NOT YET RECRUITING - This phase II trial tests how well nemtabrutinib in combination with pembrolizumab works in treating patients with Richter transformation, diffuse large B-cell lymphoma subtype (RT-DLBCL). Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cells (a type of white blood cell) in cancers such as Richter transformation at abnormal levels. This may help keep cancer cells from growing and spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving nemtabrutinib in combination with pembrolizumab may kill more cancer cells in patients with RT-DLBCL.

开始日期2025-10-15

申办/合作机构

Roswell Park Comprehensive Cancer Center

NCT07194980

/ Not yet recruiting临床2期IIT

Safety and Efficacy of the Addition of Nemtabrutinib to Lisocabtagene Maraleucel in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

This phase II trial studies how well the addition of nemtabrutinib to lisocabtagene maraleucel in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Nemtabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lisocabtagene maraleucel is a type of treatment called chimeric antigen receptor (CAR) T-cell therapy, in which a patient's T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T-cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion for treatment. Adding nemtabrutinib to lisocabtagene maraleucel may be an effective treatment for relapsed/refractory CLL/SLL.

开始日期2025-10-01

申办/合作机构

Fred Hutchinson Cancer Research Center

[+1]

NCT06572618

/ Recruiting临床2期IIT

A Phase 2 Study of BTK Inhibitor Nemtabrutinib in Combination With Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma

This phase II trial tests how well nemtabrutinib works with rituximab for the treatment of patients with mantle cell lymphoma. Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nemtabrutinib with rituximab may kill more cancer cells in patients with mantle cell lymphoma.

开始日期2025-01-22

申办/合作机构

City of Hope National Medical Center

[+1]

100 项与 Nemtabrutinib 相关的临床结果

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100 项与 Nemtabrutinib 相关的转化医学

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100 项与 Nemtabrutinib 相关的专利（医药）

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项与 Nemtabrutinib 相关的文献（医药）

2025-05-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis, and biological evaluation of novel BTK-targeting proteolysis targeting chimeras (PROTACs) with enhanced pharmacokinetic properties

Article

作者: Su, Huahua ; Yu, Xufen ; Cao, Tao ; Liu, Jing ; Lin, Ying ; Xiang, Jianpin ; Tian, Xinjian ; Wang, Yonghui ; Xie, Qiong ; Wang, Jin

Bruton's tyrosine kinase (BTK) has been an attractive target in the B-cell malignancies. Significant progress has been achieved in developing effective BTK-targeting small-molecule inhibitors and proteolysis targeting chimeras (PROTACs). Based on noncovalent inhibitor ARQ-531, we previously developed two potent BTK PROTACs 6e and SC-3e, which exhibited poor pharmacokinetic property. Herein, we present our extensive structure-activity relationship (SAR) studies focused on BTK binder, linker and cereblon (CRBN) ligand of SC-3e, resulting in two novel BTK PROTACs FDU28 (compound 25) and FDU73 (compound 27). Compounds 25 and 27 selectively induced rapid and robust degradation of wild type (WT) and C481S mutant BTK in a concentration-, time- and ubiquitin-proteasome system (UPS)-dependent manner without affecting CRBN neo-substrates. Furthermore, compound 27 displayed excellent cell antiproliferative activities, metabolic stability in mouse liver microsomes and improved bioavailability in mice. Overall, 27 is a highly effective and selective BTK degrader that is suitable for in vivo efficacy investigations.

2025-04-11·ACS Pharmacology & Translational Science

Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Review

作者: Servant, Nicole B. ; King, Alastair J. ; Jahic, Mirza ; Darragh, Antonia C. ; Lipner, Justin H. ; Hanna, Andrew M.

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput in vitro screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton's tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.

2024-11-01·CHEMICO-BIOLOGICAL INTERACTIONS

Discovery of new non-covalent reversible BTK inhibitors: Synthesis, in silico studies, and in vitro evaluations

Article

作者: Zeng, Shenxin ; Huang, Wenhai ; Wang, Wenyong ; Xu, Xiangwei ; Zhang, Chixiao ; Wang, Zunyuan ; Chi, Xinglong ; Pan, Youlu ; Kang, Youkun ; Wang, Shu

Bruton's Tyrosine Kinase (BTK) played a key role in the B cell antigen receptor (BCR) signaling pathway, and was considered a hotspot in the treatment of B cell malignant tumors and B cell immune diseases. There were 5 covalent irreversible inhibitors launched currently on the market, but C481S mutation was detected in most patients after administration. The approval of Pirtobrutinib (Jaypirca) by FDA in 2023 aroused great interest in the development of non-covalent and reversible BTK inhibitors. In order to solve the resistance of covalent irreversible inhibitors caused by C481S mutation, 11 reversible BTK inhibitors were designed based on screening in this article. The design, synthesis, in silico studies, and in vitro evaluations were performed for further verification. Among them, compound WS-11 showed best activity with IC₅₀ of 3.9 nM for wild type, 2.2 nM for C481S mutation BTK, which was comparable to the positive control Pirtobrutinib. Furthermore, WS-11 would have a good druglikeness properties predicted by pkCSM and SwissADME, which provided a promising lead for further optimization and development.

