Open, Single Arm, Multicenter, Phase 2 Trial to Evaluate Efficacy and Safety of NB02 (Poseltinib) Combined with Rituximab and Lenalidomide As a Salvage Therapy for Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

An Open, Single treatment arm, Multi-center, Prospective, Phase 2 Trial to Evaluate Efficacy and Safety of NB02 (Poseltinib) combined with Rituximab and Lenalidomide as a Salvage Therapy for Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

开始日期2024-11-25

申办/合作机构

NOBO Medicine Inc.

KCT0008105

/ Not yet recruitingN/AIIT

Chemotherapy-free salvage therapy with rituximab, lenalidomide, and poseltinib for the treatment of relapsed or refractory primary central nervous system lymphoma

开始日期2023-02-01

申办/合作机构-

JPRN-jRCT2080223586

/ Unknown status临床2期

A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects With Rheumatoid Arthritis: The RAjuvenate Study (I8K-MC-JPDA)

开始日期2017-07-10

申办/合作机构

Eli Lilly Japan KK

100 项与珀舍替尼相关的临床结果

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100 项与珀舍替尼相关的转化医学

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100 项与珀舍替尼相关的专利（医药）

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项与珀舍替尼相关的文献（医药）

2024-01-03·MOLECULAR CANCER THERAPEUTICS

Bruton's Tyrosine Kinase Inhibitors with Distinct Binding Modes Reveal Differential Functional Impact on B-Cell Receptor Signaling

Article

作者: Lundgaard, Greta ; Tse, Chris ; Yoon, Woo Hyun ; Gururaja, Tarikere ; Pan, Chin ; Liu, Jing ; Li, Wei ; Souers, Andrew J. ; Sano, Renata ; Wang, Longcheng ; Zhai, Yongjiao ; Lee, Chih-Hung ; Yang, Muhua ; DeAnda, Felix ; Apatira, Mutiah

Abstract:

Small molecule inhibitors of Bruton's tyrosine kinase (BTK) have been approved for the treatment of multiple B-cell malignancies and are being evaluated for autoimmune and inflammatory diseases. Various BTK inhibitors (BTKi) have distinct potencies, selectivity profiles, and binding modes within the ATP-binding site. On the basis of the latter feature, BTKis can be classified into those that occupy the back-pocket, H3 pocket, and the hinge region only. Hypothesizing that differing binding modes may have differential impact on the B-cell receptor (BCR) signaling pathway, we evaluated the activities of multiple BTKis in B-cell lymphoma models in vitro and in vivo. We demonstrated that, although all three types of BTKis potently inhibited BTK-Y223 autophosphorylation and phospholipase C gamma 2 (PLCγ2)-Y1217 transphosphorylation, hinge-only binders were defective in inhibiting BTK-mediated calcium mobilization upon BCR activation. In addition, PLCγ2 activation was effectively blocked by back-pocket and H3 pocket binders but not by hinge-only binders. Further investigation using TMD8 cells deficient in Rac family small GTPase 2 (RAC2) revealed that RAC2 functioned as a bypass mechanism, allowing for residual BCR signaling and PLCγ2 activation when BTK kinase activity was fully inhibited by the hinge-only binders. These data reveal a kinase activity–independent function of BTK, involving RAC2 in transducing BCR signaling events, and provide mechanistic rationale for the selection of clinical candidates for B-cell lymphoma indications.

2022-02-01·Drug metabolism and pharmacokinetics4区 · 医学

BTK-inhibitor drug covalent binding to lysine in human serum albumin using LC-MS/MS

4区 · 医学

Article

作者: Gu, Chungang ; Muste, Cathy

Irreversible Bruton's tyrosine kinase (BTK) inhibitor drugs are designed to bind covalently to a free-thiol cysteine in the BTK protein active site. However, these reactive drugs bind to off-target proteins as well. In this study, seven BTK-inhibitor drugs containing acrylamide warheads were incubated with human serum albumin (HSA) and analyzed using an LC-MS/MS peptide mapping approach to determine the amino acid sites of drug covalent binding. Significant adduction at the free-thiol cysteine of HSA was only observed for two of the drugs. However, significant adduction was observed for at least four lysine residues. This is just a small percentage of the 59 total lysine residues in HSA. These four lysine residues are likely partially buried, accessible to the drugs, and exist at least partially in a neutral state. The levels of adduction observed in the in-vitro experimental conditions are only indicative of a relative propensity for adduction with the individual lysine residues of HSA, and are not in-vivo predictions. Widespread off-target lysine binding could impact clearance and bioavailability for irreversible inhibitor drugs. However, the extent of the impact on clearance may be limited in comparison to conjugation with glutathione.

