Randomized, Double-Blinded, Placebo-Controlled Phase 2 Study for the Long Term Evaluation of Fostamatinib for the Treatment of Adult Patients With Acute Respiratory Distress Syndrome (ARDS)

This study is designed to evaluate the safety and efficacy of fostamatinib in hospitalized adult participants with acute respiratory distress syndrome (ARDS).

开始日期2026-08-30

申办/合作机构

Inova Health Care Services

[+2]

NCT06948097

/ Not yet recruiting临床1期IIT

Syk Inhibition in MItigating Lung Allograft Rejection (SIMILAR): A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose Escalation Trial to Evaluate the Safety and Tolerability of Fostamatinib in Lung Transplant Patients With Donor-Specific Antibodies.

Background:
People who have lung transplants often survive 6 or 7 years. But some people develop donor-specific antibodies (DSA) after their transplants; antibodies are proteins that attack foreign invaders in the body. Antibodies typically kill viruses and other agents that can cause disease. But when the antibodies attack a transplanted organ, they can cause the body to reject the new tissues. People who develop DSA after a transplant have a higher risk of death within 1 year.
Objective:
To test a drug called fostamatinib in people who develop DSA after a lung transplant.
Eligibility:
Adults aged 18 and older who developed DSA after a lung transplant.
Design:
Participants will continue with their standard care after a transplant.
Fostamatinib is a pill taken by mouth. Some participants will take the study drug along with their standard care; others will take a placebo. A placebo is a pill that looks just like the real drug but contains no medicine. All participants will take 1 pill per day for 2 weeks. Then they will take 2 pills per day for the next 6 weeks.
Participants will have clinic visits every 2 weeks while taking their pills. They will have a physical exam, with blood and urine tests, during each visit.
If participants have fluid samples collected from their airways during their standard treatment, some extra fluid may be collected for this study.
Participants will have a follow-up visit 4 weeks after they stop taking their pills.

开始日期2026-07-02

申办/合作机构

National Heart, Lung & Blood Institute

NCT05509582

/ Withdrawn临床2期IIT

Extension Study (Extended Access) of Syk-inhibition Using Fostamatinib to Treat Post-Transplant Immune-mediated Cytopenias

Background:
People who have a blood stem cell transplant can sometimes develop cytopenia. This means that their levels of one or more types of blood cell, such as the red cells or platelets, are lower than they should be. This can occur because a person s immune system might attack these cells after a stem cell transplant. Up to 20% of people who have blood stem cell transplants develop cytopenias, which can lead to anemia, severe bleeding, infections, and other problems. Treatments are needed to help keep blood cell levels stable after blood stem cell transplant.
Objective:
To evaluate the long-term effects of a study drug (fostamatinib) in people with cytopenia after a blood stem cell transplant.
Eligibility:
People who responded well to fostamatinib in an earlier study.
Design:
Participants will be screened. They will have a physical exam and blood tests.
Fostamatinib is an oral tablet taken by mouth. Participants will take the pills at the same dose and frequency as they did during the previous study. They will take the pills for up to 21 months. The dosage of the drug may be reduced over time if their blood cell levels are stable.
Participants will have a medical assessment every month. This can be with their local doctor or at the NIH clinic.
Participants will have blood tests every 3 months.
Participants will have a follow-up visit after they stop taking the drug. Their vital signs will be taken, and they will have blood drawn. They will answer questions about their health.

开始日期2025-11-07

申办/合作机构

National Heart, Lung & Blood Institute

100 项与福他替尼相关的临床结果

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100 项与福他替尼相关的转化医学

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100 项与福他替尼相关的专利（医药）

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557

项与福他替尼相关的文献（医药）

2026-06-07·Leukemia & Lymphoma

A phase I open label study of fostamatinib, a SYK inhibitor, in patients with lower-risk myelodysplastic syndrome and chronic myelomonocytic leukemia

Article

作者: Borthakur, G. ; Garcia-Manero, G. ; Chien, K. ; Hwang, H. ; Shneider, H. ; Huang, X. ; Romero, L. ; Bose, P. ; Pierce, S. ; DiNardo, C. ; Hatfield, M. ; Croden, J. ; Hammond, D. ; Short, N. ; Montalban-Bravo, G.

Lower-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are commonly managed with erythropoiesis-stimulating agents, luspatercept, or hypomethylating agents. Despite this, the disease often becomes refractory and patients develop transfusion dependence. Preclinical evidence suggests that targeting innate immune signaling, including NF-kB activation, may improve hematopoiesis. Fostamatinib, an oral SYK inhibitor approved for immune thrombocytopenia, was evaluated in a phase 1 open-label study in previously treated lower-risk MDS/CMML. Eleven patients received fostamatinib starting at 100 mg twice daily with dose escalation for lack of response. Patients had received a median of 3 prior therapies and most were transfusion-dependent. Over a median of 5 treatment cycles and 14.4 months of follow-up, no objective responses were observed, although all patients achieved stable disease. Transfusion needs remained largely unchanged. There were no dose-limiting toxicities. Although safe, fostamatinib demonstrated no clinical benefit, underscoring the need for alternative strategies to modulate inflammatory signaling in MDS/CMML.

2026-06-01·TRANSFUSION AND APHERESIS SCIENCE

Spleen tyrosine kinase inhibitors for immune thrombocytopenia: A meta-analysis of randomized controlled trials

Review

作者: Pereira, Nivia Lavinia Chagas ; Oliveira Torres, Francisco Brenon de ; Santos, Letícia Oliveira Souza ; Saldanha, Artur ; Costa, Milton Vieira

BACKGROUND:

Spleen tyrosine kinase (SYK) inhibitors have shown clinical benefit in immune thrombocytopenia (ITP), but a comprehensive meta-analysis, including comparative efficacy and safety across agents, is still lacking.