项与 Nemtabrutinib 相关的新闻（医药）

2025-09-08

·Firstwordpharma

Lilly touts Jaypirca's "striking" survival results in new front-line CLL study

Eli Lilly said Monday that its blood cancer drug Jaypirca (pirtobrutinib) extended progression-free survival (PFS) significantly longer than chemoimmunotherapy in newly diagnosed patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma (CLL/SLL).Results from the Phase III BRUIN CLL-313 study show "one of the most compelling effect sizes ever" seen for a single-agent BTK inhibitor in the front-line setting, according to the company.The randomised trial enrolled 282 untreated CLL/SLL patients without 17p deletions and found that Jaypirca produced a "highly statistically significant and clinically meaningful improvement" in PFS when compared to bendamustine plus rituximab, hitting the primary endpoint. Overall survival (OS) results were not yet mature at the interim analysis, but were "trending strongly" in Jaypirca's favour. A final OS readout is expected in 2026.Jacob Van Naarden, president of Lilly Oncology, called the findings "striking and provocative, across both PFS and OS endpoints… With this third positive Phase III study, we continue to build the clinical evidence supporting the possible role of [Jaypirca] in a variety of CLL/SLL treatment settings, including treatment-naïve, BTK inhibitor-naïve and BTK inhibitor exposed."The drug's safety profile mirrored earlier studies and was generally consistent across treatment settings. Detailed results will be presented at a medical congress and submitted to a peer-reviewed journal.Jaypirca — a highly selective, non-covalent BTK enzyme inhibitor — was granted accelerated approvals in 2023 for third-line CLL/SLL and mantle cell lymphoma after at least one other BTK inhibitor. Lilly is looking to move the drug, which brought in $337 million last year, earlier in the treatment algorithm.Monday's findings follow encouraging readouts from two other late-stage CLL trials. In BRUIN CLL-314, which included a cohort of treatment-naïve patients, Jaypirca showed non-inferior response rates against AbbVie and Johnson & Johnson's covalent BTK inhibitor Imbruvica (ibrutinib), with PFS trending positively (see – KOL Views Q&A: Front-line CLL data chip away at bias that Lilly's Jaypirca belongs behind covalent BTK inhibitors). Prior to that, BRUIN CLL-321 demonstrated that Jaypirca was superior to investigator's choice of treatment, cutting the risk of relapse, disease progression or death by 46% in patients previously treated with at least one covalent BTK inhibitor.Lilly says BRUIN CLL-313 and BRUIN CLL-314 will form the basis of its planned global submissions later this year.Meanwhile, Merck & Co. is advancing its own non-covalent BTK inhibitor, nemtabrutinib, though it trails Jaypirca in development. The drug is in several Phase III studies, including BELLWAVE-011, which pits it against Imbruvica and AstraZeneca's Calquence (acalabrutinib) in first-line CLL/SLL. That study is slated for completion in the second half of 2032, according to ClinicalTrials.gov.

