Bruton's tyrosine kinase (BTK) as a therapeutic target for B-cell malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other non-Hodgkin's lymphomas (NHL), has been clinically validated. Orelabrutinib (ICP-022) is a novel, potent and highly selective BTK inhibitor with excellent pharmacokinetics/pharmacodynamics (PK/PD) properties distinguished from other BTK inhibitors. Here we report the results from preclinical studies, together with safety and PK/PD data in human healthy subjects. Orelabrutinib potently inhibits BTK enzymatic activity with an IC50 value of 1.6 nM. In KINOMEscan assay conducted in parallel at 1 μM against a panel of 456 kinases, orelabrutinib only targeted BTK with > 90% inhibition while ibrutinib inhibited additional many other kinases including EGFR, TEC and BMX, demonstrating orelabrutinib's superior kinase selectivity. In addition, orelabrutinib has a favorable PK profile with an ideal T1/2 (~1.5-4 h) and good oral bioavailability (~20-80%) as well as prolonged BTK target occupancy in preclinical PK/PD studies. The superior selectivity translates into improved safety profile and large safety window in the GLP toxicology studies in rats and dogs. A randomized dose-escalation phase I study in healthy subjects was conducted to evaluate the safety, tolerability, PK and PD profiles of orelabrutinib following single dose (20, 50, 100, 200 and 400 mg) and multiple doses (100 and 200 mg QD, 100 mg BID) escalation for 14 consecutive days. Safety: Orelabrutinib was safe and well tolerated in healthy subjects who received a single dose up to 400 mg or multiple doses up to 100 mg BID or 200 mg QD for 14 days. All treatment-emergent adverse events (TEAEs) reported during the study were mild or moderate in severity and resolved before the end of studies. Petechiae and headache were the most commonly reported treatment related TEAEs. No dose limiting toxicities (DLT) were encountered, and the maximum tolerated dose (MTD) was not reached. No serious TEAEs, TEAEs leading to treatment withdrawal, or serious TEAEs resulting in death were reported during this study. PK: Systemic exposure (both AUC and Cmax) was in a well dose proportional manner, indicating a good linear PK. The mean terminal T1/2 was approximately 4 hours across all cohorts. There was no drug accumulation in plasma after repeated dosing. No significant food effect was observed following co-administration with a standard high-fat, high-calorie meal. PD: Near complete (>99%) BTK occupancy was achieved at a dose of 50 mg or higher with small inter-subject variability, and the effect was sustained for 24 hours post dosing, which is consistent with the covalent binding mode of orelabrutinib. The Cmax that required to achieve complete (>99%) BTK occupancy (EC99) is ~300 ng/mL. In summary, orelabrutinib has superior selectivity, favorable PK, prolonged PD as well as a large safety window in both preclinical and clinical phase I studies. Therefore, orelabrutinib may offer an excellent option for the treatment of B-cell malignancies in avoid of the high frequency of adverse events (diarrhea, atrial fibrillation, bleeding, etc.) observed for ibrutinib and other BTK inhibitors. Orelabrutinib is currently under investigation with multiple phase II trials in patients with B-cell malignancies.

Citation Format: Bin Zhang, Renbin Zhao, Ruixia Liang, Yingxiang Gao, Richard Liu, Xiangyang Chen, Zhengguang Lu, Zuopeng Wang, Liqin Yu, Sepehr Shakib, Jisong Cui. Orelabrutinib, a potent and selective Bruton's tyrosine kinase inhibitor with superior safety profile and excellent PK/PD properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT132.