主要目的是在已完成了2 期 M19-130 研究的SLE受试者中评价Elsubrutinib和Upadacitinib单药治疗或作为 ABBV-599（Elsubrutinib/Upadacitinib ）联合治疗的长期安全性和耐受性。次要目的是获得在RCT 研究（单药治疗和联合治疗）治疗超过48 周后的长期疗效数据，以更充分地评估每种治疗随着时间推移的获益风险。

开始日期2021-08-23

申办/合作机构

AbbVie Deutschland GmbH & Co. KG

[+2]

JPRN-jRCT2031210119 / Not yet recruiting临床2期IIT

[M20-186] A Phase 2, Long-Term Extension (LTE) Study With Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus Who Have Completed the M19-130 Phase 2 Randomized Controlled Trial (RCT)

开始日期2021-04-27

申办/合作机构-

NCT04451772 / Completed临床2期

A Phase 2, Long-Term Extension (LTE) Study With Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus Who Have Completed the M19-130 Phase 2 Randomized Controlled Trial (RCT)

Systemic Lupus Erythematosus (SLE) is an immune-mediated disease associated with inflammation of multiple organ systems. This study will evaluate how well elsubrutinib and upadacitinib given alone or as the ABBV-599 combination (elsubrutinib/upadacitinib) works within the body, in participants who completed study M19-130. This study will assess the change in disease symptoms.
ABBV-599 is an investigational drug being developed for the treatment of Systemic Lupus Erythematosus (SLE). This study is "double-blinded", which means that neither the trial participants nor the study doctors will know who will be given which study drug. Study doctors put the participants into 1 of 4 groups called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of SLE will be enrolled. Around 260 participants will be enrolled in the study in approximately 100 sites worldwide.
Participants will receive the following for up to 56 weeks:
Participants will receive oral elsubrutinib capsules and/or oral upadacitinib tablets once daily for up to 56 weeks. Participants who were receiving elsubrutinib and/or upadacitnib in M19-130 will continue to receive the same treatment in this study. Participants who were receiving placebo in M19-130 will be re-randomized to one of the 2 combination treatment arms in this study.
Arm 1: Elsubrutinib Dose A and Upadacitinib Dose A Arm 2: Elsubrutinib Dose A and Upadacitinib Dose B
There may be higher burden for participants in this trial compared to their standard of care. Participants will attend monthly visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

开始日期2020-07-27

申办/合作机构

AbbVie, Inc.

100 项与 Elsubrutinib 相关的临床结果

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100 项与 Elsubrutinib 相关的转化医学

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100 项与 Elsubrutinib 相关的专利（医药）

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项与 Elsubrutinib 相关的文献（医药）

2024-12-01·INTERNATIONAL IMMUNOPHARMACOLOGY

Bruton’s tyrosine kinase: A promising target for treating systemic lupus erythematosus

Review

作者: Zhou, Yu ; Sun, Lan ; Feng, Yifan ; Ding, Qiaoyi ; Zhang, Tiantai

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder involving multiple organs and systems. There is growing evidence that autoreactive B cells occupy a central role in the occurrence and progression of SLE due to their ability to generate pathogenic autoantibodies. Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), a crucial intracellular kinase regulating B cell development and function, emerge as a new strategy to treat SLE in recent years and are superior to biologic agents depleting B cells in many aspects. Supportive data obtained from lupus-prone mice preliminarily demonstrated the promising therapeutic potential of BTK inhibition. However, these BTK inhibitors, including elsubrutinib, evobrutinib, etc., mostly face with unsatisfactory efficacy and certain safety issues during clinical use, driving the quest for new-generation inhibitors with improved potency and higher selectivity. This paper elaborates the importance of BTK involvement in SLE pathogenesis, reviews the clinical research progress of BTK inhibitors for SLE and discusses limitations and challenges the drugs met in development, in order to contribute to a deeper understanding of disease mechanism and provide a reference for new-generation BTK inhibitor research.

2022-06-01·The Lancet. Rheumatology

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial

Article

作者: Cohen, Stanley ; Cortes-Maisonet, Gregorio ; Drescher, Edit ; Singhal, Atul ; Doan, Thao ; Blanco, Ricardo ; Taylor, Peter C. ; Housley, William ; Nader, Ahmed ; Wang, Zailong ; Fleischmann, Roy ; Lu, Wenjing ; Friedman, Alan

BACKGROUND:

ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile.

METHODS:

We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705.

FINDINGS:

Between Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85; p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23; p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44; p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41; p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13; p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups.

INTERPRETATION:

Significant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib.

FUNDING:

AbbVie.

2019-05-04·Modern rheumatology4区 · 医学

ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation

4区 · 医学

Article

作者: Long, Andrew J. ; Perham, Matthew ; Mario, Regina ; McCarthy, Richard W. ; Murdock, Sara ; Goedken, Eric R. ; Sampson, Erik ; Harris, Christopher M. ; Goess, Christian ; Mathieu, Suzanne ; Twomey, Rachel

OBJECTIVES:

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease.

