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2026-01-27

申办/合作机构

National Heart, Lung & Blood Institute

NCT06564207

/ Not yet recruiting临床2期IIT

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2025-11-30

申办/合作机构

Inova Health Care Services

[+2]

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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467

项与福他替尼相关的文献（医药）

2026-02-01·Blood vessels, thrombosis & hemostasis

The small-molecule Syk inhibitor R788 inhibits hematopoiesis and worsens anemia in sickle cell disease mice

Article

作者: Parachalil Gopalan, Bindu ; Kamimura, Sayuri ; Shet, Arun S ; Shah, Niharika ; Lee, Duck-Yeon ; Quezado, Martha ; Dagur, Pradeep ; Quezado, Zenaide

Vaso-occlusive crises, thrombosis, inflammation, and immune dysregulation contribute to organ damage and poor outcomes in sickle cell disease (SCD). Because neutrophils and dysregulated extracellular trap formation (NETosis) contribute to sickle pathophysiology, and the spleen tyrosine kinase (Syk) signaling pathway is a key driver of NETosis, we investigated the effect of targeting Syk with fostamatinib (R788). Specifically, we studied the effect of a selective Syk inhibitor, R788, on hematologic and biochemical parameters, NETosis, platelet P-selectin expression, and platelet-neutrophil aggregate formation in Townes sickle mice at baseline and after exposure to pathophysiological stressors (tumor necrosis factor α [TNF-α] and hypoxia-reoxygenation). Our results showed that at baseline R788 impaired hematopoiesis, and worsened anemia and neutropenia in sickle mice. Additionally, R788 at nontoxic doses had little, if any, effect on NETosis and platelet activation induced by TNF-α or hypoxia-reoxygenation. Severe anemia and neutropenia induced by R788 in the sickle mouse model suggests that concomitant use of Syk inhibitors with hydroxyurea in patients with SCD should be approached cautiously. Further research is required to clarify the benefits and risks of selective Syk inhibition in SCD and other hemolytic conditions exhibiting stress hematopoiesis.

2026-01-01·JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION

Integrating state-space modeling, parameter estimation, deep learning, and docking techniques in drug repurposing: a case study on COVID-19 cytokine storm

Article

作者: Dasgupta, Abhijit ; Bakshi, Abhisek ; De, Rajat K ; Gangopadhyay, Kaustav ; Basak, Sujit ; Sengupta, Souvik

Abstract:

Objective:

This study addresses the significant challenges posed by emerging SARS-CoV-2 variants, particularly in developing diagnostics and therapeutics. Drug repurposing is investigated by identifying critical regulatory proteins impacted by the virus, providing rapid and effective therapeutic solutions for better disease management.

Materials and Methods:

We employed a comprehensive approach combining mathematical modeling and efficient parameter estimation to study the transient responses of regulatory proteins in both normal and virus-infected cells. Proportional-integral-derivative (PID) controllers were used to pinpoint specific protein targets for therapeutic intervention. Additionally, advanced deep learning models and molecular docking techniques were applied to analyse drug-target and drug-drug interactions, ensuring both efficacy and safety of the proposed treatments. This approach was applied to a case study focused on the cytokine storm in COVID-19, centering on Angiotensin-converting enzyme 2 (ACE2), which plays a key role in SARS-CoV-2 infection.

Results:

Our findings suggest that activating ACE2 presents a promising therapeutic strategy, whereas inhibiting AT1R seems less effective. Deep learning models, combined with molecular docking, identified Lomefloxacin and Fostamatinib as stable drugs with no significant thermodynamic interactions, suggesting their safe concurrent use in managing COVID-19-induced cytokine storms.

Discussion:

The results highlight the potential of ACE2 activation in mitigating lung injury and severe inflammation caused by SARS-CoV-2. This integrated approach accelerates the identification of safe and effective treatment options for emerging viral variants.

Conclusion:

This framework provides an efficient method for identifying critical regulatory proteins and advancing drug repurposing, contributing to the rapid development of therapeutic strategies for COVID-19 and future global pandemics.