OBJECTIVE:

This paper aims to evaluate the efficacy and safety of SYK inhibitors in adults with chronic primary ITP and explore potential differences across agents.

METHODS:

We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (RCTs). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. The primary efficacy outcome was the stable response rate. Secondary endpoints included platelet count improvements and rescue therapy need. Safety outcomes included adverse events (AEs).

RESULTS:

Four RCTs (n = 372) were included, evaluating two SYK inhibitors: fostamatinib (3 studies: FIT-1, FIT-2, and Kuwana et al.) and sovlepenib (1 study: Hu et al.). SYK inhibitors significantly improved stable response versus placebo (RR 17.77; 95% CI 5.13-61.61; P < 0.00001), a large effect influenced by very low response rates in placebo groups. Overall response was also higher (RR 4.17; 95% CI 2.63-6.61; P < 0.0001). Among individuals with pronounced thrombocytopenia at baseline, SYK inhibitors increased platelet counts (≥30 × 10⁹/L and ≥20 × 10⁹/L) at weeks 12 and 24. While bleeding and severe AEs were similar between groups, SYK inhibitors reduced rescue treatment but increased AEs, particularly hypertension.

CONCLUSION:

SYK inhibitors may represent promising treatment options for chronic primary ITP; however, the small number of trials and limited head-to-head evidence warrant cautious interpretation, particularly regarding comparisons across agents.

2026-06-01·Lancet Rheumatology

Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study

Article

BACKGROUND:

Systemic sclerosis is an immune-mediated inflammatory disease with marked sex differences in prevalence and severity. Although genome-wide association studies (GWAS) have advanced the understanding of systemic sclerosis genetics, sex-aware approaches remain scarce. We aimed to address this gap by examining autosomal sex-specific genetic factors in systemic sclerosis.

METHODS:

Based on a chromosomal definition of sex, we conducted a sex-stratified autosomal meta-analysis of GWAS in systemic sclerosis. We retrieved patient-level and control data from a previous GWAS for systemic sclerosis and newly recruited participants from an international multicentre collaboration (data cutoff June 1, 2024). Adult patients (aged ≥18 years) were required to meet the 2013 American College of Rheumatology-European League Against Rheumatism classification criteria or the criteria for early systemic sclerosis proposed by LeRoy and Medsger, 2001. Patients with systemic sclerosis were compared with healthy controls through sex-stratified analyses. Sex-specific loci were functionally annotated and a sex-differential expression analysis was performed to validate the findings. Additionally, we performed a drug repurposing analysis to explore the clinical implications of our findings. People with lived experience of systemic sclerosis were not involved in the study design or conduct.

FINDINGS:

After quality control filtering, we included 10 653 patients with systemic sclerosis (1556 male and 9097 female) and 18 043 controls (6990 male and 11 053 female). We identified eight sex-specific loci associated with systemic sclerosis: one novel male-specific locus (BCL11A odds ratio [OR] 1·32 [95% CI 1·20-1·45], p=8·39 × 10^-9), two novel female-specific loci (IRF4 OR 0·78 [0·71-0·85], p=2·36 × 10^-8RPL3-PDGFB OR 1·19 [1·12-1·26], p=3·18 × 10^-8), and five previously known loci now characterised as female-specific. Functional analyses implicated 39 candidate genes, of which five (IL12RB2, ARHGAP31, UBL7, CSK, and MPI) showed sex-differential expression in patients with systemic sclerosis. Two approved drugs, fostamatinib and dasatinib, were identified as potential repurposing candidates for systemic sclerosis sex-aware treatment.

INTERPRETATION:

We report the first evidence of sex-specific genetic architecture in systemic sclerosis. These findings offer insight into the molecular basis of sex differences in the disease, highlighting both IL12RB2 gene and interferon signalling. These results also support the development of sex-aware precision medicine approaches.

FUNDING:

Instituto de Salud Carlos III, EU's Seventh Framework Program, and European Federation of Pharmaceutical Industries and Associations companies.