METHODS:

ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker.

RESULTS:

ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis, and reduced disease in an IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy.

CONCLUSION:

ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

项与 Elsubrutinib 相关的新闻（医药）

2024-08-30

·药智网

百济神州「BTK双剑」出鞘

提到百济神州的BTK，不假思索就会想到泽布替尼，但百济神州的BTK抑制剂不止泽布替尼，管线中在研的BGB-16673是潜在的另一把“利剑”。近日，百济神州BTK PROTAC分子BGB-16673被FDA授予快速通道资格，用于经过至少二线治疗的CLL/SLL患者，包括BTK抑制剂和Bcl-2抑制剂。解决耐药性， PROTAC邂逅BTK 自2013年首款BTK抑制剂伊布替尼获批上市以来，目前全球已有6款BTK抑制剂获批上市。尽管已有多款BTK抑制剂获批上市，且这些药物已经展示出优异的疗效，但它们仍有一定局限性，即耐药性难题。 PROTAC（蛋白降解）是近几年非常火热的研发赛道。相对小分子抑制剂来说，PROTAC降解剂具有诸多优势：扩展了可成药靶标，可以靶向那些没有小分子抑制剂或小分子抑制剂疗效不佳的靶标蛋白；催化效率高，可以使用催化量起作用，避免了像小分子长时间占有才能发挥药效的情况；克服耐药性，PROTAC降解剂不仅抑制蛋白活性，还可以降解整个蛋白从而破坏蛋白质的酶和非酶功能（例如支架）或转录功能，克服传统小分子的耐药性。包括礼来的Pirtobrutinib在内，目前获批的BTK药物都属于小分子抑制剂，容易产生耐药问题，为了进一步提高药效和克服耐药性问题，不少企业将目光投向了BTK的PROTAC药物开发，百济神州便是其中之一。早在2021年，泽布替尼还未曾大显神威的时候，百济神州就开始将PROTAC技术应用到BTK的药物开发上。资料显示，百济神州启动的首个临床PROTAC项目便是BGB-16673，于2021年8月百济神州在ClinicalTrials.gov进行了临床试验登记，2022年3月又在国内启动临床。 BGB-16673通过泛素化诱导BTK降解，展现出在解决BTK抑制剂耐药性问题上的巨大潜力。本次快速通道认定的申请主要基于BGB-16673用于解决发生疾病进展的CLL/SLL患者尚未满足的医疗需求的潜力。在今年6月举行的2024年欧洲血液学协会年会上，百济神州公布了BGB-16673正在进行的Ⅰ/Ⅱ期首次人体试验（NCT05006716）数据，突显出该药物用于治疗既往接受过多线治疗的R/R CLL/SLL患者具有可耐受的安全性和良好的有效性。此外，还在多种不同类型非霍奇金淋巴瘤（NHL）患者中表现出了可耐受的安全性和初步的有效性。迄今为止，BGB-16673全球临床开发项目已在15个国家/地区治疗了超过300例患者。目前BGB-16673正在进行BTK抑制剂后线CLL/SLL剂量扩展队列研究，百济神州预计今年底、明年初启动Ⅲ期临床试验。目前除了BGB-16673，海思科的HSK29116以及Nurix Therapeutics的NX-2127和NX-5948也都是在研的BTK PROTAC降解剂，BGB-16673进展最快。与泽布替尼互补，巩固BTK竞争地位自2013年11月，全球首个BTK抑制剂伊布替尼获FDA批准上市后，带来了血液肿瘤的革命性进展，BTK靶向药物研发热浪开始在全球铺开。