An open label, experimental medicine investigation of the safety and tolerability of 400 mg b.i.d. GSK2586184 in patients with moderate to severely active ulcerative colitis (200208) - 200208 (JAK)

开始日期2014-01-09

申办/合作机构

GlaxoSmithKline BV

NCT02000453

/ Terminated临床1期

An Open Label, Experimental Medicine Investigation of the Safety and Tolerability of 400 mg b.i.d. GSK2586184 in Patients With Moderate to Severely Active Ulcerative Colitis.

This is an open label exploratory study to investigate the safety of 400 milligram (mg ) twice a day (b.i.d.) GSK2586184 in patients with moderate to severe, active ulcerative colitis (UC). Study medication will be administered orally (as tablets), twice daily, for up to 8 weeks (56 days). Study medication will be taken with food. Each subject will have 6 out-patient visits: Screening (Day -30 to -1); Baseline and Start of treatment (Day 1); Week 2 (Day 14); Week 4 (Day 28); Week 8 (Day 56); and Follow-up (Week 12; Day 84). Visit windows for weeks 2, 4 and 8 will be + 2 days. The primary objective of this study is to assess the safety and tolerability of GSK2586184. The primary endpoints to measure safety are laboratory tests (including haematology, clinical chemistry and serum creatinine), vital signs, 12-lead electrocardiogram (ECG), physical examination, and adverse event reporting. These are standard measurements to evaluate safety.

开始日期2013-12-20

申办/合作机构

GSK Plc

NCT01953835

/ Completed临床1期

A Two-part Healthy Volunteer Study to Investigate Both the Interaction of GSK2586184 With Rosuvastatin and Simvastatin and to Compare the Pharmacokinetics of Two Different Formulations of GSK2586184

This study is a Phase I, two-part, open-label study designed to evaluate the effect of repeated doses of GSK2586184 on the pharmacokinetics (PK) of Simvastatin and Rosuvastatin in healthy volunteers (Cohort A), and to evaluate the pharmacokinetics of a new tablet formulation of GSK2586184 in healthy male volunteers (Cohort B). Cohort A is a single sequence drug interaction study in which 28 subjects (14 female and 14 male subjects) will be enrolled. Each subject will receive single doses of Simvastatin and Rosuvastatin on two occasions, once alone and once following administration of repeated doses of GSK2586184. Cohort B is a 3-way crossover PK study in which 9 male subjects will be randomized (3 subjects to each treatment sequence). Each subject will receive a single dose of the standard formulation of GSK2586184 with food and two doses of a new formulation of GSK2586184, once with food and once in a fasted state, according to their treatment sequence, with a 3-day wash out between doses. The primary aim of the study is to investigate the effects of GSK2586184 on the pharmacokinetics of the 2 statins and to assess the impact of dosing with and without food on a new formulation of GSK2586184 tablet.

开始日期2013-10-04

申办/合作机构

GSK Plc

100 项与索西替尼相关的临床结果

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100 项与索西替尼相关的转化医学

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100 项与索西替尼相关的专利（医药）

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项与索西替尼相关的文献（医药）

2023-04-01·Drugs

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Article

作者: Mok, Chi Chiu

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton's tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood-brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

2023-02-01·Biochemical pharmacology

JAK-STAT signaling as an ARDS therapeutic target: Status and future trends

Review

作者: Zhang, Yuanteng ; Luo, Peihua ; Gao, Zizheng ; Yang, Xiaochun ; He, Qiaojun ; Yang, Bo ; Yan, Hao ; Jiang, Feng ; Xu, Zhifei

Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic pulmonary edema. It has a high mortality rate and lacks effective pharmacotherapy. With the outbreak of COVID-19 worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID-19-induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular JAK/STAT pathway involved in ARDS pathology, and the progress that has been made in strategies targeting JAK/STAT to treat ARDS. Specifically, JAK/STAT signaling directly participates in the progression of ARDS or colludes with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and preclinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal future trends in the design of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.