128

项与福他替尼相关的新闻（医药）

2026-06-11

·生物通

综述：细胞外囊泡作为ARDS肺内皮功能障碍的驱动因素：机制与治疗机遇

急性呼吸窘迫综合征（ARDS）是一种复杂的、危及生命的疾病，可由直接肺部损伤（如肺炎和误吸）以及间接肺外原因（包括脓毒症和创伤）引发。ARDS发病机制的一个关键驱动因素是肺内皮屏障的破坏。在过去的几十年里，广泛的研究已经阐明了在ARDS期间发生的急性肺损伤（ALI）病理生理过程中内皮细胞（EC）功能障碍的众多机制。研究人员已鉴定出一系列EC调节因子，以及旨在恢复EC完整性的治疗策略。最近，细胞外囊泡（EVs）已成为ARDS发病机制中的关键介质，作为内皮功能的有效调节因子。EVs源于肺部局部或远处组织，可到达肺血管系统，在那里它们放大炎症信号并破坏EC屏障完整性，从而加剧损伤和疾病严重程度。本综述总结了关于来自不同细胞、组织和器官来源的EVs如何导致ALI病理生理学中内皮功能障碍的最新进展。它还探讨了新兴的针对内皮的ARDS治疗方法，涵盖临床前和临床阶段，这些方法可能对抗EV介导的致病机制，并强调了仍有待解决的关键空白。**1 Introduction** 急性呼吸窘迫综合征（ARDS）是一种以严重呼吸窘迫、广泛肺部炎症和血氧饱和度降低为特征的临床状况，其发病机制涉及急性肺损伤（ALI）过程，主要由肺泡-毛细血管屏障破坏、中性粒细胞过度浸润和炎性介质释放驱动，最终导致肺水肿。肺内皮屏障是损伤的核心部位，其破坏导致对富含蛋白质的液体通透性增加和炎性细胞过度募集。肺内皮细胞（ECs）具有维持血管完整性、调节液体交换和参与免疫反应等多种功能。在ALI中，ECs被外部刺激（如细菌、病毒或酸）及内部介质（如活性氧（ROS）、凝血酶和细胞因子）驱动进入促炎状态，表现为黏附分子（VCAM-1、ICAM-1和选择素）上调、NF-κB信号激活、氧化应激及促炎细胞因子（如IL-6、IL-8、IL-1β）分泌增强。ALI损伤还触发增加内皮通透性的信号级联反应，通过细胞骨架重组和细胞间连接破坏导致屏障破坏。此外，ECs经历多种形式的程序性和非程序性死亡，进一步损害屏障完整性。细胞外囊泡（EVs）已成为介导细胞间通讯和器官间通讯的重要介质，越来越多的证据表明它们在ALI期间驱动肺内皮功能障碍。**2 EVs and Their Role in Endothelial Dysfunction in ALI/ARDS** EVs是由几乎所有细胞类型在生理条件及细胞激活或死亡时释放的脂质双层颗粒，根据大小分为小EVs（<200nm）和大EVs（>200nm）。早期研究按生物起源分类，外泌体属于小EV类别，由多囊泡体（MVBs）与质膜融合释放；微囊泡则直接从质膜出芽。国际细胞外囊泡学会（ISEV）建议使用通用术语“EVs”，除非特定EV群体被严格分离和表征。EVs携带多种货物，包括蛋白质、脂质、RNA（mRNA和miRNA）、DNA甚至线粒体等细胞器，通过自分泌、旁分泌或内分泌/外分泌方式将分子货物转移至靶细胞，介导细胞间和器官间通讯。实验和临床研究表明，EV产生在ALI/ARDS及相关条件中发生改变，来自不同细胞来源和组织的EVs参与肺损伤。由于肺内皮具有战略位置并与循环细胞持续相互作用，它是EV介导效应的首要靶点。**2.1 Lung Endothelial-Derived EVs** 肺血管内皮在损伤性刺激（包括细菌产物、机械牵张和细胞因子）下产生具有促炎特性的EVs。研究表明，EC（HUVEC）来源的EVs通过递送卵泡抑素样蛋白1（FSTL1）激活受体ECs中的TLR4/JAK3/STAT3/IRF-1信号通路，促进ALI。TNF-α刺激的HUVEC产生的EC-EVs通过携带c-Src破坏内皮细胞间连接，增加通透性。脂多糖（LPS）处理的EC来源的EVs通过转移miR-23b靶向ZO-1，增加体外和体内内皮通透性。EC来源的EVs还可通过间接机制促进屏障破坏，例如富含核转运蛋白亚基β-1（KPNB1）的EVs刺激中性粒细胞上调中性粒细胞弹性蛋白酶（NE），导致中性粒细胞反向跨内皮迁移，这些激活的中性粒细胞通过NE降解EC连接处的连接黏附分子-C（JAM-C），加重肺损伤。**2.2 Lung Epithelial-Derived EVs** 肺泡上皮细胞在ALI发病机制中起关键作用，感染性和非感染性刺激均可触发具有独特分子货物的上皮EV释放。高氧条件下，肺上皮EVs富含caspase-3，通过ROCK-1信号激活巨噬细胞炎症反应。LPS刺激后，大鼠肺泡上皮细胞来源的EVs携带miR-92a-3p，激活体外和体内巨噬细胞中的NF-κB信号，促进ALI。此外，肺泡上皮细胞暴露于肺炎链球菌的毒力因子肺炎球菌溶血素后，释放富含炎性线粒体成分的EVs，这些EVs被中性粒细胞摄取并调控其功能，同时可能靶向肺内皮，促进血管通透性增加和炎症。来自不同来源（包括肺泡上皮细胞）的富含线粒体成分的EVs可能作为肺内皮炎症和血管功能障碍的重要介质。**2.3 Immune Cell-Derived EVs** 单核细胞是导致肺EC功能障碍的重要EV来源。LPS处理的THP-1细胞释放携带活性caspase-1和gasdermin D的EVs，被肺微血管EC摄取后导致凋亡，且脓毒症合并ARDS患者中这类EVs水平升高。巨噬细胞-EC串扰在ALI中至关重要，LPS激活的巨噬细胞释放的EVs富含花生四烯酸（AA）代谢物，破坏EC屏障完整性，该效应依赖NFATc3信号。乳酸激活的巨噬细胞释放含HMGB1的EVs，诱导EC激活和连接破坏。巨噬细胞还可释放含SCIMP（SLP65/Csk相互作用膜蛋白）的EVs，作为外周中性粒细胞的趋化因子。耐甲氧西林金黄色葡萄球菌感染肺泡巨噬细胞后释放的EVs通过递送TNF-α和miR-146a-5p触发受体巨噬细胞的坏死性凋亡。中性粒细胞激活后释放EVs，其作用存在争议，既有促炎也有抗炎报道。fMLP、LPS或PMA激活的中性粒细胞产生的EVs富含miRNA（miR-142-3p、miR-451），可转移至微血管EC触发凋亡和促炎细胞因子释放。中性粒细胞来源的EVs还可包装活性NE，这些EVs通过Mac-1与胶原纤维结合并降解细胞外基质。**2.4 Platelet-Derived EVs** 激活的血小板释放大量具有促炎和促凝血特性的EVs。储存血液制品中的血小板来源EVs通过靶向内皮参与输血相关ALI（TRALI）的发病机制。随时间储存的血小板释放增加的EVs富含长链神经酰胺，并耗尽S1P，诱导内皮屏障破坏。凝血酶激活的血小板释放含有miR-223的EVs，直接诱导HUVEC凋亡。LPS触发的血小板EVs通过磷脂酰丝氨酸结合导致内皮屏障破坏，上调炎性细胞因子和黏附分子。登革热感染期间，血小板激活释放富含IL-1β的EVs，增强内皮通透性并刺激EC释放促炎标志物。**2.5 RBC-Derived EVs** 红细胞（RBC）输血与TRALI发病相关，储存的浓缩RBC（pRBCs）释放EVs，激活肺ECs释放促炎细胞因子（如IL-6和KC）并促进黏附分子（VCAM-1和ICAM-1）脱落。这些EVs通过蛋白激酶C（PKC）依赖性通路刺激肺EC释放P-selectin和血管性血友病因子（vWF）。RBC来源的EVs通过Rab5调节的内吞作用引起肺EC激活。细胞游离血红蛋白（CFH）及其代谢物（如血红素）可直接导致内皮激活和通透性增加，并可作为EV相关分子。