2025-12-31·Hematology

Sustained response off treatment after fostamatinib in refractory immune thrombocytopenia: A series of four case reports

Article

作者: Ghanima, Waleed ; Rackwitz, Stefan ; Lucas Boronat, Francisco Javier ; Carrai, Valentina

INTRODUCTION:

A goal of most primary immune thrombocytopenia (ITP) treatments is reducing or discontinuing treatment while maintaining a response including an absence of bleeding events. We present four cases describing treatment with the spleen tyrosine kinase (SYK) inhibitor, fostamatinib, that showed sustained response off treatment (SROT).

CASE PRESENTATIONS:

Case 1 was a 66-year-old male with chronic ITP. He was pre-treated with prednisone and rituximab before being in the FIT-2 clinical trial (placebo). He received fostamatinib in the FIT-3 open-label extension for seven weeks and maintained SROT for 2.5 years. Case 2 was a 54-year-old female patient with chronic, highly refractory ITP. SROT was achieved after 6 months of fostamatinib and was maintained for more than 16 months (in remission to date). Case 3 was a 60-year-old male with chronic ITP. He was successfully treated with cycles of corticosteroids for six years prior to fostamatinib. He was treated with fostamatinib plus prednisone for approximately two months. SROT was observed in this patient for one year. Case 4 was a 67-year-old male with persistent ITP. Before fostamatinib, he was unresponsive to high-dose dexamethasone, IVIG, eltrombopag and romiplostim. After 11 months of fostamatinib, his dose was tapered for three months and ultimately discontinued. SROT was observed for more than ten months (in remission to date).

DISCUSSION:

These cases emphasize that SROT is achievable with fostamatinib in complex ITP cases unresponsive to multiple previous therapies. Additional research is needed to identify the magnitude of the underlying mechanisms, and the clinical factors associated with, and potentially predictive of, SROT.

