A Phase 3, Multi-regional, Open-label, Randomized Study of Tirabrutinib vs Rituximab and Temozolomide in Participants With Relapsed/Refractory Primary Central Nervous System Lymphoma

The purpose of this clinical trial is to evaluate efficacy and safety of tirabrutinib alone compared with rituximab and temozolomide (R-TMZ) combination therapy in participants with Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL).

开始日期2025-11-01

申办/合作机构

Ono Pharmaceutical Co., Ltd.

[+1]

NCT06541665

/ Active, not recruiting临床1期

A Multicenter, Phase I, Open-label, Uncontrolled Study of ONO-4059 in Combination With Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) Therapy for Untreated Primary Central Nervous System Lymphoma (PCNSL)

To confirm the tolerability and safety of combined administration of ONO-4059 and R-MPV therapy in untreated PCNSL patients.

开始日期2024-05-17

申办/合作机构

Ono Pharmaceutical Co., Ltd.

JPRN-jRCT2071230119

/ Not yet recruiting临床1期IIT

ONO-4059-14: relative bioavailability comparative studyOpen-label, randomized, 4-group 4-period cross-over, single-dose study to evaluate the relative bioavailability of the new high content formulation compared with the approved drug in Japanese healthy adult male subjects

开始日期2024-03-27

申办/合作机构-

100 项与替拉鲁替尼相关的临床结果

登录后查看更多信息

100 项与替拉鲁替尼相关的转化医学

登录后查看更多信息

100 项与替拉鲁替尼相关的专利（医药）

登录后查看更多信息

157

项与替拉鲁替尼相关的文献（医药）

2025-12-01·CANCER CHEMOTHERAPY AND PHARMACOLOGY

Effect of plasma exchange on tirabrutinib plasma concentration in a patient with lymphoplasmacytic lymphoma: A case report

Article

作者: Kaneta, Akiko ; Araki, Takuya ; Yashima, Hideaki ; Kobayashi, Nobuhiko ; Tsukamoto, Junko ; Miyazawa, Yuri ; Handa, Hiroshi ; Yamamoto, Koujirou ; Ogawa, Yoshiyuki ; Takei, Hisashi

PURPOSE:

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, is used to treat lymphoplasmacytic lymphoma (LPL). A hallmark complication of LPL is hyperviscosity syndrome (HVS), caused by markedly elevated serum IgM levels. Plasma exchange (PE) is a standard treatment for HVS but may also remove circulating drugs, particularly those with high protein binding, potentially reducing drug exposure and efficacy. Evaluating the impact of PE on the pharmacokinetics of drugs used to treat LPL is important for optimal treatment.

METHODS:

We report the case of a 63-year-old man with LPL who presented with acute headache and was diagnosed with HVS. Tirabrutinib (480 mg, once daily) was initiated, and PE was performed the next day because of persistent IgM elevation. To assess the impact of PE on tirabrutinib plasma concentrations, blood samples were collected approximately 3 h prior to PE (C15), immediately before PE (C18), and immediately after PE (C20).

RESULTS:

The concentrations at C15, C18 and C20 were 33.3, 16.9, and 11.4 ng/mL, respectively. The elimination rate constant (ke) was calculated as 0.226 h⁻¹ before PE and 0.197 h⁻¹ during PE. Based on the pre-PE ke, the predicted post-PE concentration (C20) assuming no PE was approximately 10.6 ng/mL, slightly lower than the observed value.

CONCLUSION:

PE appeared to have minimal impact on the tirabrutinib plasma concentration, likely due to its large volume of distribution. Although further cases are needed, this case supports the feasibility of concomitant PE during tirabrutinib therapy without significant compromise of drug efficacy.

2025-10-01·BIOORGANIC CHEMISTRY

Structure-based design of tirabrutinib derivatives as inhibitors of bacterial tryptophanyl-tRNA synthetase

Article

作者: Xiao, Lingzhen ; Xu, Jingyi ; Huang, Qingting ; Chen, Bingyi ; Zhou, Huihao ; Xia, Kaijiang ; Peng, Xiaoying

The escalating threat of antibiotic resistance poses a critical challenge to global public health, necessitating the urgent development of novel therapeutic agents with distinct mechanisms of action and unique structural scaffolds. Tryptophanyl-tRNA synthetase (TrpRS) has emerged as a promising antibacterial target. Our previous study demonstrated that the clinically utilized Bruton's tyrosine kinase (BTK) inhibitor tirabrutinib, along with several of its analogues, can simultaneously occupy both the substrates l-Trp and tRNA^Trp A76 binding sites of Escherichia coli tryptophanyl-tRNA synthetase (EcTrpRS), thereby effectively inhibiting its catalytic activity. Building on this finding, we employed structure-based drug design to systematically optimize the interactions of tirabrutinib analogues with the l-Trp and tRNA^Trp binding sites, as well as to further extend the structure to the adjacent ATP binding site within the catalytic pocket of EcTrpRS to establish additional interactions, leading to the design and synthesis of 22 new derivatives. Among these, WRS22 (a racemic mixture) demonstrated the best binding to EcTrpRS, with a ΔT_m value of 33.2 °C and 90 % inhibition rate at 10 μM concentration. Its binding affinity for EcTrpRS (K_d = 0.33 ± 0.03 μM) is superior to that of the positive control, indolmycin (K_d = 0.71 ± 0.1 μM). Notably, WRS22 displayed no affinity to human cytoplasmic TrpRS (HcTrpRS) and its interaction with human BTK is likely to be disrupted, indicating high degree of target selectivity. Therefore, the structure-guided design successfully developed new tirabrutinib analogues as inhibitors of bacterial TrpRS, presenting a promising lead compound for the development of AARS-based antibacterial agents.

2025-08-18·BRITISH JOURNAL OF DERMATOLOGY

An open-label randomized parallel-group phase I study of the oral Bruton tyrosine kinase inhibitor tirabrutinib in systemic sclerosis

Article

作者: Matsuda, Kazuki M ; Io, Toshiro ; Yoshizaki, Ayumi ; Sato, Shinichi ; Harada, Tomohiro ; Kitani, Akihiro ; Hasegawa, Minoru ; Doi, Masaaki

Abstract:

Background:

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a high risk of organ damage and mortality.

Objectives:

To investigate whether tirabrutinib, an inhibitor of Bruton tyrosine kinase, is useful for treating SSc.

Methods:

This randomized double-arm 52-week phase I study investigated the safety, efficacy and putative mechanism of action of once-daily tirabrutinib in adults with SSc (Japan Registry of Clinical Trials jRCT2031200315). The primary endpoints were safety, including treatment-emergent adverse events (TEAEs), and pharmacokinetics. Exploratory efficacy endpoints included the modified Rodnan skin score (mRSS) and mechanism of action determined via immunophenotyping and RNA sequencing (RNAseq).

