Abstract CT118: Clinical pharmacokinetic and pharmacodynamic of JBZ-001 (HOSU-53): Comparison of first-in-human data with translational preclinical predictions

Abstract 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 (Cmax, AUC), absorption (Tmax), elimination (Ke, t½), 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 Cmax 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). Citation Format: Min Hai, Nicole Abbott, James O. Larkin, Zhiliang Xie, Christopher Coss, Tamara Jovonovich, Zuzana J. Trnkova, Philippa Graham, William B. McKean, Asrar A. Alahmadi, Mitch Phelps. Clinical pharmacokinetic and pharmacodynamic of JBZ-001 (HOSU-53): Comparison of first-in-human data with translational preclinical predictions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT118.