2022-01-01·Current research in chemical biology

Discovery of a potent BTK and IKZF1/3 triple degrader through reversible covalent BTK PROTAC development

Article

作者: Cheng, Ran ; Wang, Meng C ; Qi, Xiaoli ; Guo, Wen-Hao ; Wang, Jin ; Yu, Xin ; Monroy, Erika Y ; Lin, Hanfeng ; Lu, Dong ; Ding, Lang ; Jin, Feng

Building on our previous work on ibrutinib-based reversible covalent Bruton's tyrosine kinase (BTK) PROTACs, we explored a different irreversible BTK inhibitor poseltinib as the BTK binder for PROTAC development. Different from ibrutinib, converting the irreversible cysteine reacting acrylamide group of poseltinib to a reversible covalent cyano-acrylamide group dramatically decreases the binding affinity to BTK by over 700 folds. Interestingly, one of the reversible covalent BTK PROTACs based on poseltinib with a rigid linker, dubbed as PS-RC-1, is highly potent (IC₅₀ = ~10 nM) in Mino cells but not in other mantle cell lymphoma (MCL) cell lines, such as Jeko-1 and Rec-R cells. We showed that PS-RC-1 potently induces degradation of IKZF1 and IKZF3 but not BTK or GSPT1, accounting for its toxicity in Mino cells. We further decreased the molecular size of PS-RC-1 by shrinking the BTK binding moiety and developed PS-2 as a potent BTK and IKZF1/3 triple degrader with high specificity.

项与珀舍替尼相关的新闻（医药）

2023-04-28

·FierceBiotech

Joe Jimenez's Aditum finds fresh twist on old idea, paying $10M for autoimmune BTK inhibitor

Joe Jimenez, co-founder and managing director of Aditum Bio Joe Jimenez’s VC fund has ponied up $10 million to try to crack a nut that defeated a who’s who of top drug developers. The outlay gives the fund, Aditum Bio, near-global rights to a BTK inhibitor with a twist, which is in development in autoimmune diseases including rheumatoid arthritis. A push to treat rheumatoid arthritis by targeting the kinase sputtered in the wake of the failure of assets such as Eli Lilly’s poseltinib and faltered further when AbbVie’s bid to combine inhibition of BTK and JAK also came up short. Expectations that BTK offers a route to a better rheumatoid arthritis drug have fallen to such an extent that The Lancet Rheumatology recently ran a comment piece titled “Et tu, Brutinib? Demise of a kinase target in rheumatoid arthritis?” Against that backdrop, the VC fund set up by Jimenez and Mark Fishman, respectively the former CEO of Novartis and president of the Novartis Institutes for BioMedical Research, has bet $10 million upfront on a preclinical BTK program and created a biotech to take it into the clinic. The deal, which is worth up to $477 million once milestones are factored in, gives the Aditum VC fund near-global rights to DWP213388. Developed by Korea’s Daewoong Pharmaceutical, the molecule is a dual inhibitor of BTK and ITK. The targets are implicated in the activation of B cells and T cells, suggesting the molecule may have synergistic therapeutic efficacy that improves on the lackluster performance of BTK inhibitors in some indications to date. Aditum Bio has bought into the idea. Aditum Bio has created Vitalli Bio, its ninth portfolio company, to take the drug candidate into the clinic. Human tests of the oral molecule, now renamed VIT-801, are expected to start later this year. Daewoong received FDA clearance to study the drug in humans last year. “VIT-801 has a unique profile that selectively inhibits a range of relevant immune cells, suggesting it has the potential to represent a safe and effective alternative in these difficult to treat populations,” Jimenez and Fishman said in a statement. The VC fund said VIT-801 may have “a best-in-class profile in immune disorders where multiple cell types are implicated.” The phase 1 study will mark the start of efforts to translate the signs of efficacy seen in animal studies into humans. Daewoong has presented data showing the candidate improved arthritis in mice, and “the inhibitory effect was more potent than selective BTK inhibitor.” Histological damage in the ankles and knees of mice “markedly improved” after treatment with the dual inhibitor. Daewoong published the arthritis mouse data in 2018 and released more results in a preclinical model of graft-versus-host disease the next year.