Results:

Sixteen patients were enrolled and treated with 40 mg or 80 mg tirabrutinib (n = 8 per group). All 16 patients experienced grade 1 or 2 TEAEs. Plasma tirabrutinib concentrations in steady-state conditions were within the expected ranges. The mean (SD) change in mRSS from baseline to week 52 was −4.0 (6.1) and −4.7 (3.6) in the 40-mg and 80-mg groups, respectively. The percentage of naïve B cells tended to increase, and the percentages of nonswitched memory B cells, activated memory CD95+ B cells, and plasmablasts tended to decrease in both groups. Immunophenotyping and RNAseq suggested that suppression of B-cell activity was involved in the mechanism of action of tirabrutinib.

Conclusions:

This study suggests that tirabrutinib is tolerable in patients with SSc and acts by suppressing B-cell activity.

项与替拉鲁替尼相关的新闻（医药）

2025-08-31

·丁香园 Insight 数据库

BTK 新战场，擂鼓已响

血液瘤领域的明星靶点 BTK，正在加速奔跑进入它的下一个新战场。 8 月 29 日，赛诺菲 36.8 亿美元收购 Principia 公司所得的重磅产品 Rilzabrutinib 在美国迎来全球首批，成为全球首个获批治疗免疫性血小板减少症的 BTK 抑制剂，同时也是首个专门针对自身免疫性疾病而开发的 BTK 抑制剂，代表着 BTK 在自免领域的重大突破！与此同时，赛诺菲的第 2 款自免 BTK 抑制剂 Tolebrutinib、诺华的自免 BTK 抑制剂瑞米布替尼，也有望在下半年迎来获批。这意味着，BTK 在自免战场的竞赛，擂鼓已经敲响。 BTK 自免研发驶入快车道全球在研管线超 50 款 BTK 是一种非受体酪氨酸激酶，在多种造血细胞类型中表达，包括 B 细胞、肥大细胞、中性粒细胞、髓系细胞和破骨细胞。在 B 细胞中，BTK 可通过 B 细胞抗原受体 (BCR) 和 Toll 样受体 (TLR) 信号转导促进 B 细胞的发育和激活。在免疫反应中，BTK 信号通路发挥着重要作用，是 B 细胞受体和 Fc 受体信号转导的关键介质。BTK 可显著激活 BCR 信号通路，导致 B 细胞分化为自身反应性 B 细胞。此外，BTK 还能激活先天免疫细胞，包括巨噬细胞、肥大细胞、嗜碱性粒细胞和中性粒细胞。在自身免疫疾病中，B 细胞的异常活化会产生有害的自身抗体和炎症。因此，通过阻断 BCR 信号通路，可以抑制 B 细胞的异常活化、增殖和自身抗体产生，从而达到治疗自免疾病的效果。然而，由于一代 BTK 抑制剂在治疗自免疾病时缺乏选择性、有毒性等原因，BTK 在自免领域的临床开发进展严重落后于其肿瘤领域。从首款 BTK 抑制剂获批至今的 12 年时间里，全球范围内先后有 6 款 BTK 抑制剂获批，但适应症主要是肿瘤。随着新一代 BTK 抑制剂在靶点选择性、安全性方面的提升，BTK 在自免领域的研究进展也开始驶入了快车道。根据 Insight 数据库，目前全球共有 55 款 BTK 抑制剂（仅统计活跃状态）正在开展针对自身免疫性疾病的研究，药物类型包括传统小分子抑制剂和 PROTAC。其中，有 34 款处于获批临床及以上阶段。从适应症分布来看，竞争最激烈的 TOP4 适应症为多发性硬化、类风湿关节炎、慢性自发性荨麻疹、系统性红斑狼疮，对应的 BTK 管线数量均超过了 10 个。截图来源：Insight 数据库赛诺菲、诺华等制药巨头抢滩布局 BTK 在免领域的巨大潜力，吸引了众多跨国药企布局。Insight 数据库显示，在研的 55 个管线中，30 个是进口药，研发机构不乏艾伯维、赛诺菲、诺华、礼来、阿斯利康、罗氏、吉利德等制药巨头。伊布替尼（强生/艾伯维）是全球首个 BTK 抑制剂，属于不可逆抑制剂。作为第一代 BTK 抑制剂，伊布替尼虽然在肿瘤治疗中取得了显著疗效，但其存在的脱靶效应，可能使患者出现感染风险增加、出血、心脏问题、免疫功能低下等副作用，治疗大部分自免疾病的风险收益比并不高。因此，除了移植物抗宿主病 (cGVHD) 外，该药并没有拓展至其它更广泛的自免适应症。不过，艾伯维并没有放弃自免领域的布局，其还开发了一款新型 BTK 抑制剂 Elsubrutinib（ABBV105），该药正在开展治疗红斑狼疮的 Ⅱ 期临床。同时，艾伯维还将 Elsubrutinib 和 JAK 抑制剂乌帕替尼组成了一款新型固定剂量复方制剂——ABBV-599，正在 Ⅱ 期临床中探索其治疗系统性红斑狼疮的效果。在 BTK 赛道，赛诺菲算是后入局者，但专攻自免的差异化策略已使其成为 BTK 自免领域的领跑玩家。 2020 年 9 月，赛诺菲以 36.8 亿美元收购 Principia Biopharma 公司，此举旨在囊获后者的两款 BTK 抑制剂 Rilzabrutinib 和 Tolebrutinib，拓展自免管线。 Rilzabrutinib 是一款口服、可逆、共价 BTK 抑制剂，主要开发用于治疗自免疾病。该药在 24 年 11 月向 FDA 申报上市，今年 8 月 29 日获批，是首个获批的用于治疗免疫性血小板减少症（ITP）的 BTK 抑制剂。去年 12 月，该药也已在国内递交 ITP 适应症的 NDA，目前正在审评中。目前，赛诺菲还在临床中探索 Rilzabrutinib 治疗自身免疫性溶血性贫血、特应性皮炎、慢性自发性荨麻疹、局灶节段性肾小球硬化症、格雷夫斯病等适应症的效果。另一款产品 Tolebrutinib 是一款具有脑穿透性和生物活性的 BTK 抑制剂，该药的核心优势在于能精准靶向多发性硬化症（MS）中驱动残疾进展的关键因素——神经炎症。Tolebrutinib 在 25 年 3 月向 FDA 递交了首个 NDA，首发适应症为多发性硬化（MS），PDUFA 日期为 9 月 28 日，有望成为首个斩获 MS 适应症的 BTK 抑制剂。