**2.6 EVs Within the Alveolar Space** 在ARDS中，肺泡空间成为来自巨噬细胞、中性粒细胞、单核细胞、血小板、上皮细胞和EC等多种细胞类型EVs的丰富储库。这些肺泡EVs携带炎性介质和miRNAs，靶向下游细胞。LPS处理小鼠的支气管肺泡灌洗液（BAL）EVs携带TNF-α，在肺泡上皮细胞中诱导炎性信号。ARDS患者中，分泌型磷脂酶A2-IIA（sPLA2-IIA）与EVs相关。经鼻内LPS处理小鼠肺泡空间释放的EVs含有大量AA代谢物（前列腺素和HETEs），可直接导致内皮屏障破坏。**2.7 Circulating EVs** ARDS可由直接肺源性或间接肺外原因引起，脓毒症是最常见原因。循环EVs来自脓毒症、脑外伤、胰腺炎等，通过不同机制影响肺内皮。脓毒症诱导ARDS患者血浆EVs通过递送miR-210-3p靶向ATG7，导致肺EC炎症和自噬失调。盲肠结扎穿刺（CLP）模型大鼠EVs携带升高的miR-1-3p，靶向SERP1导致EC凋亡、炎症和通透性增加。循环EVs还携带S100A8/A9、mtDNA等分子促进内皮功能障碍。严重脑外伤患者血清EVs含有炎性小体蛋白ASC，触发人肺EC焦亡。急性胰腺炎小鼠模型循环EVs通过整合素与肺内皮相互作用，导致EC连接破坏和促炎信号。肥胖患者EVs携带降低的miR-150-5p，促进VE-cadherin内吞和溶酶体降解，增加内皮通透性。**2.8 Bacterial EVs** 细菌EVs具有强促炎特性。铜绿假单胞菌EVs导致肺微血管EC屏障破坏，并在低剂量LPS预处理小鼠中诱导肺损伤。大肠杆菌EVs被微血管EC内化，通过NF-κB和TLR4依赖性通路上调黏附分子（ICAM-1、VCAM-1和E-selectin）并刺激IL-8产生。肺炎克雷伯菌EVs通过下调SIRT1加速EC衰老和超氧阴离子生成。致病菌EVs转运毒力因子，如肺炎球菌溶血素、α-溶血素、LPS和脂磷壁酸，这些均是EC损伤的已知驱动因素。总体而言，不同来源的EVs通过共同的内皮损伤通路汇聚，包括破坏内皮连接、降解细胞外基质、上调黏附分子及增强炎性介质释放，促进持续的血管炎症。**2.8.1 Limitations and Considerations** 大多数关于EVs对内皮功能影响的证据来自体外研究，残留刺激可能混淆实验结果。研究人员采用多种验证策略，如在无血清条件下评估LPS处理细胞来源的EVs活性，或鉴定特定EV货物成分的因果作用。不同分离方案引入异质性，EV制备本质上呈异质性。研究使用了多种EC类型，肺微血管ECs具有特殊屏障功能，而HUVEC等大血管模型可能无法完全再现肺微血管反应。未来研究应解析不同EC亚型中的EV信号。**3 Emerging Therapeutics That Protect the Endothelial Barrier in ARDS** 鉴于内皮功能障碍在ARDS发病机制中的核心作用，开发内皮靶向治疗具有前景。本节总结临床和临床前阶段的治疗药物，并讨论其潜在的EV介导调节作用。**3.1 Therapeutics Under Clinical Development** **eNAMPT―ALT-100**: 胞外烟酰胺磷酸核糖转移酶（eNAMPT）作为损伤相关分子模式（DAMP）激活TLR4，导致EC屏障破坏和促炎信号。ALT-100单克隆抗体正进行2期临床试验（NCT05938036）。eNAMPT可在EVs中释放，NAMPT过表达促进EV释放。**TLR4―Paridiprubart**: 抗TLR4单抗paridiprubart在2期试验中评估（NCT06701669）。TLR4激活触发促炎EV释放，EVs可激活TLR4信号，阻断TLR4可减少有害EV产生。**C5a―Vilobelimab**: 补体C5a促进促炎或促凝血EV释放，抗C5a抗体vilobelimab和STSA-1002正在ARDS临床试验中。**VEGF―Bevacizumab**: VEGF增加血管通透性，抗VEGF抗体bevacizumab在2期试验中（NCT06701656）。VEGF可在EVs中包装，bevacizumab可能无法中和EV包裹的VEGF。**Syk―Fostamatinib**: Syk抑制剂fostamatinib在2期试验中（NCT06564207），其活性代谢物R406降低激活RBC和血小板的EV产生。**p38:MK2―GEn-1124**: GEn-1124抑制p38:MK2复合物，在2期试验中（NCT05795465），EVs可激活p38信号。**NE―Sivelestat**: 中性粒细胞弹性蛋白酶抑制剂sivelestat在脓毒症和ARDS临床试验中，NE丰富的EVs降解细胞外基质，sivelestat可能抑制EV相关NE的效应。**IL-1R―Anakinra**: IL-1受体拮抗剂anakinra在2期试验中（NCT05914454），IL-1β触发EV释放，EVs携带IL-1β，anakinra可阻断IL-1R信号。**Tie2/Ang―AV-001**: 血管生成素-1（Ang-1）模拟肽AV-001在2a期试验中（NCT05123755），EVs携带Ang-2和Ang-1。**CD14―IC14**: 抗CD14抗体IC14在2期试验中（NCT06513949），CD14+ EVs在脓毒症ARDS患者BAL中升高。**cAMP Modulators―Iloprost**: 前列环素类似物iloprost正在试验中，cAMP调节剂减少炎性EV产生，如ensifentrine预处理肺泡上皮细胞可减弱EV释放及其屏障破坏效应。**ENaC―Solnatide**: ENaC激活肽solnatide（AP301）在2b期试验中，ENaC可被EVs携带和激活。**MSC-Derived EVs―ExoFlo**: 骨髓间充质干细胞来源EVs在3期试验中（NCT05354141），通过传递功能性线粒体恢复EC功能。**3.2 Emerging Therapeutics in Pre-Clinical Development** **S1P/S1PR**: S1P类似物（如Tysiponate）增强EC屏障功能。EVs可作为S1P来源，S1P类似物如fingolimod改变循环EV水平和功能。**HMGB1**: HMGB1包装在EVs中，巨噬细胞通过EVs释放HMGB1激活炎性小体。**TRPV4**: TRPV4抑制可能中断EV介导的钙信号。激活血小板释放的EVs可触发血管平滑肌细胞TRPV4。**Cell-Free Hemoglobin**: CFH包装在EVs中，CFH靶向治疗可能影响EV释放和功能。**3.3 Limitations and Considerations** 治疗策略包括小分子和生物制剂，各有优缺点。单克隆抗体适合阻断EV与靶细胞相互作用，小分子可能更有效抑制EV生物发生和改变货物组成。ARDS的异质性（病因和亚表型）影响治疗反应，EV丰度、来源和效应可能因亚表型而异，整合EV谱与亚表型分析对精准靶向至关重要。**4 Conclusion** 肺内皮是ARDS损伤的关键部位，EVs来自局部和远处细胞组织，通过共同通路加剧屏障破坏。深入理解EV介导的内皮功能障碍机制对于开发保护内皮完整性、减轻肺损伤的靶向策略至关重要。