百济神州是BTK赛道的中国骄傲，凭借泽布替尼把老将伊布替尼逐渐逼向“墙角”，在BTK市场大放异彩。 2023年全年泽布替尼全球销售额近13亿美元，成为首个年销售破十亿美元的国产新药。2024年上半年，泽布替尼的全球销售额为80.18亿元，营收占比超60%，是百济神州的“镇山之宝”。相比之下，由于竞争对手的涌入以及自身耐药性问题，伊布替尼已经在走下坡路，2024年上半年全球销售额为16.71亿美元，同比下滑6.4%。目前整个BTK赛道，不仅已上市药物你追我赶，临床在研药物也是各显神通。据不完全统计，除已上市药物，全球进入临床的有上百条管线，当下BTK抑制剂的市场角逐早就进入“白热化”阶段，竞争已经从适应症、作用机制、药物类型等方面多元化延伸。因此对于百济神州而言，虽然目前泽布替尼处在销售猛涨期，但也并非高枕无忧。攻下血液瘤之后，多数的已上市BTK药物拓展适应症势在必行，自免领域的相关适应症成了BTK的下一个用武之地。据华创证券统计，当前在自身免疫性疾病领域探索的BTK抑制剂超过20款，适应症聚焦在多发性硬化症（MS）、自发性荨麻疹、系统性红斑狼疮、类风湿性关节炎等疾病。今年4月，赛诺菲已率先领跑，其旗下的BTK抑制剂Rilzabrutinib（SAR444671/PRN-1008）治疗持续性或慢性免疫性血小板减少症（ITP）成年患者的III期LUNA 3研究达到主要终点，并计划于今年年底前向FDA递交Rilzabrutinib的上市申请。除此之外，赛诺菲的另一款BTK抑制剂Tolebrutinib和诺华的Remibrutinib均瞄准了MS，目前也在临床Ⅲ期；渤健针对MS的BIB091，艾伯维针对系统性红斑狼疮、类风湿关节炎的Elsubrutinib都已进入临床Ⅱ期。百济神州对泽布替尼也有进行自免领域的探索，不过泽布替尼治疗狼疮肾炎适应症进入II期临床，尚在临床早期。另外，非共价如礼来的Pirtobrutinib对整个BTK市场也是虎视眈眈，去年上市首年，卖出7500万美元销售额。礼来预计，2030年Pirtobrutinib将在慢淋市场占据60%市场份额，对应30亿美元的年销售额。基于非共价的耐药优势，目前全球的非共价（可逆）BTK抑制剂赛道也聚集了诸多玩家，国外有默沙东的MK-1026/ARQ531（Nemtabrutinib）、Aptose Biosciences的CG-806、罗氏的Fenebrutinib/GDC-0853等，国内有和黄医药的HMPL-760、信诺维/中国抗体的XNW1011、倍特药业/海博锐的BT-1053等。总之，百济神州寻找泽布替尼之外的具备差异化优势的BTK抑制剂对于守卫自身在BTK赛道的竞争地位非常重要。 BGB-16673是目前临床开发中进展最快的BTK降解剂，具备成为使用BTK抑制剂后疾病进展、选择有限的患者的重要治疗方案的潜力，同时，BGB-16673将巩固百济神州在血液学领域的领先地位，并与泽布替尼形成优势互补，填补泽布替尼后线市场。结语在全球范围内，BTK抑制剂市场增长迅速，2020年达到72亿美元。根据沙利文分析，BTK抑制剂市场规模以22.7%的复合年增长率增长，将在2025年达到200亿美元，并持续以5.5%的复合年增长率扩大到2030年的261亿美元。显然，百济神州势必不遗余力下好BTK这盘棋，未来，泽布替尼和BGB-16673这两把剑还会舞出怎样的江湖剑影，拭目以待。参考资料： 1、《BTK竞争红海，后来者如何弯道超车？》贝壳社 2、《BTK抑制剂“后浪”奔涌！AZ、礼来持续发力，百济神州遭遇夹击？》医学经济报声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 拉夫斯转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