由此可见，赛诺菲有望成为首家在自免领域拥有两款获批 BTK 抑制剂的公司。赛诺菲预测 Rilzabrutinib 和 Tolebrutinib 各自的年销售额均有望达到 20 亿欧元~50 亿欧元区间，成为推动公司未来业绩增长的潜在重磅炸弹药物 [3]。抢滩布局的制药巨头的还有诺华。该公司的瑞米布替尼（Remibrutinib）是一款靶向 BTK 的第二代共价抑制剂。2025 年 2 月、3 月，该药先后在中国和美国递交了上市申请，首发适应症为慢性自发性荨麻疹（CSU）患者，并被纳入了优先审评，有望成为首个获批治疗 CSU 的 BTK。此外，诺华还在开发瑞米布替尼用于治疗荨麻疹、多发性硬化、化脓性汗腺炎、重症肌无力等适应症。诺华预测瑞米布替尼的年销售额峰值有望超过 30 亿美元 [4]。其它进度比较快的产品还有：吉利德/小野制药的替拉鲁替尼，正在开展治疗天疱疮的 Ⅲ 期临床；罗氏的 Fenebrutinib，正在开展治疗多发性硬化的 Ⅲ 期临床。此外，礼来的匹妥布替尼、阿斯利康的阿可替尼、渤健的 BIIB091 等正在开展针对不同自免适应症的 Ⅱ 期临床（详见下表）。诺诚健华、百济神州等国内药企竞相入场国内企业在 BTK 自免领域也不甘落后。根据 Insight 数据库，目前共计有 25 款国产 BTK 抑制剂在开展针对自免疾病的研究，占到了全球 BTK 自免管线的 45%。其中，有 15 款已进入到获批临床及以上阶段，玩家包括百济神州、诺诚健华、正大天晴、恒瑞医药、人福医药、翰森制药等众多国内明星药企。从研究进度来看，诺诚健华、百济神州、邦顺制药的产品处于第 1 梯队，均已进入 Ⅲ 期阶段。诺诚健华从 2019 年就开始启动奥布替尼自免适应症的临床研究。目前，奥布替尼治疗免疫性血小板减少症（ITP）的 Ⅲ 期临床已经完成患者入组，预计 2026 年上半年提交上市申请，有望成为首个提交自免适应症 NDA 的国产 BTK 抑制剂。同时，诺诚健华还在开展奥布替尼治疗多发性硬化、系统性红斑狼疮、血小板减少性紫癜、视神经脊髓炎、系统性红斑狼疮等适应症的临床研究，其中多发性硬化正在全球启动 III 期注册临床试验，SLE 的 IIb 期已接近完成临床研究。奥布替尼 24 年收入 10 亿元，今年上半年创收 6.4 亿元，自免适应症将打开奥布替尼的第二增长曲线。百济神州也在加紧拓展泽布替尼的自免适应症。目前，泽布替尼正在开展针对多项自免疾病的临床研究，适应症涵盖嗜血细胞性淋巴组织细胞增多症、免疫性血小板减少症、冷凝集素病、自身免疫性溶血性贫血、多发性神经病、原发性膜性肾病、狼疮肾炎等等。其中，泽布替尼治疗嗜血细胞性淋巴组织细胞增多症已在国内完成一项单臂 Ⅲ 期试验。泽布替尼 2024 年全球销售额达到 26.44 亿美元，今年上半年大卖 17.42 亿美元，首次上榜全球畅销药 TOP50 榜单，自免适应症将进一步拉高泽布替尼的市场天花板。此外，百济神州还开发了一款靶向 BTK 的 PROTAC Catadegbrutinib，该药是全球进度最快的 BTK PROTAC，在血液癌症领域已进入 Ⅲ 期临床，在自免领域正在开展针对慢性自发性荨麻疹的Ⅰ期临床。第三款进入Ⅲ 期的国产 BTK 抑制剂为邦顺制药的邦赛替尼，该药尚未获批任何适应症，进度最快的是免疫性血小板减少症，今年 8 月在国内进入Ⅲ 期临床。同时，邦顺制药还在开展邦赛替尼治疗慢性荨麻疹的 I/II 期。此外，在自免赛道进展相对较快的产品还有：正大天晴的 TQB3702，正在开展针对系统性红斑狼疮的 Ⅱ 期临床；人福医药的 WXFL10230486，正在开展针对慢性自发性荨麻疹的 Ⅱ 期临床；恒瑞医药的 Edralbrutinib，针对视神经脊髓炎、原发性膜性肾病已进入 Ⅱ 期阶段。小结 BTK 靶点发现至今已有 30 多年。2024 年，全球 BTK 抑制剂市场规模约为 125 亿美元，主要贡献力量是肿瘤适应症。在自免赛道，BTK 尚处于蓝海市场。随着在自免领域的陆续进展和突破，BTK 将在疾病治疗领域继续书写自己的辉煌篇章。据弗若斯特沙利文预计，到 2030 年，全球 BTK 抑制剂的市场规模将有望达到 261 亿美元[5]。参考资料： [1]Targeting Bruton’s tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments [2]Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.https://pmc-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/articles/PMC8595937/#s5 [3]https://www.sanofi.com/en/media-room/press-releases/2023/2023-12-07-02-30-00-2792186 [4]Novartis, after slimming down, boosts growth projection through the end of the decade.https://www.fiercepharma.com/pharma/standing-alone-novartis-bumps-its-growth-projection-through-end-decade#:~:text=That%20list%20includes%20chronic%20spontaneous,pelcarsen%20and%20autoimmune%20contender%20ianalumab. [5]Tens of billions $ market size, how big is the future potential of BTK inhibitors?.https://www.echemi.com/cms/1058731.html [5] 各公司官方资料。 [6]Insight 数据库封面来源：站酷海洛 Plus 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：馨药 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

蛋白降解靶向嵌合体并购引进/卖出

2025-05-28

·Business Wire

ONO PHARMA Presents Positive Results From Pivotal Trial in U.S. Patients With Relapsed or Refractory PCNSL at 2025 ASCO Annual Meeting

