Clinical pharmacokinetic and pharmacodynamic of JBZ-001 (HOSU-53): Comparison of first-in-human data with translational preclinical predictions

Background: JBZ-001 (HOSU-53) is a potent and selective oral dihydroorotate dehydrogenase (DHODH) inhibitor currently in phase 1, open-label, dose-escalation and expansion, first-in-human trial to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of JBZ-001 in patients with advanced solid and hematological tumors[1]. DHODH inhibitor blocks the conversion of dihydroorotate (DHO) to orotate in de novo pyrimidine synthesis, effectively starving rapidly dividing cells. DHO is measurable in blood and can be used as a direct PD marker. Using a model-informed drug development (MIDD) framework, human JBZ-001 PK and DHO exposures and safe/efficacious dose range were predicted[2]. This analysis reports the observed human JBZ-001 PK and DHO levels from the ongoing trial and compares those with preclinical translational predictions to inform dose escalation and early recommended dose considerations. Methods: Plasma samples are collected pre- and post- JBZ-001 dose during Cycle 0 (up to 168 hours) and during Cycle 1 (Days (D) 1, 2, 8, and 15), and Cycle 2 (D1) to quantify PK and DHO. Noncompartmental analysis is performed to determine exposure (C max , AUC), absorption (T max ), elimination (K e , t ½ ), and clearance and volume parameters. The observed clinical PK/PD data are evaluated against human exposure predictions generated from a previously developed physiologically based pharmacokinetic model and in vitro experimental results. A population PK/PD model is subsequently developed de novo using nonlinear mixed-effects modeling. Results: A total of 11 participants were enrolled in the first three dose levels in the study (3 patients at 5 mg and 4 patients each at 10 mg and 17.5 mg, respectively) with no dose-limiting toxicities reported as of January 2026. JBZ-001 demonstrated approximately dose-proportional increases in exposure following both single and multiple doses, with low to moderate interindividual variability. Observed human PK was broadly consistent with preclinical allometric predictions, with slightly higher half-life, AUC, and C max across evaluated doses. DHO levels increased across the JBZ-001 dose levels but showed more variability, while still within the safety threshold established with three preclinical species. Conclusions: Early clinical PK/PD data for JBZ-001 support the predictive performance of the MIDD framework based on preclinical studies. Concordance between predicted and observed DHO suppression provides confidence in exposure-response assumptions guiding dose selection. Integration of updated PK/PD data with model-informed simulations will continue to refine the optimal biological dose and support data-driven decision-making as the Phase 1 study progresses. Clinical Trial Registration: NCT06801002, funded by Jabez Biosciences Inc. References: 1. O. A. Elgamal et al., JCI Insight. 9, e173646 (2024). 2. J. Y. Na et al., Pharmaceutics. 17, 412 (2025).