2022-12-31·Pharmaceutical biology

Pseudolycorine chloride ameliorates Th17 cell-mediated central nervous system autoimmunity by restraining myeloid-derived suppressor cell expansion

Article

作者: Li, Limei ; Zhu, Xinying ; Leng, Xiao ; Wang, Yantang ; Yang, Fan ; Li, Juan ; Mo, Chunfen ; Zhang, Gan

CONTEXT:

The alkaloids of Narcissus tazetta L. var. Chinensis Roem (Amaryllidaceae) have antitumor and antiviral activities. However, the immunopharmacological effects of one of its constituents, pseudolycorine chloride (PLY), have not been reported yet.

OBJECTIVE:

We evaluated the effect of PLY on myeloid-derived suppressor cells (MDSCs) expansion and differentiation into monocyte-like MDSCs (M-MDSCs) and examined whether PLY alleviates Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS).

MATERIALS AND METHODS:

In vitro, MDSCs were treated with PLY (0.67, 2 and 6 μM) or solcitinib (10 μM, positive control) for 48 or 96 h, and their proliferation, expansion, and differentiation into M-MDSCs were examined by flow cytometry. Myelin oligodendrocyte glycoprotein (MOG_35-55) was used to induce EAE in female C57BL/6 mice, and the mice were treated with 40 mg/kg/d PLY or 1 mg/kg/d FK-506 (tacrolimus, positive control) for 21 days. Inflammatory infiltration, spinal cord demyelination, and MDSCs and Th17 cells infiltration into the spinal cord were examined using haematoxylin and eosin staining, Luxol fast blue staining, and immunofluorescence, respectively.

RESULTS:

In vitro, PLY (IC50/24 h = 6.18 μM) significantly inhibited IL-6 and GM-CSF-induced MDSCs proliferation, expansion and differentiation into M-MDSCs at all concentrations used. However, these concentrations did not show cytotoxicity. In mice, PLY (40 mg/kg) treatment alleviated EAE and inhibited inflammatory infiltration, demyelination, and MDSCs and Th17 cells infiltration into the spinal cord.

DISCUSSION AND CONCLUSIONS:

PLY may be an excellent candidate for the treatment of MS and other autoimmune diseases.