OSAKA, Japan--(BUSINESS WIRE)--Ono Pharmaceutical Co., Ltd. (Headquarters: Osaka, Japan; President and COO: Toichi Takino; “Ono”), today announced that the results from the open label Phase 2 PROSPECT Study of tirabrutinib is to be presented at the 2025 American Society for Clinical Oncology (ASCO) annual meeting.2 Patients in the U.S. with relapsed or refractory primary central nervous system lymphoma (R/R PCNSL) who received oral tirabrutinib as a monotherapy achieved an overall response rate (ORR) of 67%.2 Tirabrutinib is a highly selective irreversible, second generation Bruton's tyrosine kinase inhibitor discovered by Ono in Japan. In March 2023, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to investigational tirabrutinib for the treatment of PCNSL.3 “PCNSL is a rare and aggressive extranodal non-Hodgkin lymphoma with historically poor survival rates and no approved treatments in the U.S.,” said Tracy Batchelor, MD, MPH, Mass General Brigham Chair of Neurology and Coordinating Investigator for the PROSPECT study. “The PROSPECT Study data show tirabrutinib provided a promising response rate in patients with R/R PCNSL, supporting its role as a potentially effective treatment option for patients living with this devastating disease.” Study Results In the PROSPECT Study, 48 patients with R/R PCNSL received oral tirabrutinib as a monotherapy once daily.2,4 The primary endpoint was ORR, and secondary endpoints included duration of response (DOR), time to response (TTR), and safety.2,4 After a median follow-up of 11.5 months, ORR was 67%, with a complete response rate of 44%.2 Median DOR was 9.3 months, and median TTR was 1.0 months.2 Exploratory endpoints included median overall survival, which was not reached, and median progression-free survival, which was 6.0 months.2 Tirabrutinib demonstrated a generally favorable safety profile.2 At data cutoff, 13 patients (27%) remained on tirabrutinib treatment.2 The main reasons for discontinuation were disease progression (54.2%) and death (8.3%); one patient discontinued due to an adverse event (AE).2 Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 56.3%.2 Any-grade treatment-related TEAEs were experienced by 75.0%, and most frequently included anemia (18.8%), rash maculo-papular (16.7%), fatigue (14.6%), neutrophil count decreased (14.6%), lymphocyte count decreased (14.6%), pruritus (14.6%), and rash (14.6%).2 Two patients died of TEAEs, which were considered unrelated to study treatment. 2 “We are deeply grateful to the study investigators and the patients who participated in this study for making this important research possible,” said Thomas Lechner, MSc. Ph.D., VP, Medical Affairs, ONO PHARMA USA INC. “Tirabrutinib is approved for relapsed or recurring PCNSL in Japan, Taiwan, and South Korea and our hope is to bring this potential treatment to those living with this hard-to-treat disease in the U.S as soon as possible.” PROSPECT Study data will be included in a regulatory submission to the FDA in the near future. About PCNSL PCNSL is a rare and aggressive extra nodal non-Hodgkin lymphoma (NHL) that is confined to the brain parenchyma, spinal cord, eye, or leptomeninges, without systemic involvement. The annual incidence rate of PCNSL is approximately five cases per 1,000,000 people in the U.S. The rate can further increase among immunocompromised people aged 65 years and older. The signs and symptoms presented in patients with PCNSL vary depending on the neuroanatomical site of the lesion, and include cranial neuropathy, neuropsychiatric symptoms, symptoms associated with increased intracranial pressure, seizures, ocular symptoms, headache, dysmotility, cranial neuropathy, and radiculopathy. There are no therapeutic products approved for the treatment of PCNSL in the U.S., and data guiding therapeutic approaches are very limited. Despite recent progress resulting in the improvement of clinical outcomes in newly diagnosed patients with PCNSL after an induction treatment, approximately 20 to 30 percent of patients are refractory to the initial treatment, and up to 60 percent of patients will eventually relapse. To learn more about R/R PCNSL, please visit navigatingpcnsl.com. About Tirabrutinib Tirabrutinib, discovered and developed by Ono Pharmaceutical Co., Ltd., is a highly potent selective BTK inhibitor. Signaling through the B-cell receptor (BCR) regulates cellular proliferation and activation, and promotes survival, differentiation, and clonal expansion of B-cells. The BCR signaling pathway plays an important role in a number of B-cell malignancies. In Japan, tirabrutinib was approved in March 2020 for the treatment of relapsed or refractory PCNSL and launched under the tradename of Velexbru® in May 2020. It was subsequently approved for the treatment of Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma in August 2020.Tirabrutinib was approved for the treatment of relapsed or refractory PCNSL in South Korea in November 2021 and in Taiwan in February 2022. About the PROSPECT Study The PROSPECT Study is a Phase 2 trial (NCT04947319) evaluating the safety and efficacy of an investigational oral medicine called tirabrutinib for the potential treatment of newly diagnosed or relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL), which is a type of cancer that either does not improve from treatment (refractory) or improves only for a limited time (relapsed). Current treatment options for R/R PCNSL are limited, and there are no medications specifically approved in the U.S. for the treatment of PCNSL. Learn more about the PROSPECT Study here: theprospectstudy.com. About ONO PHARMA USA INC. ONO PHARMA USA INC.(OPUS), established in 1998 as the U.S. subsidiary of Ono Pharmaceutical Co., Ltd., is pursuing the clinical development of new drug candidates in the U.S., from clinical development to regulatory approval and commercialization. In addition, OPUS is engaged in promotion of the discovery alliances and licensing activities to expand Ono’s development pipeline and pursue the commercialization opportunities in the U.S. In February, 2025, Ono announced that it has reorganized the operations of its local subsidiaries in the U.S. in order to accelerate the expansion of its global presence. In line with the reorganization, key functions of OPUS, including US R&D and commercial and medical affairs are being integrated into Deciphera Pharmaceuticals, Inc. (Deciphera) in July 2025. Deciphera has robust and well-developed R&D capabilities and commercial presence in the U.S. and Europe. OPUS will remain as a center for research collaboration and licensing activities. For more information, please visit us.ono-pharma.com. References 1. Schaff LR, Grommes C. Primary central nervous system lymphoma. Blood. 2022;140(9):971-979. doi:10.1182/blood.2020008377. 2. Nayak L, Grommes C, Kallam A, et al. Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: efficacy and safety from the phase II PROSPECT study. Presented at: 2025 American Society for Clinical Oncology (ASCO) meeting; May 30-June 3, 2025; Chicago, IL. 3. Tirabrutinib Receives Orphan Drug Designation From FDA. ONO PHARMA USA, Inc. Available from: https://us.ono-pharma.com/news/tirabrutinib-receives-orphan-drug-designation. Accessed February 2025. 4. ClinicalTrials.gov. Study of Tirabrutinib (ONO-4059) in Patients with Primary Central Nervous System Lymphoma (PROSPECT Study). Available from: https://clinicaltrials.gov/study/NCT04947319. Accessed February 2025.