临床1期临床申请

2022-07-07

·生物制药小编

37亿美金的教训：BTK抑制剂治疗自身免疫疾病，到底行不行？

过高的期待，在创新药研发领域从来不是好事。BTK抑制剂在肿瘤治疗领域取得了空前成功，2021年市场规模接近110亿美金。这款“重磅炸弹”产品，也是支撑百济神州、诺诚健华等头部创新药企估值的关键。鉴于此，药企们希望将BTK的成功复制到自身免疫疾病领域。海外巨头包括赛诺菲、罗氏、阿斯利康，国内包括诺诚健华、杏联药业等企业纷纷重金入局。但失败却接踵而至。日前，赛诺菲的BTK抑制剂PRN2246，在治疗多发性硬化症和重症肌无力的3期临床中，因出现多例药物引发的肝损伤副作用，而被FDA叫停临床试验。若PRN2246最终研发遇阻，将是赛诺菲在BTK抑制剂自身免疫疾病攻坚战中，遭遇的第二次失利。对赛诺菲来说，这将会是一个不小的打击，因为收购两款BTK抑制剂，公司付出了36.8亿美元。由此，还带出了一个更大的悬念：BTK抑制剂，真能治疗自身免疫疾病吗？/ 01 /36.8亿美金，豪赌BTK抑制剂自免把时间拉回到3年前。考虑到拳头产品专利到期的影响，赛诺菲开始未雨绸缪，重金布局BTK领域，希望找到下一个免疫大单品。2017年11月，赛诺菲与Principia公司达成7.65亿美金的战略合作，拿下了Principia的两款BTK抑制剂PRN1008和PRN2246。两款BTK抑制剂的设计思路不同。PRN1008旨在与BTK酶形成可逆的共价键，增强选择性和持久效力，用于治疗天疱疮等免疫疾病；PRN2246则是拥有较强的穿透血脑屏障的能力，针对多发性硬化症等中枢神经系统感染的疾病。BTK （布鲁顿酪氨酸激酶）作为一种非受体酪氨酸激酶，在各种细胞表面受体(主要包括BCR)的信号传导中发挥核心作用。比如，在B细胞癌变之后，BTK会变得异常活跃，从而刺激B细胞肿瘤生长。因此，BTK抑制剂在针对B细胞的肿瘤中，能够起到较好的治疗作用。与此同时，B细胞、巨噬细胞及小胶质细胞等同时也参与自身免疫性疾病病理过程。因此，对这些免疫细胞的发育和功能都非常重要的BTK，也有望成为免疫疾病治疗的新靶点。若BTK抑制剂在自身免疫疾病领域的适应症成功开拓，无疑会成为印钞机，也有助于帮助赛诺菲成功实现管线的“交接班”。由于自身免疫疾病难以治愈，因此普遍存在用药周期长的特点，市场前景较为乐观。这一点，赛诺菲有过充分感受。在相对不错的疗效下，其治疗多发性硬化症的产品特立氟胺上市后，销售额逐年攀升，近4年均超过20亿美元。随着PRN1008、PRN2246的2期临床数据表现优异，赛诺菲与Principia的合作加码，2020年斥资26.8亿美元将Principia收入麾下。彼时，Principia的市值一直在16亿美金附近徘徊。高溢价收购背后，无疑是赛诺菲对Principia的高期待。/ 02 /无疗效+安全性问题，或引发两次“失利”遗憾的是，赛诺菲至今还没看到豪赌胜利的曙光，反倒是负面消息接二连三。最先“失利”的，是PRN1008开发的天疱疮适应症。