蛋白降解靶向嵌合体临床3期临床1期临床结果

2024-04-29

·CPHI制药在线

BTK竞争红海，后来者如何弯道超车？

关注并星标CPHI制药在线作者：米朵自2013年伊布替尼上市以来，全球共有6款BTK抑制剂相继获批，当前BTK已是国内外各大药企扎堆的热门靶点，除已上市药物，全球进入临床的有上百条管线，后来者若想在激烈的竞争中占有一席之地，打造差异化优势至关重要。当前来看已有不少企业开始从适应症、作用机制、药物类型等方面寻求弯道超车机会。适应症：从血液瘤到自免领域拓展4月23日，赛诺菲宣布BTK 抑制剂Rilzabrutinib（SAR444671/PRN-1008）治疗持续性或慢性免疫性血小板减少症（ITP）成年患者的III 期 LUNA 3研究达到主要终点，并计划于今年年底前向 FDA 递交 Rilzabrutinib 的上市申请。如若Rilzabrutinib顺利获批，将成为全球第7款上市的BTK抑制剂，赛诺菲也将成为继强生、艾伯维、阿斯利康、礼来、吉利德之后第6个挺进BTK赛道的MNC。已获批BTK抑制剂情况图源：药渡对比几款已上市BTK抑制剂的适应症，可以发现均是用于治疗B细胞恶性血液肿瘤，包括非霍奇金淋巴瘤（NHL）的各种亚型和慢性淋巴细胞白血病（CLL）、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）、多发性骨髓瘤（MM）、边缘区淋巴瘤（MZL）、套细胞淋巴瘤（MCL）和华氏巨球蛋白血症（WM）等。与已获批的BTK抑制剂的适应症不同，赛诺菲的Rilzabrutinib以ITP作为首发适应症，将是全球首款获批ITP适应症的BTK抑制剂。除了ITP适应症以外，Rilzabrutinib正在进行治疗IgG4相关性疾病和温抗体型自身免疫溶血性贫血的IIb期实验，今年下半年，赛诺菲将启动Rilzabrutinib治疗慢性自发性荨麻疹、结节性痒疹的III期临床试验。显然，赛诺菲确实有意避开目前被围攻的“血液瘤”适应症。近年来，BTK抑制剂已经在血液瘤治疗领域取得了巨大的成功，其疗效和安全性都得到了充分的论证，总体销售额已经达到上百亿美元规模，但血液瘤领域BTK药物的市场竞争极其激烈，赛道后来者想避开内卷，少不了在适应症上做差异化布局。由于自身免疫性疾病是由自身耐受性丧失引起的，通常涉及自身反应性B细胞的异常选择和激活以及随后的自身抗体产生。每个B细胞都有一个独特的抗原受体，即B细胞受体(BCR)，它可以识别特定的抗原，从而激活B细胞。Bruton’s酪氨酸激酶（BTK）是一种至关重要的信号蛋白，它直接将BCR的信号与B细胞的活化、增殖和生存联系起来，这使得BTK成为自身免疫性疾病的一个有趣的治疗靶点。另外，全球范围内，自身免疫疾病已成为全球第二大市场，2022年已超越千亿美元规模，众多企业将BTK的目标市场由血液瘤转向自身免疫性疾病领域，当前BTK抑制剂在自免领域的研发如火如荼地进行。去年8月，诺华的Remibrutinib在治疗慢性自发性荨麻疹（CSU）的两项Ⅲ期REMIX-1和REMIX-2均达到主要终点，这是继罗氏、默沙东等大厂的BTK抑制剂相继在自身免疫疾病领域翻车之后的首次突破。虽然目前尚未有BTK抑制剂获批自免适应症，且BTK抑制剂在自免领域的开发因肝脏毒素等问题接连碰壁，但有诺华的这剂强心剂，使得各大药企对BTK抑制剂进军自免领域仍热情高涨。据华创证券统计，当前在自身免疫性疾病领域探索的BTK抑制剂超过20款，适应症聚焦在多发性硬化症（MS）、自发性荨麻疹、系统性红斑狼疮、类风湿性关节炎等疾病。除诺华的Remibrutinib，赛诺菲的另一款BTK抑制剂Tolebrutinib瞄准了MS，目前也在临床Ⅲ期；渤健针对MS的BIB091，艾伯维针对系统性红斑狼疮、类风湿关节炎的Elsubrutinib都已进入临床Ⅱ期。作用机制：从不可逆共价往可逆非共价升级从作用机制来看，BTK抑制剂可分为两类：不可逆抑制剂和可逆抑制剂，不可逆抑制剂与BTK蛋白口袋里ADP结合内的半胱氨酸残基（Cys481）共价结合，导致其活性完全抑制，药物的治疗作用较强，可提高药物利用效率，但在高浓度下存在一定的脱靶毒性，而且如果患者产生BTK耐药突变，会使得药物不能与C481残基结合，药物的效果将大打折扣；可逆抑制剂可暂时阻断靶蛋白，且不依赖于与C481残基结合发挥作用，相较于不可逆抑制剂副作用较小。从首个药物获批至今10余年，BTK抑制剂已经发展到第三代非共价抑制剂。目前已上市的6款BTK抑制剂，不可逆抑制剂包括第一代的伊布替尼，第二代的阿可替尼（阿卡替尼）、泽布替尼、Tirabrutinib和奥布替尼；可逆抑制剂包括第三代的Pirtobrutinib。