101

项与福他替尼相关的新闻（医药）

2026-01-20

·云准科技

Nature Immunology｜Xenium空间转录组+PCF空间蛋白质组同片检测精准揭示肾病进展机制

将转录组与蛋白质组分析置于同一张组织切片上进行，是实现真正意义上“多组学空间对齐”的关键一步。这不仅避免了相邻切片间的细胞丢失与空间偏移，更重要的是，它允许我们在完全相同的细胞边界内，同时读取其转录程序与蛋白功能状态，为构建因果清晰的细胞互作网络提供了前所未有的机会。发表于《Nature Immunology》的研究就提供了一个这样的空间多组学整合分析范式，该研究系统性应用 10x Genomics Xenium 空间转录组与Akoya PhenoCycler Fusion空间蛋白质组于同一张人肾活检切片，以前所未有的时空分辨率，解析了快速进展性肾小球肾炎（RPGN）中新月体形成与纤维化的核心机制。文章题目：Spatiotemporal interaction ofimmune and renal cells controls glomerular crescent formation in autoimmune kidney disease 中文题目：免疫细胞和肾脏细胞的时空相互作用控制自身免疫性肾病中肾小球新月的形成发表期刊：Nature Immunology 影响因子：IF=27.6 发表时间：2025年9月30日发表单位：汉堡-厄彭多夫大学医学中心研究团队研究背景快速进展性肾小球肾炎（RPGN）是自身免疫性肾脏疾病中最具侵袭性的一类，特别是ANCA相关性肾炎、狼疮性肾炎和抗GBM肾炎，是导致终末期肾病的常见原因。其特征是肾小球新月形成，主要由壁层上皮细胞（PECs）异常增殖和免疫细胞浸润共同驱动。但驱动其激活、增殖并最终促发纤维化的精确时空信号程序仍如黑箱。免疫细胞与肾脏固有细胞之间如何“对话”？这些信号是否遵循一个跨疾病的共同路径？回答这些问题，是开发靶向疗法的前提。该研究通过Xenium原位空间转录组学结合PCF空间蛋白组多组学分析，绘制人类RPGN肾脏的细胞空间图谱，揭示新月体形成和纤维化的时空动态机制。样本设置与技术手段样本队列： 57例高质量人肾冷冻样本（涵盖三种主要RPGN亚型）及6例健康对照，均来自汉堡肾小球肾炎注册队列。核心技术：空间转录组学：同一张FFPE切片首先进行 10x Xenium 空间原位转录组分析，采用精心设计的480基因Panel，覆盖肾脏细胞标志物、免疫细胞亚群及纤维化相关通路基因，以单细胞分辨率分析480个预设基因的表达与空间位置。单核RNA测序：对部分ANCA相关性肾炎患者（n=11）和对照（n=4）样本进行10x snRNA-seq，用于验证和补充发现。空间蛋白质组学：结合Akoya PhenoCycler Fusion平台，对同一组织切片进行多重蛋白标记（Ki-67，pERK1/2，pSMAD3等）检测，实现转录组与蛋白组的空间对齐。生物信息学分析： a.细胞分割：Baysor算法。 b.空间区域注释：NichePCA算法自动识别肾小球、肾小球周围和小管间质区域。 c.细胞互作推断：CellChat v.2，基于配体-受体表达及空间临近性（≤250μm）。 d.轨迹分析：主成分分析（PCA）与扩散伪时间分析，描绘新月体形成的连续进程。技术路线图主要研究结果 1. 10x Xenium揭示RPGN空间细胞生态系统的系统性重塑通过10x Xenium 空间转录组技术构建人类RPGN肾脏高分辨率空间细胞图谱，提供了细胞类型、基因表达和信号通路的空间位置信息。图c-e ：细胞标记基因空间定位、UMAP聚类、细胞类型比例柱状图鉴定并定位了超过320万个细胞，包括肾脏实质细胞（足细胞、系膜细胞、PECs、内皮细胞等）和免疫细胞（巨噬细胞、T细胞、B细胞等）的亚群。