作为一种罕见的慢性皮肤病，天疱疮对不依赖大量使用皮质类固醇的安全、快速起效的治疗手段，有极大的需求尚未得到满足。此前，PRN1008在2期临床中展示出不错的治疗效果。在接受3个月时间的治疗后，大约25%的患者完全缓解。不过，随着3期临床将受试者规模放大后，PRN1008的疗效数据被证伪：2021年9月份公布的3期研究结果显示，PRN1008与安慰剂达到完全缓解的患者比例无显著差异，试验未达到主要终点。虽然赛诺菲依旧信心满满，表示PRN1008还有可能在其它免疫疾病领域拥有巨大潜力。但赛诺菲还未能等来PRN1008的好消息，PRN2246的安全性问题则先降临。2022年6月30日，FDA暂停了PRN2246在多发性硬化症和重症肌无力的开展的3期临床试验，原因是出现多例药物引发的肝损伤副作用。不过，这并不意味着PRN2246的研发失败了。赛诺菲并未透露有多少患者受到影响，只说这是“数量有限的病例”。并且，赛诺菲表示，这些肝损伤的患者，很大程度上是因为自身有并发症，导致更容易出现药物性肝损伤；另外肝损伤也是可逆的，在停药后可进行恢复。最重要的是，该产品在美国之外的临床入组，仍可按计划进行。这也意味着，PRN2246后续的临床开发，或许不会受到太大影响。至于结果如何，最终还需要赛诺菲更为详细的临床数据证明自己。毕竟，自身免疫疾病药物需要长期服用，安全性尤为关键。/ 03 /巨头接连受挫，还会有下一个吗？实际上，关于赛诺菲的接连“失利”，既在意料之外，又在情理之中。新药研发充满不确定性，即使2期临床表现优异，也难保证最终的成功。更何况，在赛诺菲之前，包括新基、阿斯利康、礼来和罗氏等在内，已经有多家巨头的BTK抑制剂，在自身免疫疾病领域遭遇打击。如上图所示，核心原因无外乎两点，没有效果和过高的副作用。其中，效果不佳是核心原因。比如，2018年礼来宣布终止引进产品Poseltinib治疗类风湿关节炎的临床，理由是期中分析显示缺乏疗效。再比如，尽管罗氏表示其BTK抑制剂Fenebrutinib在治疗红斑狼疮中，有证据表明起到通路抑制作用，但最终的疗效依然差强人意……探索者们的接连失利，将矛头直接指向了BTK抑制剂治疗自身免疫疾病的“无效说”。BTK抑制剂可以治疗肿瘤的原因，是因为其可以抑制新的B细胞生成，从而阻止疾病进展。但这一机制，对于自身免疫疾病或许不管用。因为BTK抑制剂对现有的B细胞没有攻击力，而现有病变的B细胞等免疫细胞，才是造成免疫疾病的罪魁祸首。这种情况下，抑制新的B细胞生成机制，就有几分“马后炮”的意思了。“无效说”也由此而来。安全性问题还可以想办法改进，一旦治疗机制遭遇挑战，那无疑将对现有所有参与者造成重大打击，甚至堵死BTK抑制剂治疗自身免疫疾病的道路。那么，真相究竟是什么？期待更多参与者早日告诉大家答案。文／黄恺免责声明:本文（报告）基于已公开的资料信息或受访人提供的信息撰写，但氨基观察及文章作者不保证该等信息资料的完整性、准确性。在任何情况下，本文（报告）中的信息或所表述的意见均不构成对任何人的投资建议。