礼来的Pirtobrutinib是首款获批上市的非共价BTK抑制剂，与前两代BTK共价抑制剂完全不同，具备高选择性，它通过非共价、非c481依赖的结合阻断BTK的ATP结合位点，有望降低治疗产生的不良事件，可用于对第一、二代共价BTK抑制剂耐药性后的治疗。在临床前实验中，Pirtobrutinib在BTK野生型和携带BTK C481替代突变的细胞和动物模型上表现出了相似的效力。去年1月，Pirtobrutinib获美国FDA加速批准，用于治疗复发/难治性套细胞淋巴瘤（MCL）患者；去年12月，Pirtobrutinib再次获得FDA的加速批准，用于慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（CLL/SLL）成人患者的治疗。Pirtobrutinib是首个在一年内获得两次FDA加速批准的BTK抑制剂，在中国，Pirtobrutinib的上市申请也已被纳入优先审评，适应症为单药治疗既往接受过BTK抑制剂治疗的复发或难治性MCL成人患者。基于非共价的优势，目前全球的非共价（可逆）BTK抑制剂赛道也聚集了诸多玩家，国外有默沙东的MK-1026/ARQ531（Nemtabrutinib）、Aptose Biosciences的CG-806、罗氏的Fenebrutinib/GDC-0853等，国内有和黄医药的HMPL-760、信诺维/中国抗体的XNW1011、倍特药业/海博锐的BT-1053等。药物类型：从小分子到PROTACs延伸目前已获批的BTK药物都属于小分子抑制剂，作为激酶的小分子抑制剂，耐药是一个难以回避的问题，虽然Pirtobrutinib作为非共价抑制剂可用于既往BTK抑制剂治疗并产生耐药的患者，但在接受Pirtobrutinib临床实验的病人中，出现了新的耐药突变。因此，进一步提高药效和克服耐药性问题是现有BTK抑制剂的难点及突破重点。蛋白水解靶向嵌合体（PROTACs）由靶蛋白的配体、E3泛素连接酶配体和连接链三部分组成，可以招募E3泛素连接酶靠近靶标蛋白，使靶蛋白泛素化，进一步被蛋白酶体降解，相对小分子抑制剂来说，扩展了可成药靶标，可以靶向那些没有小分子抑制剂或小分子抑制剂疗效不佳的靶标蛋白；催化效率高，可以使用催化量起作用，避免了像小分子长时间占有才能发挥药效的情况；克服耐药性，PROTACs不仅抑制蛋白活性，还可以降解整个蛋白从而破坏蛋白质的酶和非酶功能（例如支架）或转录功能，克服传统小分子的耐药性的优点。目前国内外已有多家企业开发的BTK-PROTAC进入临床阶段。NX-2127由Nurix Therapeutic开发，是first-in-class的口服BTK降解剂，目前在开展针对B细胞恶性肿瘤临床试验Ⅰ期。体外实验显示NX-2127可结合并有效降解所有的BTK突变蛋白，BCR信号通路活性有所降低。在2023年ASH会议上，Nurix公布了NX-2127的积极临床数据，旨在评估NX-2127在复发或难治性（r/r）B细胞恶性肿瘤患者（CLL、MCL 和 DLBCL）的临床试验1a期剂量递增和1b期剂量扩展队列的疗效和安全性。 Nurix还在开发一款更强效的BTK降解剂NX-5948，目前正在开发用于治疗多种免疫炎症如类风湿性关节炎等，此外，国外还有Baylor College of Medicine开发的RC-1；Yale University的MT-802也是BTK-PROTAC产品；国内有海思科自主开发的HSK29116、百济神州开发的BGB-16673等产品。整体来说，全球针对BTK-PROTACs的临床实验尚在早期阶段，但若能成功上市，有效解决BTK患者的耐药难题，相信PROTACs将成BTK抑制剂的新风口。结语据弗若斯特沙利文数据，全球BTK抑制剂市场规模预计2025年达219亿美元，2030年达251亿美元，明朗和广阔的市场吸引了不少药企入局。当前全球BTK抑制剂项目众多，没有差异化优势的玩家很难在拥挤的赛道立足，对于后来者，不盲目跟风，选择有较大市场空间，同时适合自己的方向入局或许能获得更多突围的机会。参考资料：1、《一年内获FDA两次加速批准，礼来这款非共价BTK抑制剂是如何诞生的？》药明康德2、《Science丨“后浪”-BTK降解剂破解BTK抑制剂耐药难题》BioArt3、《从伊布替尼、泽布替尼到吡妥布替尼，一窥BTK药物的研发策略》药渡【智药研习社近期线下课程预告】来源：贝壳社声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床3期引进/卖出临床1期临床2期上市批准

