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Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease without a clear predisposition. Initial treatments often fail to induce long-term responses and until recent years, novel subsequent therapies such as thrombopoietin receptor agonists or the spleen tyrosine kinase inhibitor fostamatinib, have been limited in the management of ITP.1, 2 Expressed in both B and innate immune cells, Bruton's tyrosine kinase is a promising therapeutic target for immune-mediated diseases.3 Blocking the signaling molecule BTK double-hits on the BCR and Fc receptor pathways, which raises platelet counts through reducing auto-antibody production and platelet phagocytosis.4 We conducted this randomized, multicenter, open-label, phase 2 study to evaluate the efficacy and safety of orelabrutinib in adult patients with persistent or chronic ITP. This study is registered at ClinicalTrials.gov as NCT05232149. Eligible patients (aged ≥18 and ≤ 80 years old) diagnosed with persistent or chronic ITP, defined as a mean platelet count of <30 × 109/L on two occasions at least one day apart and a measured platelet count of ≤35 × 109/L, who had failed at least one prior line of standard therapy or failed to tolerate a standard therapy, were randomized 1:1 to receive orelabrutinib at either 30 or 50 mg once daily for 24 weeks. Patients in 30 mg group could increase dose to 50 mg if platelet counts were <50 × 109/L at week 4 without other safety concerns. The proportion of patients achieving platelet counts of ≥50 × 109/L for at least two consecutive weeks (without rescue medication in the prior 4 weeks) was the primary endpoint. Additionally, the study closely monitored patient safety through comprehensive evaluations, including adverse events (AEs), physical examinations, and laboratory tests. Orelabrutinib's pharmacokinetics (PK) and pharmacodynamics (PD) were explored to understand its absorption, distribution, and effects on the target molecule. Between February 21, 2022 and January 7, 2023, 33 patients were enrolled; 15 patients were randomized to receive orelabrutinib at 50 mg once daily, and 18 patients received 30 mg once daily. The cutoff date was March 5, 2023. There were seven patients in the 50 mg group and 11 patients in the 30 mg group that discontinued treatment before week 24. Of the 18 patients in the 30 mg group, 13 underwent dose escalation to 50 mg at week 4. The primary endpoint of platelet response was achieved in 12 patients (36%): six of 15 patients (40%) in the 50 mg group and six of 18 patients (33%) in the 30 mg group (p = .73), including two of 13 patients who switched from 30 to 50 mg (Table 1). A total of 10 patients (30%) achieved a sustained response of measured platelet counts of ≥50 × 109/L in four or more of the final six visits between 14 and 24 weeks. The sustained response rate was 27% (four of 15 patients) in the 50 mg group and 33% (six of 18 patients) in the 30 mg group, including two of 13 patients who switched from 30 to 50 mg. Notably, among the 12 patients with primary endpoint response, the sustained response rate was 83% (10 patients). In addition, the 50 mg group displayed a significantly faster median time to achieve an initial platelet count increase compared to the 30 mg group (9 vs. 43 days, interquartile range [IQR], 8.0–75.0). Patients in the 50 mg group experienced reduced bleeding scores and improved health-related quality of life measures compared to baseline. Moreover, the 50 mg QD group had the lowest percentage of concomitant rescue therapy use, which was reported in six of 15 patients (40%). Primary platelet response appeared to be better in the subgroup of 22 patients previously responsive to glucocorticoids or intravenous immunoglobulin (75% in 50 mg vs. 43% in 30 mg groups, respectively). And so did the sustained platelet response (50% in 50 mg vs. 43% in the 30 mg groups, respectively). The primary endpoint was not met in the other 11 patients who were non-responders to glucocorticoids or intravenous immunoglobulin. Orelabrutinib treatment improved patients' quality of life, with an average increase of 21.2 points in physical well-being and 10.3 points in emotional well-being using the 36-Item Short Form Health Survey (SF-36) scores measured at week 24. This improvement suggests potential benefits for daily lives and overall health perception. While a total of 28 patients (85%) experienced side effects, most were mild (grades 1 or 2), with only 24% considered treatment related. Common occurrences included urinary tract infections (15%, five patients), suspected COVID-19 (12%, four patients), and upper respiratory tract infections (12%, four patients). Four treatment-emergent AEs (TEAEs) of grade ≥3 (hypertriglyceridemia, iron deficiency anemia, cholecystitis, and immune thrombocytopenia) were reported, of which cholecystitis and immune thrombocytopenia were assessed as serious but were all deemed unrelated to orelabrutinib. Cholecystitis in one patient was determined instead to be caused by long-term gallstones. One patient in the 30 mg group had a treatment-related AE (TRAE) leading to treatment interruption (grade 2 pneumonia). No serious or grade ≥3 TRAEs or deaths occurred. Treatment-related bleeding events occurred in one patient in the 50 mg group who experienced skin hemorrhage, which was mild (grade 1). There were no thrombotic events. Other treatment-related