创新药专利到期免疫疗法合作并购

2018-02-19

·BioSpace

Eli Lilly and Hanmi Shutter a Failed Phase II RA Trial

Eli Lilly and its Korean collaborative partner Hanmi stopped a Phase II trial on an experimental rheumatoid arthritis treatment following less-than-stellar interim results. Eli Lilly and Company and its Korean collaborative partner Hanmi Pharmaceutical, Co., Ltd stopped a Phase II trial on an experimental rheumatoid arthritis treatment after less-than-stellar interim results were examined. Although Lilly has remained mum on the trial’s halting, Hanmi broke the news in a regulatory filing , according to Korea Biomedical Review . In a regulatory filing, Hanmi said Lilly opted to discontinue the trial after interim results showed a lack of efficacy. Lilly and Hanmi were studying the effects of a Bruton’s tyrosine kinase (BTK) inhibitor (LY3337641/HM71224) in patients with rheumatoid arthritis. Lilly and Hanmi forged a collaborative agreement for HM71224 in 2015. When the two companies struck the deal worth up to $690 million , they said that in addition to RA the drug would also be explored as a potential treatment for lupus, lupus nephritis, Sjögren’s syndrome, and other related conditions. In its filing Hanmi said the two companies are still looking to develop the drug for those other conditions, Korea BioMedical Review noted in its report today. At the time the two companies struck the deal they expressed hope for HM71224 to have an effect on prevalent autoimmune diseases. “We’re highly encouraged by the potential of HM71224 to deliver an innovative, first-in-class treatment option,” Eli Lilly said at the time the 2015 deal was struck. Shares of Hanmi Pharmaceuticals, which trades on the Korean Stock Exchange, fell about 9 percent on the news of the failure. Hanmi has several developmental partnerships in addition to the collaboration with Eli Lilly. While Hanmi said it will continue to work with Eli Lilly, if the Indianapolis-based company opts to walk away completely it won’t be the first time that’s happened to Hanmi. In October 2016 Boehringer Ingelheim walked away from its $730 million partnership with Hanmi over safety concerns of the cancer drug olmutinib. Rheumatoid arthritis affects an estimated 23.7 million people worldwide. The condition is a chronic inflammatory condition characterized by pain, swelling of the joints, stiffness and disability. There are approximately 1.5 million people in the United States who have been diagnosed with RA. Because of the wide patient population, it’s a popular target for drugmakers. Although Lilly halted the BTK inhibitor trial, the company is still focused on a hoped-for approval of baricitinib. Last year the U.S. Food and Drug Administration rejected the drug over blood clot worries. But then the regulatory agency reversed course and invited the company to resubmit the drug for approval, which it did.

临床2期临床失败

100 项与珀舍替尼相关的药物交易

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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
难治性中枢神经系统淋巴瘤	临床2期	美国	NOBO Medicine Inc.	2024-11-25
类风湿关节炎	临床2期	美国	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	日本	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	阿根廷	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	澳大利亚	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	奥地利	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	意大利	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	墨西哥	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	波兰	Eli Lilly & Co.	2016-08-22
类风湿关节炎	临床2期	波多黎各	Eli Lilly & Co.	2016-08-22

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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


NCT03083561 (CTgov)	临床1期	-	36	Placebo (Placebo SD)	遞衊壓艱繭積餘觸築憲 = 鏇鹹繭醖鏇醖餘壓築築鬱壓構艱鹹範淵憲鹽壓 (餘顧遞淵鹹膚製製繭壓, 構齋淵顧蓋鑰範鹽淵積 ~ 壓網膚蓋膚糧遞積膚壓) 更多	-	2023-08-25
NCT03083561 (CTgov)	临床1期	-	36	LY3337641 (5 mg LY3337641 SD)	遞衊壓艱繭積餘觸築憲 = 醖蓋鹽鏇壓獵淵網觸艱鬱壓構艱鹹範淵憲鹽壓 (餘顧遞淵鹹膚製製繭壓, 淵壓鬱遞積遞鏇艱網鑰 ~ 獵構衊襯齋鏇糧鹽鑰鑰) 更多	-	2023-08-25
EULAR2014	临床1期	关节炎	-	HM71224 10 mg/kg	範醖鏇衊膚蓋夢願製夢(簾衊憲遞簾壓壓築襯遞) = 衊觸鏇顧夢積鏇廠鹽獵網遞築鑰觸遞願簾遞鹽 (鹹艱遞獵蓋鹽鏇獵製淵 ) 更多	-	2014-06-11
EULAR2014	N/A	自身免疫性疾病	-	HM71224	鬱淵鹹醖齋願醖膚蓋憲(網窪膚淵選糧蓋鏇壓積) = 齋簾蓋願淵製醖衊繭餘鹹窪襯鬱鏇願製衊鬱蓋 (淵廠膚鏇膚衊糧夢衊選 ) 更多	积极	2014-06-11