2026-06-01

·allsci.com

Agios bags license to Oscotec’s SYK inhibitor cevidoplenib in USD 165m deal

Agios Pharmaceuticals (Nasdaq: AGIO) announced a license deal to obtain exclusive global rights to cevidoplenib (SKI-O-703), a next-generation oral SYK inhibitor developed by South Korean biotech Oscotec (KOSDAQ: 039200), in a deal that could reach USD 165 million in disclosed payments plus undisclosed commercial milestones and tiered royalties. The Cambridge, Massachusetts-based rare disease company is betting on cevidoplenib’s differentiated tolerability profile to carve out a position in immune thrombocytopenia, a rare autoimmune blood disorder affecting an estimated 90,000 adults in the US. Under the terms, Oscotec receives a USD 25 million upfront payment and is eligible for up to USD 140 million in development and regulatory milestones tied to as many as three indications in the US and Europe. Agios will also pay tiered royalties ranging from high single-digit to mid-teen percentages on net sales. Oscotec retains an option to reacquire exclusive development and commercialization rights in South Korea following the release of Phase III trial results. Deal context Cevidoplenib is an oral small molecule that inhibits spleen tyrosine kinase, or SYK, a signaling enzyme involved in both Fc gamma receptor-mediated platelet destruction by macrophages and B cell receptor-driven autoantibody production. Both pathways are central to ITP pathophysiology, in which autoantibodies mark platelets for immune-mediated clearance, resulting in dangerously low platelet counts and elevated bleeding risk. SYK inhibition as a mechanism in ITP is clinically validated — Rigel Pharmaceuticals’ fostamatinib (Tavalisse) was the first approved SYK inhibitor in the indication — but cevidoplenib is described by Oscotec as a next-generation compound with enhanced selectivity designed to reduce the off-target activity associated with first-generation agents. The asset has been evaluated in a global, randomized, double-blind, placebo-controlled Phase II trial (NCT04056195) enrolling 60 adults with persistent or chronic ITP who had relapsed after or were refractory to at least one prior therapy. Patients were heavily pretreated: 68.3% had received three or more prior lines of therapy, and 68.3% had platelet counts below 15,000 per microliter at baseline. The trial’s primary endpoint — platelet count at or above 30,000 per microliter with at least a doubling from baseline, without rescue medication — did not achieve statistical significance. However, Agios has pointed to durable responses across secondary endpoints aligned with primary endpoints used in ITP registrational trials, as well as a clean tolerability signal, with transient liver enzyme elevations and gastrointestinal events as the most commonly reported treatment-related adverse events. Cevidoplenib received FDA orphan drug designation for ITP in March 2024, conferring potential seven-year market exclusivity and tax advantages. Agios expects to initiate Phase III development in H1 2028, pending completion of chemistry, manufacturing, and controls work. Oscotec has been an active licensor in 2026. In March, Yatiri Bio optioned global rights to Oscotec’s multikinase inhibitor denfivontinib for acute myeloid leukemia, establishing a pattern of the Korean company licensing individual assets to Western partners while retaining optionality in its home market. The economics are modest for a late-stage rare disease asset but consistent with the uncertainty around cevidoplenib’s Phase II dataset. The trial missed its primary endpoint, limiting the basis for a larger upfront commitment, while the secondary response signals, tolerability profile and orphan drug designation give Agios a rationale to move the program into Phase III. The USD 25 million upfront payment therefore reads as a relatively low-risk entry point, with most of the deal value deferred into development, regulatory and commercial milestones. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Copyright © 2026. AllSci Corp. All rights reserved.