2023-11-06

·PRNewswire

LRA Highlights Groundbreaking Lupus Research at ACR Convergence 2023

This information is brought to you by the Lupus Research Alliance and Lupus Therapeutics and is not sponsored by, nor a part of, the American College of Rheumatology. 30+ presentations of studies funded by the LRA spanning a broad spectrum of research areas Positive results from Phase 2/3 clinical studies supported by LRA affiliate Lupus Therapeutics point to potential new treatments Lupus Therapeutics' PALS Program helps overcome challenges of diverse lupus patient trial participation SAN DIEGO, Nov. 6, 2023 /PRNewswire/ -- The Lupus Research Alliance (LRA), the largest non-governmental non-profit funder of lupus research worldwide, is pleased to announce results from more than 30 studies supported by the LRA and its clinical research affiliate Lupus Therapeutics will be presented at ACR Convergence 2023, the annual meeting of the American College of Rheumatology. Studies will represent the full continuum of research that the LRA and Lupus Therapeutics support, from innovative foundational research to lupus clinical trials evaluating potential new treatments. "The LRA and Lupus Therapeutics are extremely proud of the tremendous work we have supported that will contribute to the dynamic scientific dialogue at this important rheumatology meeting,' commented LRA President and CEO Albert T. Roy. "We also look forward to many presentations of exciting clinical research, including results from CAR-T cell therapy studies that built on pioneering work funded by the LRA and have the potential to shift the lupus treatment paradigm." FOUNDATIONAL RESEARCH FUNDED BY THE LRA LRA-funded investigators will be presenting their recent breakthroughs across a broad spectrum of lupus research, including the impact of lupus on various organs such as the skin, kidney, and brain, the contribution of the gut microbiome to lupus, dysregulation of a variety of immune cell types underlying lupus, and more. ORAL PRESENTATIONS Sunday, Nov. 12 APOL1 High Risk Genotype in SLE: A Genes in Context Story Abstract # NA, 12:00 PM – Room 11A-B ROCK1 Orchestrates B-cell Differentiation Under Stress Abstract #0729, 2:30 PM – Room 30D-E Lupus Nephritis Flares Linked to Platelet Activation During Gut Pathobiont Blooms Abstract #0851, 5:00 PM, Exhibit Hall A-B Monday, Nov. 13 CXCL13+ T cell differentiation in systemic lupus erythematosus is controlled by opposing effects of aryl hydrocarbon receptor and type I interferon Abstract #1580, 11:15 AM – Exhibit Hall A-B Metabolic Mechanisms that Control Inflammation and Immune-related Disorders Plenary Session II, 12:00 PM – Room 30D-E Keratinocyte VISTA Suppresses Skin IFN-I Production by Regulating DNA Damage Repair and Cytosolic DNA Sensing Abstract #1586, 2:15 PM – Room 32A-B Single-Cell RNA Sequencing Reveals Cellular Drivers of UV-mediated Skin Injury in Cutaneous Lupus Abstract #1599, 2:30 PM – Room 6F/6C Identifying Potential Neuroimaging Biomarkers of Neuropsychiatric Lupus in Children Using Deep Learning Abstract #1625, 3:00 PM – Room 7A-B Tuesday, Nov. 14 Longitudinal Gut Microbiome Analyses and Blooms of Pathogenic Strains during Lupus Disease Flares Abstract #NA, 8:20 AM – Room 6F/6C Development of Engineered Smith-Specific Regulatory T Cells to Treat Lupus Nephritis Abstract #2444, 2:15 PM – Room 26A-B Targeting of Endothelial Dysfunction in Lupus Nephritis: Effect on Human Renal Endothelial Cell Gene Expression and Outcomes in Murine Lupus Nephritis Abstract #2445, 2:30 PM – Room 26A-B UV Light Exposure Induces a Type I Interferon Dependent Activation and Migration of Inflammatory Dendritic Cells to Local Lymph Nodes Abstract #2448, 3:15 PM – Room 26A-B Wednesday, Nov. 15 In Situ Adaptive Immunity in Human Lupus Nephritis Abstract # N/A, 8:30 AM – Room 29A-D POSTER PRESENTATIONS – Poster Hall Sunday, Nov. 12 Elevated Serum Levels of S100A8/A9 Discriminate Systemic Lupus Erythematosus Patients with Cognitive Impairment from Patients Without Impairment Abstract #0558, 9:00 AM Comparison of Plasma Protein Profiles and Endothelial Function in Patients with Pediatric-Onset Systemic Lupus Erythematosus and Healthy Controls Abstract #0568, 9:00 AM Monday, Nov. 13 Specificity of Brain-Intrinsic and Hematopoietic-Derived Mechanisms in Mediating Neuropsychiatric Symptoms of Systemic Lupus Erythematosus Abstract #0890, 9:00 AM Adverse Childhood Experiences in a Paediatric Systemic Lupus Erythematosus Cohort Abstract #1241, 9:00 AM Agreement Between Parent- and Self-Report of Executive Function in Adolescents with Childhood-Onset Systemic Lupus Erythematosus Abstract #1242, 9:00 AM Proinflammatory Neutrophils and NETs Mediate Skin and Kidney Inflammation During Lupus Flare in Asymptomatic Lupus-prone Mice Triggered by UVB Abstract #0920, 9:00 AM IL-4 Acts Through Aryl Hydrocarbon Receptor to Antagonize TLR7-induced Double Negative 2 B Cells in Lupus Abstract #0925, 9:00 AM Examining the Relationship Between Socioenvironmental Factors and Cognitive Functioning in Youth with Childhood-Onset Systemic Lupus Erythematosus Abstract #1226, 9:00 AM Longitudinal Assessment of Self-reported Executive Function in Youth with Childhood-Onset Lupus Abstract #1229, 9:00 AM Complement Deposition on Extracellular Mitochondria Induces Platelet Activation in Vitro Abstract #0900, 9:00 AM The Cellular and Spatial Type I Interferon Response Following Skin Exposure to Ultraviolet Light Abstract #0894, 9:00 AM Tuesday, Nov. 14 Brain Activity Patterns and Behavioural Performance in SLE Patients During a Spatial Working Memory and Sustained Attention Task Abstract #2258, 9:00 AM The Effects of