临床3期临床结果加速审批临床2期

2025-08-30

·药明康德

致敬时代 | 近90%患者癌细胞减少或几乎“全消失”！无需再依赖化疗，多款新型抗癌药为这类患者点亮希望

编者按：2025年，药明康德迎来创立25周年的重要里程碑。值此契机，我们向所有与我们共同书写产业变革篇章的科学家、医药人和投资者致以衷心感谢与诚挚敬意，也特别推出“致敬时代”系列，回顾全球同仁如何借助科学与合作的力量，不断拓展治疗边界、改善患者命运。四分之一个世纪的坚守，只为加速每一款新药的诞生。下一个25年，我们将继续心怀感恩与敬畏，依托独特的CRDMO模式，与全球伙伴携手同行，共赴健康未来。白血病是威胁人类生命的常见恶性血液肿瘤之一。但有一种白血病偶尔被人们称为“最轻的白血病”，那就是慢性淋巴细胞白血病（简称慢淋，CLL）。这是一种成熟B淋巴细胞克隆增殖性肿瘤，表现为外周血淋巴细胞增多。慢淋常见于中老年患者，大致可分为两类，有一种生长非常缓慢，患者往往无明显症状，在很长一段时间里不需药物治疗，只需定期找医生随诊；另一种则生长更快、也更严重。尤其是出现耐药和复发的患者，将面临更差的预后。在欧美国家，慢淋是最常见的白血病类型，大约占白血病总体患者的25%～30%。虽然慢淋在亚洲人群里发生率相对较低，但检出率及诊断率也在逐步上升。到目前为止，慢淋唯一可根治的手段就是异基因造血干细胞移植，但不幸的是，很多患者因为年龄、身体状况、供者等各方面原因，没机会接受这样的治疗。因此对大多数慢淋患者来说，治疗的目标是带病生存，能够长期维持在一个比较好的生活状态。图片来源：123RF 直到20世纪中叶，各类白血病依然缺乏有效的治疗手段。20世纪40年代，科学家们发现氮芥对慢性白血病等血液肿瘤有积极作用，白血病自此进入化疗时代。50~70年代，苯丁酸氮芥和环磷酰胺等烷化剂类药物的研发，让慢淋患者获得了30%~40%的缓解率。80~90年代，氟达拉滨等嘌呤类似物成为慢淋的主要治疗手段，让缓解率提升至50%左右。但化疗带来的细胞毒性等问题，依然影响着患者的生活质量。进入21世纪后，慢淋治疗有了非常大的突破，从传统的化疗走向了以靶向治疗为主的时代，还有层出不穷的新型治疗方案正改变着慢淋治疗的版图。作为全球医药及生命科学行业值得信赖的合作伙伴和重要贡献者，药明康德在25年发展历程中，很荣幸见证了多款慢淋新疗法从实验室到临床的突破历程，更通过提供一体化、端到端的新药研发和生产服务，助力全球合作伙伴加速多款慢淋创新疗法的研发进程，造福病患。今天这篇文章将再次回望近25年来慢淋新疗法的攻坚历程，向那些以勇气、坚持与热爱迎难而上的人们致敬。单克隆抗体疗法：开启靶向时代世纪之交，单克隆抗体疗法率先打破了慢淋治疗主要依赖化疗的局面。其中一个重要靶点是CD20。这是一种B细胞分化抗原，在95%以上的B细胞性淋巴瘤中表达，而在造血干细胞、血浆细胞和其他正常组织中不表达。 1997年，基因泰克（现为罗氏旗下子公司）与渤健共同开发的靶向CD20的利妥昔单抗（rituximab，商品名：Rituxan）问世，随后在各类癌症治疗领域都发挥了重要作用，也包括慢淋。科学家发现，利妥昔单抗与氟达拉滨等化疗药物联用比先后单独使用两款药物效果更好。2010年，利妥昔单抗的新适应症获FDA批准，与氟达拉滨和环磷酰胺联合用于治疗初治和既往经治的CD20阳性慢淋患者。利妥昔单抗的成功，也启发产业不断迭代以CD20为目标的单抗药物，例如由Genmab公司与诺华联合开发的第二代CD20单抗代表药物奥法妥木单抗（ofatumumab）。它是一款全人源化单抗，其结合的表位也与利妥昔单抗不同，主要用于对其它治疗或其它单抗不再有应答的患者。2009年，奥法妥木单抗获FDA批准（商品名：Arzerra），用于对氟达拉滨和阿仑珠单抗耐药的慢淋患者。如今，这两款药物均已成为慢淋的主要治疗药物。由GlycArt Biotechnology、罗氏旗下基因泰克与渤健共同开发、2013年获FDA批准用于慢淋的奥妥珠单抗（obinutuzumab，商品名：Gazyva）属于第三代CD20抗体。与前两款药物相比，它杀死慢淋细胞更直接、作用更强，并且早期试验已证实了该药可快速将B细胞从外周血细胞中清除出去。它可与化疗药物或靶向药物伊布替尼一起作为慢淋初治疗法，也可单独治疗复发或对其它治疗无应答的慢淋。除了上述几种单抗，还有针对CD52抗原的单抗药物阿仑珠单抗（alemtuzumab，商品名：Lemtrada）。它由拜耳与赛诺菲共同开发，2001年获美国FDA批准用于治疗对烷化剂和氟达拉滨耐药的进展期慢淋。 BTK抑制剂：伊布替尼惊艳问世，同类靶向药多点开花说到近十多年慢淋靶向疗法的发展，就不得不提到布鲁顿氏酪氨酸激酶（BTK）抑制剂。其中一款重磅新药战绩尤其辉煌，让慢淋化疗成为了历史——它，就是伊布替尼（ibrutinib），一度被称为“慢淋领域的格列卫”。这款新药背后，有着跌宕起伏的研发历程。 20世纪90年代，一种后来被命名为BTK的酪氨酸激酶进入了科学家的视野。BTK被发现在B细胞受体（BCR）信号通路中起着关键作用；而在慢淋的癌细胞里，BTK蛋白水平会出现异常升高。 BTK自然成为了B细胞恶性肿瘤中富有吸引力的一个治疗靶点，很多公司开始针对BTK设计具有激酶选择性的抑制剂，其中也包括Celera Genomics公司。 21世纪初，Celera公司在探索中孕育了一款靶向BTK并与之共价结合的小分子。由于共价药物可与人体内蛋白非选择性、不可逆、永久结合，一旦脱靶结合到正常的人体蛋白上，可能引起严重的毒副作用，这种潜在风险使共价药物一度成为药物研发的禁忌。因此，Celera公司最初并没有把它作为候选药物，而只是当作“工具化合物”协助BTK抑制剂的筛选。 2006年，一家名为Pharmacyclics的公司收购了这款在Celera公司没能得到充分重视的小分子。Pharmacyclics当时的首席执行官、血液肿瘤专家理查德·米勒（Richard Miller）博士敏锐地意识到了它在B细胞癌症中的潜力。尽管他和团队在B细胞淋巴瘤动物模型中证实了这款药物的活性，但很多研发人员对这款共价结合机制的药物仍然持犹疑态度。然而，很多患者正在死亡的边缘。米勒博士不愿意因为对“共价机制”的风险担忧，而让这些患者无止境地等下去。 2009年，这款小分子的1期临床试验启动了。2011年，Pharmacyclics公司报告了它在1b/2期试验中用于一系列B细胞恶性肿瘤的积极数据，不久后，强生旗下杨森制药（现更名为强生创新制药）也宣布与Pharmacyclics进行合作，共同研发这款新药。 2013年11月，以“伊布替尼”之名，这款不负众望的新药获FDA加速批准上市（商品名：Imbruvica）用于套细胞淋巴瘤的治疗。同一时期，它在慢淋中也表现出惊人的疗效，并在2014年2月获得FDA批准用于既往至少接受过一种治疗的慢淋患者。