临床结果临床2期孤儿药上市批准ASCO会议

2025-05-28

·靶点圈

一文带你了解BTK抑制剂的十年变革：从血液肿瘤到自身免疫病的跨界征途

01BTK的分子结构与作用机制BTK的分子结构BTK是一种由659个氨基酸组成的非受体酪氨酸激酶，分子量约76kDa，属于Tec激酶家族。其结构包含5个主要功能域，从N端到C端依次为：● PH结构域：结合磷脂酰肌醇三磷酸(PIP3)，介导细胞膜定位；● SH3结构域：结合富含脯氨酸的蛋白(如BCAP)，参与信号复合物组装，是BCR信号激活的前提；● SH2结构域：识别磷酸化酪氨酸残基，与活化的CD79a/b等分子结合，传递BCR信号；● SH1/TK结构域：包含关键的催化位点(Cys481、Tyr551)和ATP结合口袋；● C端尾部：含核定位信号(NLS)和核输出信号(NES)，调控BTK在胞质与细胞核间的穿梭，影响其功能多样性。这些结构域通过协同作用，实现BTK的膜定位、信号传导和底物磷酸化功能。图1 BTK的化学结构BTK的信号通路调控BTK通过BCR、TLR、CXCR4等受体激活，从而磷酸化下游分子(如PLC-γ)激活NF-κB和MAPK通路，参与免疫应答和炎症反应。图2 BTK在BCR、TLR、趋化因子受体和FcR信号转导通路中的作用BTK与其他激酶的协同作用与Lyn、Syk、PI3K等激酶形成信号网络。Lyn磷酸化CD79A/B的ITAM招募Syk，Syk激活BTK，共同维持BCR通路活化。PI3K通过生成PIP3激活Akt/mTOR通路，与BTK协同促进细胞生存代谢。图3 刺激B细胞中BTK活化的细胞表面受体02BTK的表达调控与生物学功能BTK的广泛表达BTK不仅表达于B细胞，还存在于髓系细胞(如单核细胞/巨噬细胞、树突状细胞、肥大细胞、中性粒细胞)中，参与多种免疫细胞的信号传导。BTK的功能及作用机制● 调控B细胞活化与自身抗体产生：1)B细胞发育与激活：BTK是B细胞受体(BCR)信号通路的关键激酶，调控B细胞的发育、活化与分化，促进B细胞增殖与抗体分泌。其异常激活与B细胞恶性肿瘤(如慢性淋巴细胞白血病CLL、套细胞淋巴瘤MCL)、自身免疫病密切相关。2)B细胞代谢调控：BTK抑制B细胞线粒体呼吸，影响其活化状态。在多发性硬化(MS)中，BTK通过调节B细胞代谢，增强其刺激T细胞分泌促炎因子(如IFN-γ、TNF-α)的能力。3)B细胞与T细胞的协同作用：BTK抑制B细胞表面共刺激分子(如CD80/CD86)的表达，减少其对T细胞的激活，抑制Th1/Th17型免疫反应。反之，BTK过度激活会增强B-T细胞相互作用，加剧自身免疫炎症。图4 NLC、LAM和恶性B细胞之间的相互作用和信号转导● 调控固有免疫细胞的炎症放大作用：1)巨噬细胞与树突状细胞(DCs)：BTK通过Toll样受体(TLR)信号通路激活巨噬细胞和DCs，促进M1型促炎表型，增加促炎因子(如IL-23、TNF-α)和趋化因子(如CXCL13)的分泌，参与银屑病、RA等炎症性疾病的发病。2)肥大细胞与嗜碱性粒细胞：在慢性自发性荨麻疹(CSU)中，BTK介导IgE-FcεRI信号，促进肥大细胞释放组胺和炎症介质，引发过敏反应和气道高反应性。3)中性粒细胞与破骨细胞：BTK调控中性粒细胞的氧化应激反应(如超氧化物生成)，参与银屑病皮损炎症；同时促进破骨细胞分化，加剧类风湿关节炎(RA)患者的骨侵蚀。图5 BTK在骨髓细胞中的作用BTK的结构异常与疾病关联● XLA(X连锁无丙种球蛋白血症)：BTK基因缺失或突变(如C481突变)导致B细胞发育停滞，表现为抗体缺乏和反复感染。● 自身免疫病：BTK过度激活或构象改变(如C端尾部磷酸化异常)可增强B细胞和固有免疫细胞的活化，促进自身抗体产生和炎症反应(如SLE、RA)。03BTK抑制剂的分类与耐药机制BTK抑制剂(BTKIs)的分类图6 BTK抑制剂的作用机制● 共价不可逆抑制剂：不可逆结合BTK的C481位点(如伊布替尼、阿卡替尼、泽布替尼)，阻断BCR信号，用于B细胞恶性肿瘤，显著改善患者生存。但长期使用易诱导C481S突变，导致耐药。● 共价可逆抑制剂：可逆结合C481位点(如瑞扎布替尼)，减少脱靶效应。但仍可能因C481S或L528W突变耐药。● 非共价可逆抑制剂：不结合C481，通过阻断ATP结合或降低激活标记物(如芬布替尼)，适用于C481突变(如C481S)的耐药患者。但可能因T474I、L528W等新突变导致耐药。表1 BTK抑制剂分类由BTK基因突变引发的耐药● 激酶功能型突变：1)C481位点突变：如C481S/R/F/Y，占共价抑制剂耐药的60–90%。突变导致BTK与共价抑制剂(如伊布替尼)的共价结合失效，但保留激酶活性，维持BCR信号传导。2)T474I突变：位于激酶结构域，增强BTK自身磷酸化(Y223位点)，激活下游PLCγ2/NF-κB通路，常见于阿卡替尼治疗后。● 激酶失活型突变：1)L528W突变：导致BTK激酶活性丧失，但通过“支架功能”与HCK、ILK等激酶结合，维持下游信号传导，常见于泽布替尼治疗后的CLL。2)其他位点突变：如V416L、A428D、M437R等，通过改变BTK构象或与抑制剂结合口袋，导致非共价抑制剂(如吡托布鲁替尼)耐药。● 下游信号通路激活：1)PLCγ2突变：如S707F、R665W、E1139del，激活下游NF-κB通路，绕过BTK信号维持B细胞存活，常见于WM、CLL。图7 BTK和PLCγ2突变由其他因素引发的耐药● 肿瘤微环境(TME)：基质细胞通过CXCL12/CXCL13及整合素(如VLA-4)提供生存信号，激活PI3K/AKT通路增强肿瘤细胞黏附与存活，绕过BTK抑制的凋亡信号。● 表观遗传与转录因子：如TCF4过表达在ABC-DLBCL中替代BTK激活PLCγ2，导致伊布替尼耐药。如EP300、MLL2突变，通过表观遗传机制维持肿瘤细胞存活，与CLL耐药相关。04BTK抑制剂与降解剂BTK抑制剂的临床应用● 第一代BTKIs(如伊布替尼)：用于CLL、MCL、WM等，显著延长患者生存期。但存在脱靶效应(如抑制EGFR、TEC)导致出血、房颤等毒性，60%患者因C481S突变耐药。● 第二代BTKIs(如阿卡替尼、泽布替尼)：选择性更高，毒性更低，因安全性优势逐渐替代伊布替尼。阿卡替尼不抑制ITK和EGFR，房颤发生率低于伊布替尼，用于CLL/SLL和MCL。泽布替尼在CLL中ORR更高，但仍面临L528W等突变耐药。Tirabrutinib(日本获批用于PCNSL)、Orelabrutinib(中国获批用于R/RCLL/MCL)。● 第三代BTKIs(如吡托布鲁替尼)：可克服C481S突变耐药，对野生型和突变型BTK均有抑制作用。用于C481S突变的复发患者，但需警惕非C481突变(如L528W、T474I)导致交叉耐药。Fenebrutinib(用于RA、SLE)、Nemtabrutinib(针对C481S突变)处于II/III期试验。表2 已上市的BTKIs药物清单表3 目前正在进行临床试验的BTKIs药物清单BTK的靶向新策略：蛋白降解剂(PROTACs)● 作用机制及优势：通过双功能分子连接BTK配体与E3泛素连接酶，诱导BTK泛素化并经蛋白酶体降解，而非单纯酶抑制。可降解突变型BTK，且降解效率高，初步显示对耐药突变有效，但长期安全性尚需验证。图8 BTK降解剂作用机理● 代表药物与临床进展：1)NX-2127：降解BTK野生型及C481S、L528W突变体，同时降解IKZF1/3(增强T细胞功能)。I期试验显示，在复发CLL中缓解率33%，BTK降解率达86%。2)NX-5948：选择性降解BTK，血脑屏障穿透性强，用于中枢神经系统淋巴瘤，I期显示良好的耐受性和BTK降解效果。3)BGB-16673：I/II期数据显示在R/RCLL中可快速降低BTK水平，部分患者达部分缓解，但需警惕A428D突变导致的耐药。● 联合疗法：BTK降解剂与其他靶向药物(如BCL-2抑制剂)联用可能克服PLCγ2突变等非BTK依赖耐药机制。05BTK在不同疾病中的病理机制淋巴瘤● 原发性中枢神经系统淋巴瘤(PCNSL)PCNSL高频突变的MYD88和CD79B可异常激活BCR通路，使肿瘤细胞高度依赖BTK存活。BTKIs通过阻断PLCγ2，抑制肿瘤细胞增殖并诱导凋亡。此外，BTKIs还可调节肿瘤微环境，减少免疫逃逸，与免疫检查点抑制剂联用可增强抗肿瘤免疫应答。表4 用于PCNSL的BTKIs的临床试验● 慢性淋巴细胞白血病(CLL)BTK参与调节CLL细胞与肿瘤微环境的相互作用，影响疾病的进展。BTKIs可阻断BCR信号传导，诱导肿瘤细胞凋亡，同时调节免疫微环境，减少Treg细胞、增强CD8+T细胞功能并抑制巨噬细胞M2极化。图9 CLL细胞及其环境中的BTK抑制● 套细胞淋巴瘤(MCL)在MCL中，持续激活的BCR-BTK信号通路可促进MCL细胞的增殖和存活，影响肿瘤的发展。同时，BTK还与MCL细胞的黏附、迁移等过程相关，影响肿瘤细胞在体内的弥散。● 弥漫大B细胞淋巴瘤(DLBCL)在ABC型DLBCL中，BTK的持续激活可导致NF-κB通路的过度活化，驱动肿瘤细胞的生长和存活。然而在GCB型DLBCL中，BTK的依赖性相对较低。研究表明，部分DLBCL患者中存在BTK基因的扩增，与疾病的侵袭性和不良预后相关。伊布替尼单药治疗客观缓解率不高且无进展生存期短，目前多探索联合治疗方案。● 华氏巨球蛋白血症(WM)BTK的激活可促进WM细胞的存活、增殖以及免疫球蛋白的分泌。有研究显示，WM患者中常见的MYD88突变可增强BTK的活性，进一步促进肿瘤细胞的生长。伊布替尼、泽布替尼均获批用于WM治疗，客观缓解率较高。