Systematic Lupus Erythematosus Related Cognitive Impairments on Activities of Daily Living and Life Role Participation: A Qualitative Framework Study Abstract #2259, 9:00 AM Association of Mycophenolate and Azathioprine Use with Cognitive Function in Systemic Lupus Using a Bayesian Longitudinal Item-response Theory Model Abstract #2290, 9:00 AM CLINICAL TRIALS SUPPORTED BY LUPUS THERAPEUTICS As the clinical research affiliate of the LRA, Lupus Therapeutics collaborates with biotechnology and pharmaceutical companies, as well as lupus experts from their Lupus Clinical Investigators Network (LuCIN) to help design and conduct high-quality, patient-centric, and diverse lupus studies, including several with results being presented at ACR Convergence 2023. ORAL PRESENTATIONS Tuesday, Nov. 14 Efficacy and Safety of ABBV-599 High Dose (Elsubrutinib 60 mg and Upadacitinib 30 mg) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: A Phase 2, Double-blind, Placebo-controlled Trial Abstract #2488, 2:00 PM – Ballroom 20D Phase 2 Safety and Efficacy of Subcutaneous (s.c.) Dose Ianalumab (VAY736; Anti-BAFFR mAb) Administered Monthly over 28 Weeks in Patients Abstract #2487, 2:00 PM – Ballroom 20D POSTER PRESENTATIONS – Poster Hall Monday, Nov. 13 Treatment with Upadacitinib in Patients with Systemic Lupus Erythematosus Results in the Inhibition of B-Cell–related Biomarkers: Analysis of the M19-130 (SLEek) Phase 2 Study Abstract #1489, 9:00 AM Disease Course and Complement as Predictors of Response to Standard of Care Plus Placebo in Patients with SLE: A Post Hoc Analysis of Dapirolizumab Pegol and Epratuzumab Clinical Trial Data Abstract #1503, 9:00 AM Steroid-sparing Effects of Afimetoran (BMS-986256), an Equipotent Toll-like Receptor (TLR)7 and TLR8 Antagonist, in a Lupus Mouse Model Abstract #0897, 9:00 AM Transcriptomic Analysis of the Impact of Iberdomide on Patients with SLE Abstract #1694, 4:00 PM Tuesday, Nov. 14 Dapirolizumab Pegol Impacts Important Immunologic Pathways in SLE: Pharmacodynamic Analysis of B Cell and Type I Interferon Pathways from a Phase 2b Trial Abstract #2333, 9:00 AM Modulation of B Cell and Interferon Pathways by Ianalumab in Patients with Systemic Lupus Erythematosus: Findings from a Phase 2 Clinical Trial Abstract #2342, 9:00 AM WORK CONDUCTED THROUGH THE LUPUS THERAPEUTICS PALS PROGRAM Patient Advocates for Lupus Studies (PALS) is a peer support program that aims to improve participation in lupus clinical trials through increased education and availability of information about clinical trials. Individuals living with lupus who have clinical research act as peer educators, or PALs, to deliver educational sessions to others living with lupus. The PALS program was piloted from 2019-2021 and demonstrated significant increases in knowledge about, attitudes toward, and intentions to participate in lupus clinical trials among program participants. POSTER PRESENTATION – Poster Hall Sunday, Nov. 12 Barriers and Facilitators to Recruiting Underrepresented Participants for Clinical Trials: Insights from the Lupus Clinical Investigators Network (LuCIN) Abstract #0183, 9:00 AM WORK CONDUCTED BY THE ACCELERATING MEDICINES PARTNERSHIP The LRA is a partner in Accelerating Medicines Partnership® Autoimmune Mediated Disease (AMP® AIM), which brings together 20 organizations from the public, private, and nonprofit sectors to accelerate the identification and validation of new therapeutic targets by reconstructing shared immune response pathways through spatial and multi-omics technologies. The project is managed by the FNIH and builds on the success of AMP RA/SLE in which LRA was also a partner. The presentation of results from an AMP® AIM lupus study is noted below. ORAL PRESENTATION Monday, Nov. 13 Single Cell Transcriptomics in Kidney Tissue from African American Patients Enrolled in the Accelerating Medicines Partnership (AMP) Implicates Tubular Cells in the Pathogenesis of APOL1 Associated Lupus Nephritis Abstract #1695, 4:30 PM – Room 6F/6C About Lupus Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. More than 90 percent of people with lupus are women, often striking during the childbearing years of 15-45. Blacks/African Americans, Hispanics, Asians, and Native Americans are at two to three times greater risk than Caucasians for developing lupus. In lupus, the immune system, meant to defend against infections, produces antibodies that mistakenly recognize the body's own cells as foreign, prompting other immune cells to attack and potentially damage organs such as the kidneys, brain, heart, lungs, blood, skin, and joints. About Lupus Research Alliance The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately, cure for lupus. Because the Lupus Research Alliance's Board of Directors funds all administrative and fundraising costs, 100% of all donations goes to support lupus research programs. About Lupus Therapeutics Lupus Therapeutics, the clinical research affiliate of the Lupus Research Alliance, aims to accelerate the development of curative treatments for all patients living with lupus. Lupus Therapeutics collaborates with academic institutions, biotechnology, and pharmaceutical partners through the unprecedented Lupus Clinical Investigators Network (LuCIN) to drive rapid and meaningful progress in the treatment of lupus patients. The organization elevates the patient voice, engages community stakeholders, and strives for representation of the diverse lupus community in the clinical research process with the most innovative and renowned experts throughout North America. Visit lupustherapeutics.org for more information. SOURCE Lupus Research Alliance