项与索西替尼相关的新闻（医药）

2021-01-29

·佰傲谷BioValley

风波叒起，辉瑞JAK抑制剂Ⅳ期临床研究失败

昨日（2021年1月27日），辉瑞在声明中宣布，其JAK抑制剂Xeljanz在一个叫做ORAL Surveillance的类风湿关节炎（RA）Ⅳ期临床研究中未能达到主要终点。错过主要终点 Xeljanz是一种janus激酶1（JAK1）和janus激酶3（JAK3）的抑制剂，可选择性抑制JAK激酶，阻断JAK/STAT通路，该信号通路是一条由细胞因子刺激的信号转导通路，参与细胞的增殖、分化、凋亡以及免疫调节等多个重要的生物学过程。 Xeljanz也是第一个上市的JAK抑制剂，目前获批四个适应症：治疗中度至重度活动性类风湿性关节炎（RA）成人患者；治疗活动性银屑病关节炎（PsA）成人患者；治疗中度至重度溃疡性结肠炎（UC）成人患者；治疗≥2岁、有活动性多关节病程的幼年特发性关节炎（pcJIA）儿童和青少年患者。此外，Xeljanz治疗强直性脊柱炎(AS)的适应症正被FDA审查。 ORAL Surveillanc是一项FDA要求Xeljanz上市后安全性研究，共计入组了4362名受试者，主要评估两种剂量Xeljanz（5mg和10mg，每天两次）与TNF抑制剂（TNFi）相比，治疗50岁或以上、至少有一个额外心血管危险因素的类风湿关节炎（RA）患者的安全性。该研究的主要终点是在主要心血管不良事件（MACE）和恶性肿瘤（不包括非黑色素瘤皮肤癌 -NMSC）方面，与TNFi相比，Xeljanz的非劣效性。结果显示，在对Xeljanz联合剂量与TNFi进行初步比较后发现，不符合预先规定的非劣效性标准，该研究未达到共同主要终点。根据预先指定的二级比较，两种剂量的Xeljanz治疗组在主要终点上没有差异。这项研究是FDA要求的上市后试验，包括了4362名接受研究治疗的受试者，初步分析发现，Xeljanz治疗组出现了135例MACE患者和164例恶性肿瘤患者（不包括NMSC）。基于Cox比例风险模型分析显示，Xeljanz组有98例发生心血管事件，而TNFi组只有37例；122名服用Xeljanz的患者诊断出了癌症，而42名服用TNFi的患者诊断出了癌症。根据该药物治疗患者的报告数据分析，最常见的MACE是心肌梗死，最常见的恶性肿瘤（不包括NMSC）是肺癌。在已知的MACE和恶性肿瘤危险因素患病率较高的受试者中（如年龄较大、吸烟），所有治疗组的MACE和恶性肿瘤事件发生率都较高。阴霾笼罩事实上，不良反应问题一直Xeljanz研发以来就面临的挑战，一直伴随着Xeljanz进入市场。FDA于2018年给出了引发肺栓塞的安全警告。2019年，Xeljanz又收到了FDA “较高剂量的Xeljanz存在肺部血栓和死亡风险” 的药物安全红色警告。同年7月，FDA进一步收紧了对Xeljanz的限制，不仅为其添加了一项黑框警告，还严格限制了10mg Xeljanz的处方。Xeljanz因安全隐患此被EMA拒绝上市，直到2017年辉瑞提供了补充数据才得以在欧盟上市。安全性问题不只是Xeljanz独有，其他多款被批准治疗RA上市的JAK抑制剂都面临着不同程度的安全性挑战。在研究数据提示严重血栓风险后，FDA只批准了礼来低剂量Olumiant，同时要求Olumiant在说明书中增加黑框警告等内容，明确告知服用后的潜在风险。拒绝高剂量的理由是需要更多数据以明确该药物治疗的安全问题。去年获FDA批准上市的Rinvoq（艾伯维）也没能逃过安全阴霾，标签上也同样附带血栓风险的黑框警告。另外，吉利德和Galapagos联合开发的JAK1选择性抑制剂filgotinib，虽在欧盟和日本获批，但在美上市进度就因安全隐患问题受阻，去年8月filgotinib的上市申请出人意料的遭到FDA拒绝，在完全回复函（CRL）中，FDA表示了对200mg剂量filgotinib的整体收益风险状况的担忧，FDA表示需要通过对来自于MANTA和MANTA-RAy临床研究的数据以完成上市审评。受此打击，吉利德已宣布暂停filgotinib在银屑病关节炎的III期临床研究、强直性脊柱炎、葡萄膜炎的II期临床研究。除了已经上市的产品外，正在临床开发阶段的JAK抑制剂也在突破安全性障碍上困难重重，葛兰素史克开发的Solcitinib在Ⅱ期临床试验中由于严重的不良事件（肝酶升高，药疹伴嗜酸粒细胞增多和系统症状）以及与他汀类药物相互作用而停止该药的开发。Vertex公司的开发的JAK3抑制剂Decernotinib在一项治疗RA的Ⅱ/Ⅲ期临床试验中，引起中性粒细胞减少，目前已终止研究，停止了针对RA适应症的临床开发。总结 JAK抑制剂竞争还是不小的，8款获批上市，11款产品进入III期临床阶段。但安全性这个最为紧要的问题仍然没能得到实质性解决，现在看来，辉瑞的这款药物存在的心血管以及致癌风险使其市场推广面临更大的挑战。不过，从作用机制上来看，JAK抑制剂属于广谱性免疫抑制剂，本身存在的安全性风险就很高。对于加入这个赛道的新玩家而言，若能在其安全性方面有所突破，那将在这个领域具备很大的话语权。参考出处： 1.https://www.biospace.com/article/pfizer-s-ra-hopeful-fails-to-meet-co-primary-endpoint-in-safety-study/ 2.https://endpts.com/pfizers-xeljanz-flunks-its-post-marketing-safety-study-renewing-harsh-questions-for-jak-class/ 版权声明：本文转自佰傲谷，如不希望被转载的媒体或个人可与我们联系，我们将立即删除【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。点分享点点赞点在看