表5 已发表的针对CLL/SLL、MCL、WM、MZL的共价BTKIs表6 用于CLL/SLL、MCL、WM、MZL的非共价BTKIs和降解剂自身免疫性疾病● 自身免疫性水疱病BTK激活B细胞产生抗桥粒芯蛋白(如Desmoglein)的IgG抗体，破坏皮肤细胞间黏附，导致水疱形成；同时激活固有免疫细胞(如中性粒细胞、肥大细胞)，释放蛋白酶和炎症介质，加重表皮损伤。Rrilzabrutinib在II期试验中快速控制病情，减少糖皮质激素用量，尤其适用于抗桥粒芯蛋白抗体介导的自身免疫性水疱病。表7 自身免疫性水疱病临床前和临床试验中测试的BTKIs● 系统性红斑狼疮(SLE)BTK促进B细胞过度产生抗核抗体，形成免疫复合物沉积于肾脏、皮肤等组织，激活补体系统并诱发组织损伤；同时调控T细胞极化，促进Th1/Th17型免疫反应。在小鼠模型中，BTKIs可减少抗核小体抗体和组蛋白抗体，抑制DC和巨噬细胞过度活化，改善狼疮肾炎，但对抗dsDNA抗体影响有限，在人类II期试验中(如Fenebrutinib、Evobrutinib)疗效也有限。表8 系统性红斑狼疮临床前和临床试验中测试的BTKIs● 类风湿关节炎(RA)BTK在滑膜巨噬细胞和破骨细胞中激活，促进IL-6、MMPs等因子分泌，导致关节炎症、软骨破坏和骨侵蚀。B细胞通过BCR信号分泌类风湿因子(RF)和抗瓜氨酸化蛋白抗体(ACPA)，加剧自身免疫反应。BTKIs可抑制B细胞活化和抗体产生，减少滑膜炎症。临床前模型显示，CGI1746、GDC-0834等可减轻关节损伤，但部分II期临床试验(如BMS-986142)未达主要终点。表9 类风湿性关节炎临床前和临床试验中测试的BTKIs● 干燥综合征(SS)BTK驱动B细胞异常增殖和自身抗体(如抗SSA/Ro、抗SSB/La)分泌，导致唾液腺和泪腺的炎症及功能障碍。固有免疫细胞(如DCs)通过TLR-BTK通路分泌趋化因子，招募免疫细胞至外分泌腺体。Remibrutinib和Tirabrutinib在早期试验中尝试调节B细胞和唾液腺炎症，但疗效尚未突破。表10 干燥综合征临床前和临床试验中测试的BTKIs● 多发性硬化(MS)BTK通过调控B细胞和髓系细胞参与神经炎症和脱髓鞘过程，此外，BTK可能通过调节B细胞代谢(如线粒体呼吸)影响其与T细胞的交互作用。BTKIs穿透血脑屏障，抑制中枢神经系统内B细胞和髓系细胞的BTK信号，减少促炎因子释放和自身抗体产生，从而减轻炎症和神经损伤。Evobrutinib、Tolebrutinib在II期试验中减少MRI病灶，改善神经功能。表11 在多发性硬化症和重症肌无力的临床前和临床试验中测试的BTKIs炎症性疾病● 慢性自发性荨麻疹(CSU)BTK通过FcεRI信号激活肥大细胞和嗜碱性粒细胞，促进IgE介导的组胺释放和炎症细胞浸润，导致风团和瘙痒。● 银屑病BTK调控中性粒细胞的BTK通路，维持氧化应激和炎症状态；同时激活γδT细胞分泌IL-17A，促进角质形成细胞过度增殖。● 哮喘BTK参与IgE-FcεRI介导的气道炎症，促进Th2型细胞因子(如IL-4、IL-13)分泌和嗜酸性粒细胞浸润，导致气道重塑和高反应性。表12 在银屑病、慢性自发性荨麻疹、特应性皮炎和哮喘的的BTKIs06BTK抑制剂的不良反应与安全性常见副作用● 出血：与BTK/TEC抑制导致血小板功能障碍相关(如伊布替尼引起瘀斑、鼻衄)。● 心血管事件：房颤(与CSK或PI3K信号抑制有关)，第二代抑制剂(如泽布替尼)风险较低。● 感染：抑制中性粒细胞和巨噬细胞的抗菌功能，增加曲霉、肺孢子菌等机会性感染风险，尤其在CLL患者中。● 皮肤毒性：出现皮疹(EGFR脱靶效应)、指甲改变(如伊布替尼)。表13 BTKIs的不良事件当前挑战● 毒性管理：需监测血小板功能、心电图及肝功能，权衡疗效与感染风险，尤其是长期用药患者。● 耐药监测：实时检测BTK突变选择合适的抑制剂类型以便及时地调整治疗方案。未来方向● 新型抑制剂开发：高选择性非共价抑制剂(如Vecabrutinib)、双功能降解剂(如LP-168)，覆盖耐药突变，减少脱靶毒性。● 联合疗法：BTKIs+免疫检查点抑制剂、CAR-T细胞疗法、JAK抑制剂或补体抑制剂联用，增强抗肿瘤免疫。● 早期干预与预防：探索BTKIs在癌前病变或高风险人群中的应用。抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，小编将持续更新相关内容～参考文献Liu X, Lin Y, Zhuang Q, Deng H, Liu A, Sun J. BTK inhibitors resistance in B cell malignancies: Mechanisms and potential therapeutic strategies. Blood Rev. 2025 May;71:101273. Kim HO. BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies. Arch Pharm Res. 2025 May 8. Grainger BT, Cheah CY. "The End of the Golden Weather": therapeutic strategies for mantle cell lymphoma relapsed or refractory to covalent BTK inhibitors. Haematologica. 2025 Mar 1;110(3):576-587. Gupta S, Sharma A, Shukla A, Mishra A, Singh A. From development to clinical success: the journey of established and next-generation BTK inhibitors. Invest New Drugs. 2025 Apr;43(2):377-393. Tian G, Chen Z, Wang B, Chen G, Xie L. Small-molecule BTK inhibitors: From discovery to clinical application. Bioorg Chem. 2025 Apr;157:108242. Salvaris RT, Brennan J, Lewis KL. BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL. Cancers (Basel). 2025 Feb 6;17(3):557. Xing Y, Zhao K, Zhang Y, Wang Y. BTK inhibition in primary central nervous system lymphoma: mechanisms, clinical efficacy, and future perspectives. Front Oncol. 2024 Dec 24;14:1463505.Bravo-Gonzalez A, Alasfour M, Soong D, Noy J, Pongas G. Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies. Cancers (Basel). 2024 Oct 10;16(20):3434. Jiang Q, Peng Y, Herling CD, Herling M. The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond. Cancers (Basel). 2024 Oct 23;16(21):3574. Tavakoli GM, Yazdanpanah N, Rezaei N. Targeting Bruton's tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments. Adv Rheumatol. 2024 Aug 21;64(1):61. Cool A, Nong T, Montoya S, Taylor J. BTK inhibitors: past, present, and future. Trends Pharmacol Sci. 2024 Aug;45(8):691-707.Mehra S, Nicholls M, Taylor J. The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas. Int J Mol Sci. 2024 Jul 9;25(14):7516.Schaff L, Nayak L, Grommes C. Bruton's tyrosine kinase (BTK) inhibitors for the treatment of primary central nervous system lymphoma (PCNSL): current progress and latest advances. Leuk Lymphoma. 2024 Jul;65(7):882-894.Nawaratne V, Sondhi AK, Abdel-Wahab O, Taylor J. New Means and Challenges in the Targeting of BTK. Clin Cancer Res. 2024 Jun 3;30(11):2333-2341.

