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.

Background: Somatic oncogenic fusions of NTRK with other genes, such as ETV6, LMNA, TPM3, PAN3, etc. occur in a wide range of adult and pediatric tumors. Clinical application of 1st generation TRK inhibitors, i.e., larotrectinib and entrectinib, for the treatment of NTRK fusion-positive cancer patients has achieved high response rates regardless of tumor types. However, prolonged treatment often leads to acquired drug resistance attributed to various mutations in TRK kinase domains. Here we report the development of a 2nd generation pan-TRK inhibitor, ICP-723, potently inhibits activities of wild-type and some mutant forms of TRK. Results: ICP-723 effectively inhibits kinase activities of TRKA, TRKB, TRKC with IC50 values < 1 nM. In the KINOMEscan, at a concentration of 100 nM, ICP-723 competitively binds to TRKA/B/C with 100% of inhibition rate, indicating high selectivity for pan-TRK. To evaluate the anti-proliferative activity of ICP-723 in TRK-driven tumor cells, KM12 colorectal cancer cell line bearing TPM3-NTRK1 fusion, as well as a panel of 19 Ba/F3 pro-B murine cell lines over-expressing wild-type or mutant forms of NTRK fusions are tested. ICP-723 demonstrates robust in vitro efficacy in all wild-type TRK-driven tumors. It also overcomes solvent front mutations (e.g., TRKA G595R, TRKC G623R/E) often developed following 1st generation TRK inhibitor treatment. Amongst other TRK mutations, ICP-723 exerts reduced activity in gatekeeper mutations (e.g., TRKA F589L, TRKB F633L, TRKC F617L) and some xDFG mutations (e.g., TRKA G667C/S, TRKB G709C); but retains activity in other xDFG mutations (e.g., TRKA G667A, TRKC G696A/C) and unclassified mutations (e.g., TRKA V573M, TRKA A608D, TRKB V689M). In vivo efficacy studies further demonstrate its robust anti-tumor effects in xenograft models. Treatment with 1 mg/kg of ICP-723 results in 89.5% TGI of KM12 tumors, similar to the efficacies of larotrectinib or selitrectinib at 30 mg/kg dose levels. Treatment with 1 or 3 mg/kg of ICP-723 leads to 100% survival of mice bearing Ba/F3 LMNA-NTRK1 G595R tumors, confirms the effectiveness of ICP-723 against solvent front mutant TRKA. The in vivo efficacy of ICP-723 is also well accompanied by pharmacodynamic modulation of TRK phosphorylation, where ICP-723 exposure levels correlate with the inhibition of TRK phosphorylation. The pharmacokinetic parameters of ICP-723 are overall favorable, with high oral bioavailability. Preclinical safety evaluations also exhibit acceptable drug tolerance in SD rats and Beagle dogs. Conclusions: ICP-723 is a novel, 2nd generation pan-TRK inhibitor with broad-spectrum anti-tumor activities against wild-type and various acquired drug-resistant mutations of NTRK gene fusions. ICP-723 is now in phase I clinical trial in China and United States. Citation Format: Ruixia Liang, Chao Zhou, Yingrui Han, Prince Lu, Charles Ying Wang, Zuopeng Wang, Richard Liu, Norman Kong, Jason Bing Zhang, Jasmine Jisong Cui, Davy Xuesong Ouyang. ICP-723 is a potent pan-TRK Inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations of NTRK fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6187.