免疫疗法

2014-08-08

·BioSpace

Galapagos NV, GlaxoSmithKline Abandon Joint Drug Project Due To Adverse Effects

Galapagos, GlaxoSmithKline Abandon Joint Drug Project Due To Adverse Effects var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false}); August 8, 2014 By Krystle Vermes , BioSpace.com Breaking News Staff Belgian biotech firm Galapagos has announced that its partner, GlaxoSmithKline , has stopped their joint drug development project , according to Reuters. The company reportedly did so out of concerns about the adverse effects that could come from the drug. The two companies were working to develop a drug called GSK2586184, which would have been used to treat ulcerative colitis and psoriasis. GlaxoSmithKline decided to stop the joint project because they determined that it would not mix well with certain types of cholesterol drugs. GlaxoSmithKline is considering next steps in the process now that development has ceased. Until then, Galapagos is not authorized to comment on the matter. Investors of Galapagos now wonder if they should be concerned about other drugs in its portfolio, such as JAK1 inhibitors and GLPG0634, which is the company’s most developed product. GLPG0634 is the result of a partnership with the U.S. group, AbbVie . This drug is designed to treat rheumatoid arthritis in patients. “I think investors are now worried about the company’s main product which is a large part of its valuation,” KBC Securities analyst Jan De Kerpel told Reuters. Galapagos has carried out testing for GLPG0634 and has not seen any adverse side effects, which would mean that investors have little to worry about. However, the recent news on its joint project coming to a standstill has resulted in the drop of shares to a two-year low. As 2014 winds down, Galapagos claims that it will have more cash than originally thought when the year comes to an end. This is primarily because of its sale of its services division. Galapagos is on pace to have 175 million (approximately $234 million U.S. dollars) Euros at the end of 2014, which is 5 million above its initial prediction. Galapagos has fluctuated numerous times throughout the year. In March, it forecasted its revenue to be 180 million, but then lowered it to 100 million as the result of expected payouts from drug development programs. However, the future looks bright for Galapagos as of now. Several test results are slated to become available to the company within the next 18 months. As a result, shares may increase in value. Regardless of what happens with this shelved project with GlaxoSmithKline, Galapagos has established a presence in the industry that will carry it through the controversy. Read more recent phase II news . var switchTo5x=true;

财报临床2期引进/卖出临床失败

100 项与索西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
斑块状银屑病	临床2期	德国	GSK Plc	2013-03-01
斑块状银屑病	临床2期	英国	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	美国	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	阿根廷	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	智利	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	捷克	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	爱沙尼亚	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	法国	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	德国	GSK Plc	2013-03-01
系统性红斑狼疮	临床2期	希腊	GSK Plc	2013-03-01

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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


NCT01782664 (CTgov)	临床2期	斑块状银屑病	68	Placebo	獵製醖醖築蓋獵繭鹹遞 = 齋鏇廠醖簾廠願範廠繭鏇襯壓壓廠簾窪廠鑰鬱 (積簾簾窪蓋選構觸鑰窪, 壓願製鏇壓艱觸鏇衊餘 ~ 鹹餘獵構製獵糧網憲網) 更多	-	2017-08-03
NCT01777256 (JAK115919, Pubmed \| Lupus) 人工标引	临床2期	系统性红斑狼疮	50	GSK2586184	膚夢憲顧壓鏇窪鏇簾壓(遞築窪膚襯淵範鏇壓襯) = Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. 範淵鏇夢獵蓋網選鑰餘 (願築築膚願獵窪艱淵製 )	不佳	2016-11-01
				Placebo
ECCO2016	N/A	活动性重度溃疡性结肠炎	2	GSK2586184 400 mg b.i.d.	鏇範鹹艱鏇憲簾遞鹽衊(鹹醖鏇築鹹製鹹衊顧憲) = GSK2586184 was well tolerated and no serious adverse events or drug related adverse events were reported 鑰網願願範範簾壓鬱艱 (壓餘鏇餘夢壓衊淵繭憲 )	积极	2016-02-12
				Placebo