2026-05-22

·今日头条

【脑类器官】病毒 “细胞周期密码” 破解：吉林大学白求恩第一医院团队以脑类器官解码TBEV致病新机制

蜱传脑炎病毒（TBEV）是蜱媒传播的黄病毒，会侵入中枢神经系统，引发脑炎、脑膜炎等重症，致死率与后遗症风险高，严重威胁公共健康。目前尚无特效抗病毒药物，疫苗存在突破感染风险，其致病机制、病毒 - 宿主互作网络尚不清晰，制约治疗靶点开发。黄病毒常通过劫持宿主通路实现复制，既往研究多聚焦单一病毒蛋白，缺乏系统性互作解析，且传统细胞模型难以模拟神经感染微环境，脑类器官作为 3D 神经模型，为 TBEV 致病机制与药物筛选提供了理想工具。 2026年4月，吉林大学白求恩第一医院刘全教授团队在期刊《iScience》（IF：4.1）发表了题为：Virus-host interactome reveals host cellular pathways perturbed by tick-borne encephalitis virus infection 的研究论文。团队系统绘制 TBEV - 宿主互作图谱，鉴定 583 个高置信互作靶点，发现病毒靶向免疫、自噬、细胞周期等核心通路。明确NS5 蛋白结合 P300，上调 P16、下调 CDK4，诱导宿主 G0/G1 期阻滞，助力病毒复制。该机制在脑类器官中得到验证，证实 TBEV 直接调控神经细胞周期。筛选出 P300 抑制剂、CDK4 激动剂等 9 种候选药物，可显著抑制病毒复制，为抗 TBEV 治疗提供新策略。全景绘制：TBEV - 宿主互作网络图谱研究通过亲和纯化 - 质谱技术，全面解析 TBEV 全蛋白（结构 + 非结构）与宿主蛋白的互作关系，鉴定 583 个高置信互作靶点（图 1）。富集分析显示，这些靶点集中在天然免疫、自噬、核糖体合成、细胞周期等关键通路，揭示病毒多维度劫持宿主的策略（图 2）。对比其他黄病毒（登革、寨卡），TBEV 与寨卡病毒互作模式更相似，为黄病毒共性机制研究提供参考。系统构建蜱传脑炎病毒（TBE）与宿主蛋白互作网络。通过亲和纯化 - 质谱技术，鉴定出583 个高置信互作蛋白，覆盖 TBEV 全部结构与非结构蛋白（图 1A、B）。富集分析显示，互作蛋白集中在天然免疫、自噬、核糖体合成、细胞周期等关键通路（图 1C）。对比登革热、寨卡等黄病毒，TBEV 与寨卡病毒共享 55 个宿主因子，互作模式更接近（图 1D、E）。核心互作蛋白如 PAF1、LEO1 等，参与转录调控，为理解 TBEV 重编程宿主机制提供全景视角，也为后续机制研究锁定关键靶点。聚焦 TBEV 各蛋白的特异性互作与功能富集。结果显示，NS5 主要富集于染色质重塑、核糖体合成相关蛋白（图 2A）；prM 偏向自噬与泛素化通路；NS2B/NS3 关联内质网降解过程。通过免疫共沉淀，验证了prM-CHUK、NS5-PAF1/LEO1等关键互作（图 2B-E）。结合磷酸化、乙酰化修饰数据，发现 TBEV 感染可调控 LEO1 等蛋白的转录活性（图 2F）。该图明确不同病毒蛋白的分工：NS5 主导核内转录调控，prM 干扰免疫与自噬，为解析 TBEV 多蛋白协同致病提供直接证据。通路破解：锁定细胞周期调控关键机制通过网络扩散分析，聚焦 TBEV 对细胞周期的调控作用（图 3）。实验证实，TBEV 感染会诱导宿主细胞 G0/G1 期阻滞，且呈病毒剂量依赖性，该状态可显著促进病毒基因表达（图 4）。多细胞系验证发现，从感染后 12 小时开始，细胞即出现周期偏移，持续至 48 小时，明确周期阻滞是 TBEV 复制的关键 “宿主适配策略”。整合互作组与蛋白质组数据，解析 TBEV 干扰的核心通路。网络扩散分析显示，TBEV 多蛋白协同调控自噬、DNA 损伤、细胞周期、核糖体合成四大模块（图 3A）。NS5 通过 UTP14、Imp4 等互作，抑制核糖体 RNA 合成（图 3B）；prM 通过 AKT1、VPS11 激活自噬（图 3C）；NS5 还结合 SMARCA2 等，重塑染色质状态（图 3D）。特别发现，TBEV 靶向细胞周期 G1/S 检查点，为病毒复制创造有利环境（图 3E）。该图从全局揭示 TBEV 通过多靶点、多通路协同破坏宿主稳态，为后续机制研究指明方向。证实 TBEV 感染可诱导细胞G0/G1 期阻滞，且呈剂量与时间依赖性。流式结果显示，感染后 G0/G1 期细胞比例由 61.12% 升至 71.04%，S 期比例显著下降（图 4A、B）。动态监测发现，感染 12 小时即出现周期偏移，持续至 48 小时（图 4C）。同步化细胞实验表明，无论初始周期阶段，TBEV 均能推动细胞向 G0/G1 期聚集（图 4D-I）。