临床1期细胞疗法引进/卖出

100 项与替拉鲁替尼相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D11070	替拉鲁替尼	L01XE	DB15227

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
巨球蛋白血症	日本	Ono Pharmaceutical Co., Ltd.	2020-08-21
原发性中枢神经系统淋巴瘤	日本	Ono Pharmaceutical Co., Ltd.	2020-03-25

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
难治性中枢神经系统淋巴瘤	临床3期	-	Ono Pharmaceutical Co., Ltd.	2025-11-01
天疱疮	临床3期	日本	Ono Pharmaceutical Co., Ltd.	2022-08-15
慢性荨麻疹	临床2期	-	Gilead Sciences, Inc.	2021-07-01
干燥综合征	临床2期	美国	Gilead Sciences, Inc.	2017-05-01
干燥综合征	临床2期	波兰	Gilead Sciences, Inc.	2017-05-01
干燥综合征	临床2期	西班牙	Gilead Sciences, Inc.	2017-05-01
干燥综合征	临床2期	英国	Gilead Sciences, Inc.	2017-05-01
难治性慢性淋巴细胞白血病	临床2期	德国	Gilead Sciences, Inc.	2016-12-13
慢性淋巴细胞白血病	临床1期	美国	Gilead Sciences, Inc.	2015-06-16
慢性淋巴细胞白血病	临床1期	法国	Gilead Sciences, Inc.	2015-06-16