临床2期临床结果

100 项与 Elsubrutinib 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
系统性红斑狼疮	临床2期	美国	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	中国	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	日本	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	阿根廷	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	澳大利亚	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	保加利亚	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	加拿大	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	哥伦比亚	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	法国	AbbVie, Inc.	2019-07-25
系统性红斑狼疮	临床2期	德国	AbbVie, Inc.	2019-07-25

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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


NCT03978520 (SLEek, CTgov)	-	系统性红斑狼疮	341	Placebo for upadacitinib (Elsubrutinib Placebo/Upadacitinib Placebo)	構選範觸顧鑰淵膚襯餘(鏇觸簾鬱憲夢齋鹽觸選) = 醖襯鏇鏇壓醖廠鏇淵憲遞蓋廠糧遞餘鏇築遞餘 (構壓鬱艱積願鹽蓋壓鑰, 繭鹽鏇糧壓鏇壓艱窪願 ~ 鬱築蓋積遞選艱鹽製夢) 更多	-	2023-07-21
				Elsubrutinib+Upadacitinib (ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg))	構選範觸顧鑰淵膚襯餘(鏇觸簾鬱憲夢齋鹽觸選) = 鑰遞顧觸窪餘艱製襯鑰遞蓋廠糧遞餘鏇築遞餘 (構壓鬱艱積願鹽蓋壓鑰, 鬱鏇鏇積醖積獵鬱衊獵 ~ 獵膚艱膚顧顧獵觸艱製) 更多
NCT03978520 (SLEek, EULAR2023)	临床2期	系统性红斑狼疮	341	ABBV-599 High Dose (ELSUBRUTINIB 60 mg and UPADACITINIB 30 mg)	鹽憲襯鏇餘鑰願獵齋壓(餘鑰鹽襯築窪獵觸廠簾) = 鏇蓋壓窪膚襯鹽選膚顧窪築鹹廠艱壓積餘鹹壓 (顧範範顧選壓選網獵衊, (1.0 ~ 1.6)***) 更多	积极	2023-05-31
				UPADACITINIB 30 mg	鹽憲襯鏇餘鑰願獵齋壓(餘鑰鹽襯築窪獵觸廠簾) = 糧壓廠選廠鹽製壓築衊窪築鹹廠艱壓積餘鹹壓 (顧範範顧選壓選網獵衊, (1.5 ~ 2.3)*) 更多
NCT03823378 (CTgov)	临床2期	类风湿关节炎	97	Elsubrutinib+Upadacitinib (ABBV-599 in M16-063/ABBV-599 in M16-763)	積顧廠獵襯餘願糧膚願(壓夢繭獵廠選網觸衊糧) = 鑰觸觸醖鬱窪願膚蓋淵鏇鬱醖積膚積餘壓鏇願 (襯廠艱餘憲選鬱膚醖衊, 淵網簾築淵遞範願築鬱 ~ 簾網製鹹淵衊鬱齋繭齋) 更多	-	2021-09-16
				Placebo for upadacitinib+Elsubrutinib (ABBV-105 60 mg/UPA Placebo)	積顧廠獵襯餘願糧膚願(壓夢繭獵廠選網觸衊糧) = 顧齋夢鬱願艱遞選願觸鏇鬱醖積膚積餘壓鏇願 (襯廠艱餘憲選鬱膚醖衊, 繭顧糧壓窪範廠築蓋鑰 ~ 襯衊觸選製齋憲鏇膚鬱) 更多
NCT03682705 (CTgov)	-	类风湿关节炎	242	Placebo for upadacitinib (ELS Placebo/UPA Placebo)	顧窪鬱壓膚顧網餘積築(願獵淵顧鏇壓窪襯膚觸) = 鹽願構願淵窪夢醖襯艱淵襯鏇壓製築選膚蓋膚 (膚鬱顧獵淵夢齋獵選選, 鏇憲鑰糧獵繭簾積夢獵 ~ 鑰構網蓋構構鑰衊鬱構) 更多	-	2021-05-03
				Elsubrutinib+Upadacitinib (UPA 15 mg/ELS 60 mg)	顧窪鬱壓膚顧網餘積築(願獵淵顧鏇壓窪襯膚觸) = 顧夢觸餘膚觸鬱艱壓餘淵襯鏇壓製築選膚蓋膚 (膚鬱顧獵淵夢齋獵選選, 獵鑰顧選願齋繭齋鹹壓 ~ 齋夢觸憲憲憲鏇獵簾鏇) 更多