图a-c： NichePCA算法的工作流，用于肾小球及其肾小球周围生态位的自动注释和空间映射，以及代表性的 H&E 图像显示了由 NichePCA 定义的肾小球 (蓝色)，它们相应的肾小球周围区域 (绿色) 和剩余的小管间隙区域 (橙色)。图d-e ：不同区域细胞类型空间分布与比例通过使用NichePCA自动进行了空间域注，分析782个肾小球及其周围区域，定义了新月体形成的连续轨迹（PC1轴）。疾病组肾小球内，PECs比例显著增加（从对照的6%升至抗GBM的15%），同时伴随常驻巨噬细胞等天然免疫细胞的浸润。适应性免疫细胞则主要聚集于肾小球周围区域。这揭示了肾病中免疫应答具有精确的空间分区特征（图e）。图a-c ：PCA图显示782个独特的ROI，每个包含一个不同的肾小球及其相关的肾小球周围区域，ROI按聚集（左）和疾病状况（右）来着色；分配给ROI的PC1值在四种疾病条件下的分布；对每个样本的中位数PC1和肾功能（eGFR）进行Spearman相关性分析通过PCA分析发现，不同病因的RPGN（ANCA-GN, SLE，抗-GBM）共享一条从正常到硬化的连续疾病进展轨迹（PC1轴），提示存在共同的致病机制。PC1值与肾功能(eGFR)负相关（图a-c）。图a-b ：细胞互作网络、靶向PECs的热图，揭示在疾病状态下，PECs从“静默”的囊壁细胞转变为活跃的信号接收与整合中心。其接收的来自内皮细胞、系膜细胞及免疫细胞的信号显著增强，其中 PDGF 与 TGF-β 信号通路最为突出。图c, f：PDGF与TGF-β信号通激活拟时序图，揭示PDGF信号在疾病早期激活，促进PECs增殖（Ki-67表达升高）；TGF-β信号在晚期上升，与纤维化评分正相关，推动肾小球硬化。图e：通过PCF蛋白检测在同一切片上验证Ki-67在PECs中的表达随疾病进展升高。图d，g：10x snRNA-seq数据分析显示的PDGF信号通路和TGFβ信号通路的示意图，在独立样本中验证PDGF信号通路（如下游基因NRG1, ADAMTS1）和TGF-β信号通路（如COL4A1, NOX4, BMPR1A）相关基因显著高表达。图h：散点图显示了PECs中TGFβ通路得分与纤维化评分的相关性（上方）和患者中位数TGFβ通路得分与个人肾功能（下方）的Spearman相关性。图i：PDGF介导和TGFβ介导PECs激活在cGN新月形成和肾小球硬化中作用的示意图。通过Cellchat细胞互作分析进一步揭示揭示驱动新月体形成的核心信号通路：PDGF与TGF-β的时序性作用。在病变肾小球中，PECs是细胞通信网络的枢纽。两条关键信号通路靶向PECs：早期PDGF信号：主要来源于内皮细胞、系膜细胞等，驱动PECs的激活与增殖（Ki-67表达升高），促进细胞性新月体形成。晚期TGF-β信号：主要来源于纤维化系膜细胞、巨噬细胞、T细胞等，驱动PECs表达细胞外基质成分（如COL1A1），导致纤维化和肾小球硬化。沿疾病轨迹（PC1/伪时间）分析显示，PDGF通路活性在早中期升高，随后下降；而TGF-β通路活性则持续上升，并与纤维化评分正相关，与eGFR负相关。snRNA-seq数据用于验证从空间数据中发现的通路激活，验证PECs中PDGF与TGF-β通路基因特异性上调（图d-g）。 2. PCF在蛋白水平上共同验证了PECs的激活、增殖和纤维化过程研究人员使用VALIS软件通过DAPI信号将蛋白质数据与空间转录组数据进行像素级对齐，基于Ki-67（增殖标记）、Claudin-1、Synaptopodin、PAX8（PECs身份标记）、pERK1/2、CD44、pSMAD3（信号通路激活标记）、a-SMA（纤维化标记）等关键标志物，将转录组定义的PECs与蛋白质检测到的通路活性（如Ki-67阳性）精确关联。图e-f：Ki-67蛋白空间表达及沿PC1的变化曲线检测增殖蛋白Ki-67，发现其在病变肾小球的PECs中高表达，且其表达水平沿疾病轨迹（PC1）先升高后下降，与PDGF信号活性变化一致，证实PECs的增殖行为及其时序性。