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04947319 (PROSPECT, ASCO2025) 人工标引	临床2期	原发性中枢神经系统淋巴瘤	48	Tirabrutinib 480 mg	鏇積壓繭顧醖艱鹽鹹壓(壓鏇壓顧蓋築淵築製鏇) = 壓獵鑰壓餘顧遞積廠構齋積鏇構遞積蓋鬱夢夢 (淵獵顧鬱獵簾蓋築憲膚 ) 更多	积极	2025-05-30
NCT04947319 (PROSPECT, EHA2025)	临床2期	难治性中枢神经系统淋巴瘤	48	Tirabrutinib 480 mg	範醖觸糧憲鬱齋蓋窪蓋(衊鏇遞積簾構醖蓋鹹膚) = 簾廠網觸顧壓憲壓鏇鬱襯艱膚糧艱糧壓糧築遞 (繭襯窪築鬱選範壓繭窪 ) 更多	积极	2025-05-22
PS1875 (EHA2025)	N/A	脊髓小脑性共济失调	22	Tirabrutinib	鑰窪淵願艱製繭構願鹹(鑰遞窪齋醖窪憲蓋鹽艱) = Skin eruptions (grade 2) were the most notable event; however, they were successfully managed 鏇製鬱鏇鬱鹽網艱廠鹹 (廠築簾淵淵網簾獵鏇網 )	-	2025-05-14
ASH2024	N/A	难治性中枢神经系统淋巴瘤	-	Tirabrutinib	積餘網艱餘蓋膚獵遞鬱(窪膚構膚鑰願簾鹹衊膚) = 1 patient without antiviral agent prophylaxis 衊壓積觸獵獵積襯構獵 (鹽衊鹽廠夢範鏇鹽窪窪 ) 更多	-	2024-12-09
ASH2024	N/A	难治性中枢神经系统淋巴瘤	-	Tirabrutinib	壓築築齋鏇廠願顧淵衊(遞構觸製衊觸製範衊網) = TRAEs of any grade were observed in 92 (57.1%) patients 壓築壓網構壓範憲獵鹹 (淵淵糧構鹹壓選齋膚築 ) 更多	-	2024-12-08
CTNI-12 (SNO2024)	N/A	难治性中枢神经系统淋巴瘤	-	Tirabrutinib (Recurrent PCNSL patients)	齋廠願遞夢構醖構餘觸(選窪範製觸衊製糧廠鹹) = 醖襯鹽選構淵齋醖鹹廠顧築網築範鬱鏇鬱膚衊 (衊醖夢鹹網壓衊遞鬱廠 ) 更多	积极	2024-11-11
CTNI-12 (SNO2024)	N/A	难治性中枢神经系统淋巴瘤	-	Tirabrutinib (Refractory PCNSL patients)	齋廠願遞夢構醖構餘觸(選窪範製觸衊製糧廠鹹) = 憲窪製淵艱壓製積願網顧築網築範鬱鏇鬱膚衊 (衊醖夢鹹網壓衊遞鬱廠 ) 更多	积极	2024-11-11
ONO-4059-02 (ASH2023)	临床1/2期	难治性中枢神经系统淋巴瘤	44	Tirabrutinib 320 mg	餘夢顧蓋齋範獵夢願鏇(淵顧範齋築積獵顧鹹鏇) = 糧餘醖觸簾糧鬱壓夢壓繭觸壓繭蓋製製鬱鬱糧 (構鹽淵蓋獵鹽壓鏇鏇憲 ) 更多	-	2023-12-11
ONO-4059-02 (ASH2023)	临床1/2期	难治性中枢神经系统淋巴瘤	44	Tirabrutinib 480 mg	餘夢顧蓋齋範獵夢願鏇(淵顧範齋築積獵顧鹹鏇) = 築網鹹窪築壓簾遞鏇簾繭觸壓繭蓋製製鬱鬱糧 (構鹽淵蓋獵鹽壓鏇鏇憲 ) 更多	-	2023-12-11
JPRN-JapicCTI-173646 (ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	难治性中枢神经系统淋巴瘤 \| 复发性中枢神经系统淋巴瘤	44	tirabrutinib (320 mg QD)	製製選築繭簾鬱壓窪衊(淵壓網鹹鏇簾醖積簾積) = 願鬱齋衊鏇鹹構網壓衊願醖獵簾齋鏇餘獵積淵 (蓋艱遞簾鬱鑰餘憲膚窪, 36.1 ~ 80.9) 更多	积极	2023-05-31
JPRN-JapicCTI-173646 (ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	难治性中枢神经系统淋巴瘤 \| 复发性中枢神经系统淋巴瘤	44	tirabrutinib (480 mg QD)	製製選築繭簾鬱壓窪衊(淵壓網鹹鏇簾醖積簾積) = 衊願鏇醖願遞糧襯淵積願醖獵簾齋鏇餘獵積淵 (蓋艱遞簾鬱鑰餘憲膚窪, 59.0 ~ 100.0) 更多	积极	2023-05-31
DDRE-44 (SNO2021)	临床1/2期	复发性中枢神经系统淋巴瘤 Bruton’s tyrosine kinase (BTK)	-	Tirabrutinib	衊願鑰網糧築鬱鹽範衊(憲鑰襯網鬱簾醖憲蓋鏇) = 窪淵構築獵鬱襯醖網鹽廠繭衊蓋顧糧觸鬱窪餘 (膚糧簾餘網艱淵壓夢觸 ) 更多	积极	2021-11-12
NCT02626026 (CTgov)	临床1期	类风湿关节炎	42	Tirabrutinib (Cohort 1, Part A: Tirabrutinib 20 mg QD)	醖鹽壓膚壓衊獵窪繭襯 = 餘範齋簾憲艱鹽製蓋淵觸觸顧觸範遞夢範積構 (蓋夢淵夢餘觸鑰憲簾窪, 積憲構廠衊蓋壓窪範觸 ~ 醖醖網遞餘淵繭觸遞膚) 更多	-	2020-09-09
NCT02626026 (CTgov)	临床1期	类风湿关节炎	42	Placebo (Cohort 1, Part A: Placebo)	醖鹽壓膚壓衊獵窪繭襯 = 鬱鹽網醖夢淵積鏇觸窪觸觸顧觸範遞夢範積構 (蓋夢淵夢餘觸鑰憲簾窪, 顧簾築顧鑰鹹鏇醖膚觸 ~ 選遞遞範淵願顧膚壓廠) 更多	-	2020-09-09