后续发表于2015年的3年随访结果显示，伊布替尼单药治疗就让90%的慢淋既往经治患者和84%的初治患者获得缓解，达到完全缓解的患者分别占7%和23%，总缓解率为88%。也就是说，近90%的患者肿瘤细胞数明显下降或几乎“全消失”。这是一个激动人心的结果，意味着患者可以摆脱对化疗的依赖。图片来源：123RF 更长期的8年随访研究表明，在经治和初治的慢淋患者中，伊布替尼的总缓解率分别高达89%和87%，分别有10%和35%的患者获得完全缓解，中位无进展生存期分别长达52个月和尚未达到，7年总生存率分别达到55%和84%。 2015年，艾伯维以高达210亿美元的金额收购了拥有伊布替尼的Pharmacyclics，与强生共同继续伊布替尼的研究工作。2016年3月，FDA批准了伊布替尼的第5个适应症，单药用于慢淋患者的一线治疗。这是FDA批准的首个“无化疗”慢淋一线治疗方案，意味着伊布替尼可替代化疗作为慢淋的一线治疗选择，是一个重要的里程碑。在推动此次获批的3期临床试验中，与化疗组相比，接受伊布替尼单药治疗的初治慢淋患者总缓解率达到82.4%，是前者（35.3%）的2倍多，无进展生存期显著延长，疾病进展或死亡风险降低84%。如今，伊布替尼已获FDA批准治疗10余项适应症，并成为多种血液肿瘤的一线治疗选择。目前伊布替尼已在全球100多个国家和地区获批，惠及全球超30万患者。此后，更多BTK靶向药物接连问世，让包括慢淋在内的B细胞恶性肿瘤患者的生活迎来了巨大改善。已获FDA批准的BTK抑制剂还包括由百济神州研发的泽布替尼（zanubrutinib），由礼来、Redx Pharma与LOXO Oncology共同开发、可破解共价BTK抑制剂耐药困局的首个非共价（可逆）BTK抑制剂匹妥布替尼（pirtobrutinib），以及由阿斯利康与Acerta Pharma共同开发的阿可替尼（acalabrutinib）。在中国获批用于慢淋的BTK抑制剂还有由诺诚健华与渤健共同研发的奥布替尼。其它靶向抑制剂：瞄准更多靶点随着医药科技的进步，还有更多重要靶点被发现、更多新的重磅药物诞生。与BTK类似，PI3K蛋白在多种B细胞恶性肿瘤中也存在过度表达的现象，而抑制PI3K不仅会影响BCR信号通路，还会对炎症、细胞信号传导和血管生成产生抑制，从而影响与肿瘤增殖有关的微环境。由ICOS与吉利德共同开发的艾代拉利司（idelalisib，商品名：Zydelig）是第一代口服PI3K-delta抑制剂。它于2014年获FDA批准上市治疗复发/难治性慢淋。它临床活性显著，可诱导细胞凋亡、抑制恶性B细胞系/原发肿瘤细胞系增殖，还能阻断多种信号通路，降低肿瘤细胞的生存能力。由Infinity Pharmaceuticals和Verastem共同开发的度恩西布（duvelisib，商品名：Copiktra）则是一款口服PI3K-delta和PI3K-gamma双重抑制剂。它于2018年获FDA批准用于治疗此前至少使用两种其它疗法的成人复发/难治性慢淋。其对PI3K-delta的抑制导致恶性肿瘤细胞凋亡，而对PI3K-gamma的抑制则减少了肿瘤微环境中支持细胞的分化和转移。 B细胞淋巴瘤因子-2（BCL-2）也是一个重要靶点。BCL-2可阻止细胞凋亡，并在某些类型癌症中过度表达，与耐药性的形成相关。比如由艾伯维与罗氏旗下基因泰克共同开发的维奈克拉（venetoclax，商品名：Venclexta），就是一种口服、选择性BCL-2抑制剂，通过选择性抑制BCL-2的功能，恢复细胞的通讯系统，让癌细胞自我毁灭，达到治疗肿瘤的目的。2016~2019年，维奈克拉先后获FDA批准了多项慢淋相关适应症。今年还有一款在中国获批慢淋适应症的BCL-2抑制剂——由亚盛医药研发的利沙托克拉。探索仍在继续过去25年间，美国FDA共批准了至少14款治疗慢淋的新疗法，除上述药物之外，还有2008年获批的化疗药物苯达莫司汀（bendamustine，商品名Treanda），以及2024年获批的靶向CD19的CAR-T细胞疗法lisocabtagene maraleucel（liso-cel，商品名Breyanzi）。药明康德很高兴能为其中多款疗法提供赋能、助力合作伙伴的这些创新疗法来到全球患者身边。为更好地提高慢淋患者的生活质量、解决药物长期使用带来的耐药等问题，产业圈仍在携手努力。当下还有近200款针对慢淋的新疗法正处于积极的临床研究中，有望在未来造福更多患者。其中多款药物已进入3期临床阶段，涵盖小分子靶向药和靶向蛋白降解剂等多种类型。比如由默沙东与ArQule共同研发的nemtabrutinib，近期研究证实其对BTK抑制剂耐药（包括携带BTK C481S突变）的复发或难治性慢淋患者有效，且在TP53异常亚组中仍有疗效，安全性可控。目前科学家正在进行一项3期试验，以评估这款新药对比维奈克拉+利妥昔单抗联合疗法的疗效。在抗击慢淋的漫漫旅途中，这些令人兴奋的成就源于科学家敢于挑战传统的洞见和勇气，也离不开转化医学中来自学术界和产业界的携手努力。最后，让我们再次向那些在慢淋治疗领域不懈探索的英雄们致以崇高的敬意。药明康德也期待与业界同仁继续同行，助力让更多创新疗法来到患者身边。参考资料： [1] Ponader, S., & Burger, J. A. (2014). Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. Journal of clinical oncology, 32(17), 1830-1839. https://doi-org.libproxy1.nus.edu.sg/10.1200/JCO.2013.53.1046 [2] The Wild Story Behind A Promising Experimental Cancer Drug. Retrieved Aug 27, 2025, from https://www.forbes.com/sites/davidshaywitz/2013/04/05/the-wild-story-behind-a-promising-experimental-cancer-drug/ [3] 打造一“键”封喉的共价抗癌药——专访北大深圳研究生院潘峥婴博士. Retrieved Aug 27, 2025, from https://www.wuximediaglobal.com [4] Pharmacyclics. Retrieved Aug 27, 2025 from https://www.pharmacyclics.com/home/who-we-are/history [5] Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., ... & O'Brien, S. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New England Journal of Medicine, 369(1), 32-42. DOI: 10.1056/NEJMoa1215637 [6] Johnson & Johnson, Pharmacyclics, Inc. Breakthrough Drug Wins FDA Approval. Retrieved Aug 27, 2025, from https://www.biospace.com/article/releases/johnson-and-johnson-pharmacyclics-inc-breakthrough-drug-wins-fda-approval-/ [7] The drug that may make chemo a thing of the past. Retrieved Aug 27, 2025, from https://www.mdanderson.org/publications/conquest/spring-2014/the-drug-that-may-make-chemo-a-thing-of-the-past.html [8] New Drug Application (NDA): 205552. Retrieved Aug 27, 2025 from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=205552 [9] 西安杨森. Retrieved Aug 27, 2025 from https://www.xian-janssen.com.cn/ [10]上海合全药业2018年度报告. Retrieved Aug 27, 2025 from http://pdf.dfcfw.com/pdf/H2_AN201903221308711829_1.pdf [11] AbbVie Completes Acquisition of Pharmacyclics. Retrieved Aug 27, 2025 from https://investors.abbvie.com/news-releases/news-release-details/abbvie-completes-acquisition-pharmacyclics [12] Ozcan, M., Lavie, D., Chaudhry, A., Zhou, X., Paydar, I., Farooqui, M. Z., & Ghia, P. (2024). BELLWAVE-010: A phase 3 study of nemtabrutinib plus venetoclax versus venetoclax plus rituximab (VR) in previously treated patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).https://doi-org.libproxy1.nus.edu.sg/10.1200/JCO.2024.42.16_suppl.TPS7089 [13] Thomas, X. (2013). First contributors in the history of leukemia. World Journal of Hematology, 2(3), 62-70. doi: 10.5315 / wjh.v2.i3.62 [14] Mehranfar, S., Zeinali, S., Hosseini, R., Akbarzadeh, A., Mohammadian, M., & Feizi, A. H. P. (2017). History of leukemia: diagnosis and treatment from beginning to now. Galen Medical Journal, 6(1), e702-e702. DOI: https://doi-org.libproxy1.nus.edu.sg/10.31661/gmj.v6i1.702 [15] Innovation of CLL Treatments: Chemotherapy Era - HealthTree for Chronic Lymphocytic Leukemia. Retrieved Aug 27, 2025 from https://healthtree.org/cll/community/articles/innovation-cll-treatment-chemotherapy-era [16] Rai, K. R., & Jain, P. (2016). C hronic lymphocytic leukemia (CLL)—Then and now. American journal of hematology, 91(3), 330-340. https://doi-org.libproxy1.nus.edu.sg/10.1002/ajh.24282 [17] Perez-Carretero, C., Gonzalez-Gascon-y-Marin, I., Rodriguez-Vicente, A. E., Quijada-Alamo, M., Hernandez-Rivas, J. A., Hernandez-Sanchez, M., & Hernandez-Rivas, J. M. (2021). The evolving landscape of chronic lymphocytic leukemia on diagnosis, prognosis and treatment. Diagnostics, 11(5), 853. doi: 10.3390/diagnostics11050853 [18] 慢性淋巴细胞白血病/小淋巴细胞淋巴瘤诊疗指南（2022年版）. Retrieved Aug 27, 2025 from https://www.nhc.gov.cn/yzygj/c100068/202204/0c1f7d3aca0545abbeb02030ce255930/files/1732863055385_61833.pdf [19] Troubled Infinity licenses cancer drug to Verastem | BioPharma Dive）. Retrieved Aug 27, 2025 from https://www.biopharmadive.com/news/Infinity-duvelisib-verastem-license/429724/ [20] 中国抗癌协会血液肿瘤专业委员会,中华医学会血液学分会,中国慢性淋巴细胞白血病工作组,(2025). 