图a-b：使用Xenium检测的ANCA-GN患者的对照样本和肾脏样本片进行PCF蛋白检测，验证磷酸化蛋白pERK1/2和pSMAD3、以及CD44等标记在与转录组相同的空间位置上的信号通路激活状态和细胞行为通过检测磷酸化蛋白pERK1/2（PDGF-MAPK通路下游关键分子）、pSMAD3（TGF-β通路下游核心转录调控因子）和激活标记CD44，验证PDGF通路和TGF-β通路在PECs中的功能性激活。 3.动物模型验证靶向干预的时机关联性图a，f：用 nintedanib和fostamatinib药物进行 PDGF和TGFβ信号通路阻断的小鼠实验设置。图b，g：对相关组肾切片进行周期酸-希夫染色结果图。图c，h：量化显示药物干扰后小鼠新月形减少和肾小球硬化的减少。图d、e、i、j：为pERK1/2、pSMAD3、α-SMA的PCF结果，用于在小鼠肾炎模型中的功能验证在人类样本上的通路激活。在小鼠肾炎模型中的功能验证完美支持了人类发现：在疾病早期（第5-9天）使用PDGF受体抑制剂尼达尼布，可有效减少新月体形成；而在纤维化期（第10-19天）使用具有TGF-β抑制活性的福斯塔马替尼，则可显著减轻肾小球硬化。总结本研究通过 Xenium（空间假设）→ snRNA-seq（组学验证）→ Phenocycler（蛋白功能验证）的递进式、多维度证据链，强有力地证实了 “早期PDGF驱动PECs增殖形成新月体，晚期TGF-β驱动纤维化导致硬化” 的时空动态新机制。不仅深化了对自身免疫性肾病机制的理解，更展示了Xenium + PCF 同片共检在解析复杂疾病空间生物学中的强大能力。这种“一张切片、多层信息”的研究模式，为未来肿瘤、神经、免疫等领域的高分辨率空间病理研究提供了可行路径与技术范本。原文链接：https://www.nature.com/articles/s41590-025-02291-8#Sec33 文案：李曼曼图片来源：图片均来源于参考文献云准科技云准医药科技（上海）有限公司是一家专注于提供单细胞多组学、空间多组学和SomaScan蛋白质组学科研服务的公司。围绕疾病生物学研究、药物研发、新型诊断技术开发等生物医学领域和公共卫生等全民健康领域，云准实验室已经与众多客户产生合作。合作方向涉及肿瘤、免疫、慢病、罕见病等诸多方向以及公共卫生等全民健康领域。涉及疾病机理机制研究和分子分型、生物标记物发现、药物新靶点发现、药物机理机制研究、临床前和临床研究以及临床检测等细分领域。一直以来，质量意识和技术创新都是云准实验室的立身之本。未来，云准将以创新为驱动，继续对产品进行深度整合与开发，推动慢病诊疗、罕见病研究、肿瘤免疫治疗、病理诊断技术以及药物研发领域的突破性发展，必将为这些领域带来革命性变化。单细胞+空间多组学技术服务单细胞原位空间蛋白组表型分析服务 | 空间转录组整体解决方案服务 | PhenoImager多色荧光免疫成像技术服务 | 单细胞多组学解决方案 | 流式细胞分选技术服务 | 激光显微切割服务显微成像扫片服务活细胞成像及玻片扫描服务 | Marianas LightSheet 成像技术服务 | CTLS 组织透明化成像服务基因测序服务全外显子测序服务 | MassARRAY 核酸质谱基因分型检测 | 肿瘤分子诊断服务高通量蛋白组学服务 SomaScan新一代高通量蛋白组学检测服务 | Krex自身抗体检测方案全代谢组检测服务非靶向代谢检测服务 | 全靶向代谢检测服务 | 靶向代谢检测服务云准医药科技（上海）有限公司地址：上海市徐汇区桂平路333号5号楼7楼电话：021-64157928 邮箱：marketing@accuramed.com 云准医药科技（广州）有限公司地址：广州市海珠区广州国际生物岛，百济神州创新中心5楼510-511 电话：020-22066070 雲準生物科技有限公司地址：香港新界香港科技园二期9W1楼CCC13室电话：852 5933 6081