events associated with BTK inhibitors in oncology trials, including neutropenia, atrial fibrillation, grade ≥3 infection, and malignancy, were not reported. In a concise analysis of 28 patients, orelabrutinib displayed dose-dependent PK, mirroring trends seen in healthy subjects and other patient groups. Notably, the 50 mg dose resulted in significantly higher drug exposure (2083 ng.h/mL vs. 1176 ng.h/mL). Both doses achieved near complete and sustained occupancy of the target molecule, BTK. Median occupancy exceeded 99% 4 h after administration, remaining above 93% throughout the 24-h dosing interval. These findings not only confirm dose-dependent exposure but also highlight the robust target engagement potential of orelabrutinib across both dosage levels, underscoring its potential therapeutic efficacy. Efficacy results of orelabrutinib were similar to those of rilzabrutinib in a phase 1/2 study. Rilzabrutinib resulted in 24 of 60 (40%) patients achieving the primary endpoint and 17 of 60 (28%) patients achieving sustained response with a median onset time of 11.5 days.5 Our phase 2 data of orelabrutinib further suggest that inhibition of BTK may be a potentially effective treatment for ITP patients. In this study, patients had a median 9 years of ITP history, and more than 60% (20 patients) had a disease course of 5 years or more, with five previous different ITP drugs, indicating that the enrolled participants had prolonged and severe illness, and were refractory to treatment. Among these relapsed or refractory patients, the primary endpoint response rate reached 40% (six of 15) in the 50 mg group. In the subgroup of patients who had previously responded to glucocorticoids or intravenous immunoglobulin, the primary endpoint response rate reached as high as 75% (six of eight) in the 50 mg group, indicating that orelabrutinib is more effective in patients who responded to previous first-line therapy. Improvement of skin and mucosa bleeding by ITP-specific bleeding assessment tool (ITP-BAT) was observed in the 50 mg group. This study suggests that orelabrutinib 50 mg may effectively increase platelet counts and improve bleeding symptoms in ITP patients, although caution is warranted in drawing these conclusions due to the patient dropout rate. Preclinical active ITP murine models demonstrated that orelabrutinib was effective in elevating the platelet counts by promoting B-cell apoptosis and inhibiting phagocytic activity of monocyte-derived macrophages. Both 30 and 50 mg doses of orelabrutinib achieved near-complete BTK target occupancy in peripheral blood cells. This high level of target engagement lasts for at least 24 h. However, immune cells in the spleen and bone marrow also play critical roles during ITP pathogenesis.6 It is possible that the 50 mg dose might achieve higher BTK occupancy in these other organs. While 30 mg of orelabrutinib achieved near-complete BTK occupancy, only 33% of patients responded effectively to this dose. 72% of patients on 30 mg needed to switch to 50 mg due to insufficient platelet response. These patients generally had more severe ITP, suggesting higher doses might be needed. Orelabrutinib was generally well tolerated. It is important to acknowledge that this study was conducted during a period when COVID-19 prevalence was significant, which may explain why TEAEs such as suspected COVID-19 and upper respiratory tract infection were reported but deemed unrelated to the study drug. Once daily oral administration of orelabrutinib effectively increased platelet counts in patients with primary immune thrombocytopenia, especially in those who previously responded to glucocorticoids or intravenous immunoglobulin. Our study, though limited by a relatively small sample size, provides compelling evidence for the potential of orelabrutinib as a safe and effective therapy for patients with ITP. Further investigation through larger, randomized, placebo-controlled trials is warranted to definitively confirm these findings and establish orelabrutinib as a valuable treatment option for ITP management. All authors contributed to the concept and design of the trial, data analysis and interpretation, writing, critical revision of the publication, and final approval to submit. All authors were accountable for the accuracy and integrity of the publication. The authors thank the patients, caregivers, and investigators. The authors also acknowledge Irene Xue (InnoCare Pharma, Inc.) who provided editorial assistance. The study was funded by InnoCare Pharma Tech Co., Ltd. The funder of the study participated in the study design, data analysis, data interpretation, and writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors declare no competing interests. All patients signed an informed consent form before enrollment. This study is registered with ClinicalTrials.gov, NCT05232149. eFigure 1. Trial profile. eFigure 2. Patient response to orelabrutinib. eFigure 3. Line chart of platelet count in subjects who discontinued the study (FAS). eFigure 4. BTK occupancy. eTable 1. Demographic and baseline characteristics of patients. eTable 2. Adverse events reported by 2 or more patients. eTable 3. Change from baseline in HRQoL: SF-36 at week 24. eTable 4. Summary of orelabrutinib Steady-state exposure parameters. eTable 5. Summary of selectivity of BTK inhibitors. eMethods References Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.