中国慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的诊断与治疗指南（2025年版）. 中华血液学杂志,46(02)：105-112.DOI:10.3760/cma.j.cn121090-20241209-00551 [21]IMBRUVICA® (ibrutinib) Pooled Outcomes Data from Three Phase 3 Studies Suggest Potential Clinical Efficacy in Patients with High-Risk Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) . Retrieved Aug 27, 2025 from https://www.prnewswire.com/news-releases/imbruvica-ibrutinib-pooled-outcomes-data-from-three-phase-3-studies-suggest-potential-clinical-efficacy-in-patients-with-high-risk-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll-300457242.html [22]de Claro, R. A., McGinn, K. M., Verdun, N., Lee, S. L., Chiu, H. J., Saber, H., ... & Pazdur, R. (2015). FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clinical Cancer Research, 21(16), 3586-3590. [23] Byrd, J. C., Furman, R. R., Coutre, S. E., Burger, J. A., Blum, K. A., Coleman, M., ... & O'Brien, S. (2015). Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, The Journal of the American Society of Hematology, 125(16), 2497-2506. https://doi-org.libproxy1.nus.edu.sg/10.1182/blood-2014-10-606038 [24] Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K., ... & O'Brien, S. (2020). Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib/II PCYC-1102 study. Clinical Cancer Research, 26(15), 3918-3927. https://doi-org.libproxy1.nus.edu.sg/10.1158/1078-0432.CCR-19-2856 [25] IMBRUVICA® (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia. Retrieved Aug 27, 2025 from https://news.abbvie.com/2016-03-04-IMBRUVICA-ibrutinib-Approved-by-U-S-FDA-for-the-First-line-Treatment-of-Chronic-Lymphocytic-Leukemia [26] The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy | PNAS. Retrieved Aug 27, 2025 from https://www-pnas-org.libproxy1.nus.edu.sg/doi/10.1073/pnas.1004594107 [27] Byrd, J. C., Blum, K. A., Burger, J. A., Coutre, S. E., Sharman, J. P., Furman, R. R., ... & O'Brien, S. M. (2011). Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study. Journal of Clinical Oncology, 29(15_suppl), 6508-6508. [28] Phase Ib/II Study of the Activity and Tolerability of the Bruton’s Tyrosine Kinase Inhibitor PCI-32765 in CLL/SLL | Research To Practice. Retrieved Aug 27, 2025 from https://www.researchtopractice.com/index.php?q=5MJCASCO2011/CLL/1 [29] Pharmacyclics Forms Pact to Develop and Commercialize PCI-32765 for Hematologic Cancers with Janssen Biotech, Inc. (prnewswire.com) . Retrieved Aug 27, 2025 from https://www.prnewswire.com/news-releases/pharmacyclics-forms-pact-to-develop-and-commercialize-pci-32765-for-hematologic-cancers-with-janssen-biotech-inc-135271818.html [30] Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., ... & Fowler, N. H. (2012). Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of Clinical Oncology, 31(1), 88-94. doi: 10.1200/JCO.2012.42.7906 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床研究