G1 期同步化可显著增强病毒复制（图 4J），证实G0/G1 期环境利于 TBEV 增殖。该图明确 TBEV 通过调控细胞周期创造复制优势，揭示病毒关键致病策略。核心揭秘：NS5-P300 轴驱动周期紊乱进一步探究机制，发现病毒 NS5 蛋白是诱导周期阻滞的核心因子，其可直接结合组蛋白乙酰转移酶 P300（图 5）。该结合依赖 P300 酶活性，会上调抑癌蛋白 P1、下调周期蛋白 CDK4/6，最终触发 G0/G1 期阻滞。脑类器官模型验证（图 6）：TBEV 感染类器官后，CDK4 表达显著降低、P16 升高，与细胞实验结果一致，精准模拟神经感染的周期紊乱特征。揭示 TBEV NS5 蛋白通过结合 P300 诱导 G0/G1 阻滞。过表达实验显示，NS5 是诱导周期阻滞的核心病毒蛋白，且呈剂量依赖性（图 5A、B）。免疫共沉淀与荧光共定位证实 NS5 与组蛋白乙酰转移酶 P300 直接互作（图 5C、D）。NS5 过表达上调 P16、下调 CDK4/6，触发 G1 期停滞（图 5E-G）。P300 酶活突变体可逆转该效应，敲低 P300 则抑制 NS5 介导的周期紊乱（图 5H-K）。机制上，NS5 劫持 P300 的乙酰化功能，激活 P16 转录、抑制 CDK4，形成NS5-P300-P16-CDK4调控轴，为抗 TBEV 靶点提供精准方向。模型实证：脑类器官复刻神经感染特征脑类器官作为核心验证模型，由诱导多能干细胞分化而成，含神经元、神经祖细胞等，模拟人类大脑发育微环境（图 6B-D）。TBEV 感染后，类器官可支持病毒复制（图 6E-F），且重现 CDK4 下调、P16 上调的周期调控异常（图 6G），填补传统细胞模型无法模拟神经组织感染的空白，为机制验证提供生理相关模型。利用人源脑类器官验证 TBEV 对神经细胞周期的影响。成功构建含神经元（TUJ1）、神经干细胞（SOX2）、少突胶质细胞（Olig2）的脑类器官（图 6B-D）。TBEV 感染后，类器官中CDK4 表达显著降低、P16 表达升高，与细胞实验结果高度一致（图 6E-G）。免疫荧光显示病毒 NS1 蛋白在类器官中广泛分布，证实感染成功（图 6E、F）。该类器官模型模拟人类神经组织微环境，首次在 3D 神经组织中证实 TBEV 诱导周期紊乱，为研究 TBEV 神经致病机制提供生理相关模型，弥补传统细胞模型不足。药物筛选：靶向周期轴阻断病毒复制基于机制，筛选 P300 抑制剂（C646、CPI-637）、CDK4 激动剂（白杨素）等药物（图 7）。实验证实，这些药物可逆转 TBEV 诱导的周期阻滞，显著抑制病毒 RNA 与蛋白表达。扩大筛选获得 9 种候选药物（图 8），靶向 P300、XIAP 等靶点，为抗 TBEV 药物研发提供候选分子。验证靶向P300-CDK4 轴的抗病毒策略有效性。P300 抑制剂 C646、CPI-637 可剂量依赖性抑制 TBEV 复制，IC₅₀低至 1.46 μM（图 7A、B），并逆转病毒诱导的 G0/G1 阻滞（图 7F）。CDK4 激动剂白杨素（Chrysin）同样显著抑制病毒，IC₅₀达 0.81 μM（图 7I）。机制上，P300 过表达促进病毒复制，酶活突变体则抑制（图 7G、H）；白杨素通过激活 CDK4 恢复细胞周期，阻断病毒利用 G0/G1 期环境（图 7J-L）。该图证实抑制 P300 或激活 CDK4可有效抗 TBEV，为临床治疗提供宿主靶向新策略。基于互作网络筛选潜在抗 TBEV 药物。聚焦病毒 - 宿主关键互作，锁定P300、CDK4、XIAP、RIOK1、KAT6A等可药靶点（图 8A）。筛选发现，舒尼替尼（Sunitinib）、福他替尼（Fostamatinib）抑制 RIOK1/BRD9，IC₅₀达 0.17 μM（图 8B）；地喹氯铵靶向 XIAP，IC₅₀为 0.27 μM（图 8C）；WM-1119 抑制 KAT6A，有效抑制病毒（图 8D）。这些药物多为临床已批准或进入临床试验，成药性高、广谱潜力大。该图提供多靶点、低耐药风险的抗 TBEV 候选药物库，为后续药物研发与临床转化奠定基础。本研究首次系统绘制 TBEV - 宿主互作全景图，破解病毒通过 NS5-P300 轴调控细胞周期、促进复制的核心机制，脑类器官的应用为神经病毒致病机制研究提供了关键模型支撑。研究筛选的 9 种候选药物，为 TBEV 特效治疗提供全新方向，突破现有无针对性药物的困境。未来，可基于该互作网络开发广谱抗黄病毒药物，推动类器官在病毒药物高通量筛选、疫苗研发中的应用；同时深入探究 TBEV 神经损伤的深层机制，为降低后遗症风险提供理论基础，助力蜱传脑炎的精准防控。参考文献：

