Vienna, Austria. 2016. http://www.R-project.org/Guidance for Industry. Also available at: http://www.R-project.org/
3. Mark N. Stein et al. Pasritamig, a First-in-Class, Bispecific T-Cell Engager Targeting Human Kallikrein 2, in Metastatic Castration-Resistant Prostate Cancer: A Phase I Study. J Clin Oncol 43, 2515-2526 (2025)
4. K. Autio et al. Translational analyses of T cell phenotypes and their association with clinical efficacy in the first-in-human (FIH) trial of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer (mCRPC). ESMO Congress 2025; October 17-21, 2025; Berlin, Germany
Reference: PAGE 34 (2026) Abstr 12211 [www.page-meeting.org/?abstract=12211]
Poster: Drug/Disease Modelling - Oncology