2025-06-23

·精准药物

BTK，卷出新机遇

近日，云顶新耀公布新型BTK抑制剂1b/2a期临床结果，针对自身免疫性肾脏疾病。这意味着BTK抑制剂在完成血液肿瘤领域的迭代升级后，正以不可阻挡之势“卷”入自免新战场。作者｜momo 01 迭代加快布鲁顿酪氨酸激酶（BTK）作为B细胞受体（BCR）信号通路的核心枢纽，其异常活化是驱动多种B细胞恶性肿瘤（如CLL、MCL、WM）生长的关键因素。由于BTK在B细胞及部分造血细胞（如巨噬细胞、肥大细胞）中特异性表达，而在T细胞中缺失，使其成为极具潜力的精准靶点。BTK抑制剂正是通过高特异性结合BTK，阻断其自身磷酸化及活化，从而切断致癌信号传导，诱导肿瘤细胞凋亡（图1）。图1.BCR信号是B细胞存活的重要信号通路自2013年第一代抑制剂伊布替尼获批至今，BTK抑制剂的发展呈现出显著的迭代加速特征，其核心驱动力直指临床亟待解决的痛点。伊布替尼的诞生具有里程碑意义，它引领B细胞恶性肿瘤治疗进入“无化疗时代”。然而，其选择性不足导致脱靶抑制（如EGFR、TEC、BMX等），引发皮疹、房颤、腹泻和高血压等显著副作用，成为临床应用的主要掣肘（表1）。表1.全球已上市 BTK 抑制剂这一缺陷迅速催生了第二代BTK抑制剂的密集研发与上市，通过结构优化大幅提升对BTK的选择性，有效减轻脱靶效应，显著改善了治疗安全性。当通过与BTK活性位点的Cys481形成不可逆共价结合的第一、二代共价BTK抑制剂成为CLL/SLL等疾病的标准治疗并展现优于化疗的无进展生存期（PFS）获益时，耐药性问题浮出水面。Cys481位点突变（在MCL和高危CLL/SLL中发生率更高）导致药物结合失效，成为患者疾病进展的主要原因。这一难题直接推动了第三代非共价可逆BTK抑制剂的突破性进展。它们无需依赖Cys481结合，通过可逆方式抑制BTK，成功绕开了共价抑制剂的主要耐药机制，为耐药患者提供了关键解决方案（表1）。图2.全球 BTK 抑制剂销售额（亿美元）（左）BTK 抑制剂全球市场规模（亿美元）（右）此外，市场动态是这一快速迭代最直观的印证。伊布替尼曾长期主导市场，其全球销售额连续四年超80亿美元，但近年已出现连续下滑。与此同时，第二代产品如阿可替尼和泽布替尼展现出强劲增长势头。根据Deutsche Bank Report 2022 数据，BTK抑制剂全球市场仍处于扩张期，预计2026年规模将达204亿美元（图2）。这一此消彼长的格局清晰表明，更安全、更有效的迭代产品正快速赢得临床认可。 02 肿瘤激战当前BTK药物在肿瘤领域竞争已进入白热化阶段。截至目前，全球处于临床阶段的BTK抑制剂候选药物多达40种，但其中仅默沙东的非共价可逆抑制剂Nexitamubtin（奈他布替尼）进展到III期临床（图3）。这种研发火热但临床转化艰难的局面，为现有的六款上市药物巩固市场地位提供了时间，同时也迫使企业寻求差异化策略以建立竞争优势。图3.BTK抑制剂重点药物当前竞争的核心，聚焦于新一代（三代）BTK抑制剂的正面较量。礼来凭借目前唯一上市的三代药物吡托布鲁替尼率先发力。该药采用非共价结合机制，有望克服约30%患者因BTK C481S突变而产生的耐药性问题。礼来正通过一系列积极的头对头III期临床试验发起攻势：在套细胞淋巴瘤（MCL）领域，同时挑战伊布替尼、阿卡替尼和泽布替尼这三款“前辈”；在慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）领域，则直接对标伊布替尼。更显雄心的是，礼来还在探索吡托布鲁替尼挑战CD20单抗作为一线治疗的潜力，试图改变现有的治疗模式。另外，默沙东的三代候选药物Nemtabrutinib的II期数据已展现出竞争力：在CLL/SLL患者中客观缓解率（ORR）达到56%，边缘区淋巴瘤（MZL）患者ORR高达64%，MCL联合治疗的ORR也达到64%，为其即将参与的市场争夺打下了基础。正当小分子药物激战正酣之时，百济神州的BTK降解剂BGB-16673凭借全新的作用机制开辟了另一条战线（图4）。这款PROTAC药物通过招募E3泛素连接酶来诱导BTK蛋白降解，从源头上解决耐药蛋白累积的问题。图4.BTK CDAC有望成为cBTKi后同类最佳MOA其早期临床数据令人瞩目：在I期CaDAnCe-101研究中，经过大量前期治疗的CLL患者ORR达到78%，在200mg剂量组更飙升至94%；华氏巨球蛋白血症（WM）患者ORR为90%，边缘区淋巴瘤（MZL）患者ORR更是达到100%。基于这些积极结果，百济神州于2025年5月启动了BGB-16673头对头挑战吡托布鲁替尼的III期研究，随着头对头临床试验数据的陆续揭晓，真正的赢家将逐渐浮出水面。 03 进军自免BTK抑制剂这一在血液肿瘤领域缔造了巨大商业价值的靶向疗法，正强势进军自免这片“兵家必争之地”。目前全球共有33款针对自免的在研BTK抑制剂，其适应症聚焦于多发性硬化症（MS）、慢性自发性荨麻疹（CSU）、系统性红斑狼疮（SLE）及类风湿性关节炎（RA）等核心领域，一场围绕BTK靶点的差异化开发竞赛已然擂鼓喧天。其中，诺华的Remibrutinib作为“先锋”，已在国内提交上市申请，剑指CSU。其关键III期研究（REMIX-1和REMIX-2）数据确证了显著疗效：经治CSU患者接受瑞米布替尼（25mg，每日2次）治疗12周后，关键指标如每周荨麻疹活动度评分（UAS7）、瘙痒严重程度评分（ISS7）和荨麻疹严重程度评分（HSS7）均较安慰剂组显著下降。图5.Remibrutinib治疗难治性CSU的III期临床研究结果更令人鼓舞的是，据《新英格兰医学杂志》公布的III期结果（图5），治疗第1周即可快速减轻瘙痒和荨麻疹症状，至第24周约30%患者症状完全消失，第52周时近半数患者实现无瘙痒和荨麻疹症状。诺华选择CSU这一存在大量抗组胺药应答不佳患者的领域作为突破口，成功开辟了差异化路径。几乎同期，赛诺菲的Rilzabrutinib（图6）在免疫性血小板减少症（ITP）领域取得关键进展。其针对持续性或慢性ITP成年患者的III期LUNA 3研究达到主要终点，与安慰剂组相比，Rilzabrutinib组实现持久血小板应答的患者比例显著更高（23% vs 0%，p<0.0001）。该药已获美国FDA优先审评，国内上市申请亦于2024年12月30日获受理，有望成为首个获批治疗ITP的BTK抑制剂。图6.Rilzabrutinib作用机制除上述临近上市的“排头兵”外，更多药企正依托BTK靶点的广泛适用性，在各自免细分领域进行纵深布局，构建多层次竞争格局。罗氏的口服、可逆、非共价BTK抑制剂Fenebrutinib，凭借其穿透血脑屏障的独特优势，在多发性硬化症（MS）领域展现出潜力。其II期FENopta开放标签扩展研究显示，接受治疗长达1年的复发性MS患者中96%疾病无复发，残疾状况未进展，III期结果预计2025年底公布；而赛诺菲的另一款产品Tolebrutinib同样瞄准MS，其III期HERCULES研究显示对非复发性继发进展型MS（SPMS）患者残疾进展延缓31%，但在复发性MS的两项III期研究中未达显著降低年复发率的主要终点；云顶新耀开发的EVER001则聚焦自身免疫性肾脏疾病，进一步拓宽了BTK抑制剂在自免领域的治疗疆域。结语从血液肿瘤到自身免疫疾病，BTK抑制剂通过跨领域“内卷”持续拓展治疗边界，重塑全球药物研发格局。参考资料[1]Cool, Allison et al. “BTK inhibitors: past, present, and future.” Trends in pharmacological sciences vol. 45,8 (2024): 691-707. [2]https://www-nejm-org.libproxy1.nus.edu.sg/doi/pdf/10.1056/NEJMoa2408792[3]平安证券研报[4]财通证券研报[5]各企业官网及各种公开资料等声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床1期引进/卖出临床结果

100 项与 Nemtabrutinib 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
B细胞淋巴瘤	临床3期	美国	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	阿根廷	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	澳大利亚	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	比利时	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	巴西	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	加拿大	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	智利	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	哥伦比亚	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	法国	Merck Sharp & Dohme LLC	2023-08-08
B细胞淋巴瘤	临床3期	德国	Merck Sharp & Dohme LLC	2023-08-08