100 项与福他替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09348	福他替尼	B02BX09	DB12010

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
免疫性血小板减少症	美国	Rigel Pharmaceuticals, Inc.	2018-04-17
血小板减少症	美国	Rigel Pharmaceuticals, Inc.	2018-04-17

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性特发性血小板减少性紫癜	申请上市	韩国	JW PHARMACEUTICAL Corp.	-
新型冠状病毒感染	临床3期	美国	Rigel Pharmaceuticals, Inc.	2021-03-25
新型冠状病毒感染	临床3期	阿根廷	Rigel Pharmaceuticals, Inc.	2021-03-25
新型冠状病毒感染	临床3期	巴西	Rigel Pharmaceuticals, Inc.	2021-03-25
新型冠状病毒感染	临床3期	墨西哥	Rigel Pharmaceuticals, Inc.	2021-03-25
自身免疫性溶血性贫血	临床3期	美国	Rigel Pharmaceuticals, Inc.	2019-04-24
自身免疫性溶血性贫血	临床3期	澳大利亚	Rigel Pharmaceuticals, Inc.	2019-04-24
自身免疫性溶血性贫血	临床3期	奥地利	Rigel Pharmaceuticals, Inc.	2019-04-24
自身免疫性溶血性贫血	临床3期	白俄罗斯	Rigel Pharmaceuticals, Inc.	2019-04-24
自身免疫性溶血性贫血	临床3期	比利时	Rigel Pharmaceuticals, Inc.	2019-04-24

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临床结果

适应症

分期

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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


NCT04904276 (FORTE, EHA2026)	临床4期	免疫性血小板减少症二线	15	Fostamatinib	範鏇窪鬱壓鑰餘淵構積(餘顧鑰艱製鏇淵鹽襯膚) = 壓選繭鏇窪構積遞範齋窪襯顧遞構襯醖餘餘艱 (糧鑰獵艱積繭鑰構鹽夢 ) 更多	积极	2026-05-12
EHA2026	N/A	免疫性血小板减少症	97	TPO-RAs	鹽製鏇齋製齋艱獵範遞(網膚觸衊淵餘鹹簾遞鬱) = 鬱鹽製願願蓋選構廠範範製繭鬱範鬱願窪築範 (醖窪願糧醖憲憲壓築構 ) 更多	积极	2026-05-12
EHA2026	N/A	免疫性血小板减少症	97	TPO-RAs	鹽蓋觸膚積鬱糧製觸糧(構襯衊築鏇範遞築憲壓) = 觸鹽構鏇醖簾淵糧範選繭構築繭夢顧鬱襯膚蓋 (遞顧膚壓鑰鑰鬱鬱鏇憲 )	积极	2026-05-12
ASH2025	N/A	免疫性血小板减少症	30	Fostamatinib	膚鹹夢窪繭鑰廠製壓鏇(繭鹽築範淵獵醖糧獵衊) = shorter Lag Time (LT) in thrombin generation associated with PS content of microparticles (MPs) in relapsed patients 鑰構衊膚廠餘網淵製製 (壓構膚製鏇獵醖鹽鹽築 )	积极	2025-12-06
ASH2025	N/A	免疫性血小板减少症	164	Fostamatinib	壓簾獵選艱範遞鹽蓋餘(鑰鏇醖膚憲襯簾獵範壓) = 醖鏇繭鹽鹹憲窪齋窪鬱鏇遞範鏇獵觸選願壓積 (鏇壓窪願餘願鏇鏇憲觸 ) 更多	积极	2025-12-06
NCT05502783 (CTgov)	临床2期	免疫性血小板减少症 \| 慢性移植物抗宿主病 \| 血细胞减少症 ... 更多	1	fostamatinib	鹹遞襯構襯壓廠壓築蓋 = 鹹壓選範膚憲鏇製糧選鬱鑰顧築齋製淵窪築構 (顧觸廠膚願壓夢餘夢膚, 淵簾壓淵遞壓膚糧鏇顧 ~ 醖淵繭獵壓膚鑰鑰餘糧) 更多	-	2025-12-05
NCT04132050 (CTgov)	临床3期	免疫性血小板减少症 \| 慢性特发性血小板减少性紫癜	34	R788 (R788 Group)	築鑰鬱夢壓獵膚襯簾夢 = 醖膚淵網積鏇鹹繭糧構獵蓋窪構鹽鹹鹹願衊網 (齋淵遞遞醖壓網窪觸壓, 願壓齋積夢簾鏇艱蓋願 ~ 鑰夢糧鹹鏇築夢廠襯廠) 更多	-	2025-08-11
NCT04132050 (CTgov)	临床3期	免疫性血小板减少症 \| 慢性特发性血小板减少性紫癜	34	Placebo (Placebo Group)	築鑰鬱夢壓獵膚襯簾夢 = 網鹹艱衊糧構築艱蓋糧獵蓋窪構鹽鹹鹹願衊網 (齋淵遞遞醖壓網窪觸壓, 顧選範齋顧蓋鬱衊糧繭 ~ 壓襯鑰範選蓋醖簾構獵)	-	2025-08-11
NCT05030675 (PS1637, EHA2025)	临床1期	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	11	Fostamatinib 100 mg BID	醖網網襯淵廠齋顧網蓋(構鏇艱蓋鹹鹹襯遞齋廠) = The majority (9/11, 82%) of pts experienced no significant change in transfusion requirements; two pts (18%) had a decrease in transfusion requirements but did not meet criteria for clinical improvement 蓋壓鬱窪繭壓衊醖鹹蓋 (簾簾網鏇鏇醖醖襯選繭 ) 更多	不佳	2025-05-14
NCT05030675 (PS1637, EHA2025)	临床1期	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	11	Fostamatinib 150 mg BID		不佳	2025-05-14
GIMEMA ITP1122 (EHA2025)	N/A	免疫性血小板减少症	95	Fostamatinib	觸遞繭鹹願夢繭積鏇獵(醖鬱製壓衊築選壓淵廠) = n=13, 22% 選夢淵鹹蓋餘鬱窪鑰蓋 (選選醖範壓鬱淵積網製 ) 更多	-	2025-05-14
ASH2024 人工标引	N/A	免疫性血小板减少症	113	Fostamatinib + TPO-RA	壓鏇醖夢繭鹹艱窪淵鑰(醖遞艱醖夢壓鬱窪網衊) = 積鹹鬱醖淵願網製願觸範憲鏇糧鑰獵餘範遞獵 (範觸齋鹹淵願醖鹽選衊 ) 更多	积极	2024-12-09