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04728893 (BELLWAVE-003, EHA2025)	临床2期	难治性滤泡性淋巴瘤	49	Nemtabrutinib 65 mg PO QD	鹹獵鬱觸製獵憲廠鏇餘(鬱觸鹹鬱積淵選顧膚夢) = Any-grade adverse events (AEs) occurred in 45 participants (92%) 鬱鏇衊淵願觸遞膚襯襯 (製繭衊鹽遞憲窪鑰鬱襯 ) 更多	积极	2025-05-14
NCT04728893 (BELLWAVE-003, EHA2025)	临床2期	难治性边缘区淋巴瘤	-	Nemtabrutinib 65 mg QD	選鏇繭鏇艱製鏇築積構(窪製觸鬱衊簾鹽獵齋網) = 20 pts (91%) experienced any grade adverse events (AEs) 顧夢構鹹網鏇淵鬱網衊 (構遞鏇獵鬱淵簾鏇顧廠 ) 更多	积极	2025-05-14
NCT04728893 (BELLWAVE-003, ASH2024) 人工标引	临床2期	边缘区B细胞淋巴瘤	12	Nemtabrutinib 65 mg	膚遞鹽遞夢窪築顧鑰衊(鹹鬱壓顧簾顧遞鏇範獵) = 壓憲選壓鹽選餘遞範鹽醖鏇餘積構鑰艱鑰鬱製 (選壓鹹膚鑰鑰衊憲獵夢, 31 ~ 89) 更多	积极	2024-12-08
ASH2024	N/A	滤泡性淋巴瘤	-	Nemtabrutinib 65 mg once daily	築範蓋觸鑰襯壓範鹹蓋(衊襯糧壓繭憲鏇壓襯顧) = Any-grade adverse events (AEs) occurred in 31 (86%) pts, most commonly neutropenia in 10 (28%) pts, decreased platelet count (8 [22%], and anemia (7 [19%]) 獵願鹹衊糧餘繭築蓋網 (憲鑰壓淵齋廠齋醖夢鑰 ) 更多	-	2024-12-07
NCT03162536 (MK-1026-001, Pubmed) 人工标引	临床1期	慢性淋巴细胞白血病 \| B细胞淋巴瘤三线 C481S mutant BTK	47	nemtabrutinib 65 mg	窪齋網製範顧鑰齋蓋願(糧鏇鏇壓獵簾鏇憲觸糧) = 糧積淵餘獵鏇製築鹽繭膚願蓋選觸衊醖糧築繭 (淵醖廠獵衊範積餘蓋蓋 ) 更多	积极	2024-01-12
NCT03162536 (BELLWAVE-001, ICML2023)	临床1/2期	B细胞淋巴瘤 C481S-mutant BTK	112	Nemtabrutinib 65 mg	鏇醖繭壓襯膚憲齋糧醖(壓鬱淵獵顧淵積廠餘願) = 齋鬱選夢顧鹽醖網繭積鑰糧築糧鏇壓獵餘夢鬱 (餘餘齋繭憲蓋醖憲選選, 42 ~ 69) 更多	积极	2023-06-09
NCT04728893 (MK-1026-003 \| 1026-003 \| BELLWAVE-003, ASCO2023)	临床2期	血液肿瘤	450	Nemtabrutinib 80 mg QD	選願鬱簾簾顧範顧鑰願(獵繭艱淵壓壓夢顧積鹽) = 鏇繭積憲繭積鬱顧艱夢憲淵鏇淵鑰積築築艱淵 (襯蓋廠獵簾夢願艱鬱糧 )	-	2023-05-31
	临床2期	血液肿瘤	450	Nemtabrutinib 65 mg QD	選願鬱簾簾顧範顧鑰願(獵繭艱淵壓壓夢顧積鹽) = 襯窪簾繭鹽醖齋齋憲蓋憲淵鏇淵鑰積築築艱淵 (襯蓋廠獵簾夢願艱鬱糧 )	-	2023-05-31
NCT03162536 (1026-001 \| ARQ 531-101 \| Bellwave-001 \| MK-1026-001, ASH 12022 \| ASH 22022) 人工标引	临床1/2期	慢性淋巴细胞白血病三线	57	Nemtabrutinib (CLL/SLL)	繭積鹽鬱願繭積鏇鏇遞(繭積壓襯築築壓糧鏇淵) = 鹽鏇鏇醖鬱蓋選廠顧窪繭觸鏇顧構夢鹽醖齋製 (選糧鬱窪鹹淵壓齋鬱壓, 42 ~ 69) 更多	积极	2022-11-15
	临床1/2期	慢性淋巴细胞白血病三线	57	Nemtabrutinib (overall)	顧齋築齋膚鑰鹽壓網築(鏇構觸夢艱製膚繭醖鏇) = 鏇選糧製積範醖製簾膚夢醖積鏇遞積鑰鹽選積 (衊範簾襯膚襯夢簾構壓 ) 更多	积极	2022-11-15
NCT03162536 (1026-001 \| ARQ 531-101 \| BELLWAVE-001 \| MK-1026-001, EHA2022)	临床2期	慢性淋巴细胞白血病	118	Nemtabrutinib	積艱願廠鹽遞願鏇廠構(餘積範廠夢艱襯膚選獵) = 獵窪艱艱艱餘選積鏇淵鹽餘衊夢壓範繭蓋顧壓 (夢選築襯壓膚觸鬱構夢 )	-	2022-05-12
NCT03162536 (1026-001 \| ARQ 531-101 \| MK-1026-001, AACR2018)	临床1期	慢性淋巴细胞白血病	-	ARQ 531	齋觸網繭鬱鬱範醖醖襯(選觸簾襯衊蓋繭願積顧) = 願繭遞鹽壓築願壓製願餘網膚窪鏇鹽願壓齋齋 (鑰構憲衊淵糧鹽製顧廠 )	-	2018-07-01