2026-01-16

·N C S

早期研发与靶点验证技术体系---基因组学_蛋白质组学筛选技术

1. 引言：靶点验证技术在现代药物研发中的战略地位1.1 靶点验证技术的发展历程与重要性靶点验证是药物研发早期的核心环节，为后续开发提供科学依据。随着人类基因组计划完成，靶点验证已从单一基因研究转向基因组规模系统性筛选。其发展可追溯至20世纪90年代酵母双杂交系统的建立，实现了蛋白质相互作用高通量筛选；后续RNAi技术虽推动了基因功能研究，但存在敲除不彻底、脱靶效应等缺陷。CRISPR-Cas9系统的出现标志着靶点验证进入精准编辑时代，凭借操作简便、效率高、特异性强的优势成为主流平台。近年来，CRISPRi/CRISPRa、碱基编辑器等衍生技术进一步拓展了应用范围，提升了靶点验证的效率与准确性。1.2 基因组学/蛋白质组学筛选技术的技术体系架构基因组学/蛋白质组学筛选技术体系涵盖基因扰动、文库构建与筛选、表型检测与数据获取、数据分析与验证四大核心环节。基因扰动技术平台是基础，包括CRISPR系列系统、RNAi、TALEN等，各类技术各具特点适配不同需求；文库构建与筛选策略是关键，分为全基因组、靶向基因、条件性等多种文库类型，分别满足无偏向筛选、针对性筛选和时空特异性研究需求；表型检测技术构成输出层，涵盖细胞增殖检测、FACS、单细胞测序等，从多维度捕获生物学效应；数据分析与验证是保障，通过高通量数据分析、生物信息学挖掘和功能验证实验，确保筛选结果的可靠性。1.3 疾病领域的差异化需求与技术选择不同疾病领域的靶点验证需求存在显著差异，直接决定技术平台选择。肿瘤领域聚焦致癌基因、肿瘤抑制基因等靶点，因肿瘤细胞遗传异质性高，偏好全基因组CRISPR-Cas9文库等大规模筛选技术；神经退行性疾病面临血脑屏障、神经元不可再生等挑战，注重疾病模型的病理模拟，优先选择CRISPRi/CRISPRa等非破坏性技术及精准引导编辑器；代谢疾病关注胰岛素信号、脂质代谢等机制，需适配多组织动态监测的技术平台。此外，各领域验证标准亦有区别，肿瘤侧重短期细胞增殖指标，神经退行性疾病关注长期神经元功能，代谢疾病则综合多种生理指标。2. 核心技术原理与机制详解2.1 CRISPR-Cas9系统：基因敲除与激活技术2.1.1 CRISPR-Cas9基因编辑的分子机制 CRISPR-Cas9系统源于原核生物适应性免疫系统，核心由Cas9核酸酶和sgRNA组成。sgRNA通过20个核苷酸引导序列识别目标DNA，支架结构与Cas9结合稳定复合物，目标序列需含sgRNA互补序列及PAM基序（SpCas9为NGG）。结合后，Cas9的RuvC和HNH结构域切割DNA产生双链断裂，其修复机制决定编辑结果：NHEJ易错修复产生indel导致移码突变，实现基因敲除；HDR依赖外源模板实现精准编辑。靶点验证中多利用NHEJ机制，选择基因早期外显子作为靶点以确保功能丧失（图一）。 2.1.2 CRISPRi/CRISPRa转录调控技术 CRISPRi和CRISPRa技术基于催化失活的dCas9蛋白，保留DNA结合能力但丧失核酸酶活性，通过融合转录调控结构域实现基因表达调控。CRISPRi将dCas9与KRAB抑制结构域融合，结合基因转录起始位点附近招募异染色质蛋白，抑制转录效率可达90%以上；CRISPRa经多代迭代，从早期dCas9-VP64发展为VPR、SunTag、SAM等高效系统，实现基因表达10-1000倍激活。相较于基因敲除，二者具有可逆性和剂量依赖性优势，可实现基因功能的动态调控和剂量效应研究（图二）。 2.1.3 全基因组文库筛选策略与实施流程全基因组CRISPR文库筛选通过系统性扰动基因组基因解析复杂生物学过程，流程包括文库设计、细胞筛选、数据获取与分析验证。文库设计需覆盖18000—20000个人类基因，每个基因设计3—6个sgRNA，兼顾特异性与编辑效率；细胞筛选分正选择（筛选生存优势相关基因）和负选择（筛选必需基因），采用低MOI慢病毒转导确保单细胞单一sgRNA整合；实施过程含细胞培养、药物处理、基因组DNA提取、sgRNA扩增测序等步骤，通过比较不同时间点sgRNA丰度变化评估基因功能；数据分析需结合统计方法筛选显著效应基因，再经独立sgRNA或交叉技术验证，结合细胞生物学实验确认靶点功能（图三）。 2.2 CRISPR-Cas12/13系统：RNA编辑与检测技术2.2.1 Cas12/13系统的技术特点与应用范围 Cas12属于V型CRISPR系统，可产生交错DNA切割，Cas12a蛋白体积更小，且能自主处理crRNA阵列，简化多重编辑操作；Cas13属于Ⅵ型系统，是RNA引导的RNA靶向核酸酶，不影响基因组DNA，且具有识别目标RNA后非特异性切割周围RNA的反式切割活性。应用范围上，Cas13主要用于RNA水平基因敲低、RNA碱基编辑及高灵敏度核酸检测，Cas12则在DNA编辑和多重筛选中具有优势，二者弥补了Cas9系统在RNA调控领域的空白（图四）。 2.2.2 RNA编辑与检测的创新应用 Cas13系统在RNA编辑和检测领域开辟了新路径。RNA碱基编辑方面，REPAIR系统将dCas13与ADAR脱氨酶融合，实现腺苷到肌苷的精准转换，在不改变基因组的前提下调整蛋白质序列；在RNA检测领域，基于反式切割活性开发的SHERLOCK技术，检测灵敏度达单分子水平，30分钟内可完成检测，适用于病毒检测、基因突变筛查及基因表达实时监测；此外，dCas13融合荧光蛋白可实现RNA实时追踪成像，揭示RNA细胞内动态行为，招募效应蛋白还可调控RNA稳定性、翻译效率等（图五）。 2.3 酵母双杂交系统：蛋白质相互作用网络解析2.3.1 酵母双杂交系统的基本原理与技术发展酵母双杂交系统基于GAL4转录因子结构域分离重组原理，将BD和AD结构域分别与诱饵蛋白、猎物蛋白融合。当二者相互作用时，BD与AD靠近重建转录因子功能，激活下游HIS3、LacZ等报告基因，通过报告基因表达判断相互作用。自1989年建立以来，该技术从小规模验证发展为全基因组网络构建工具，实现了自动化与标准化升级。通过多载体系统、严格筛选条件、阵列化筛选等改进策略，有效提升了系统的灵敏度与特异性（图六）。 2.3.2 蛋白质相互作用网络的构建与分析酵母双杂交系统在大规模蛋白质相互作用网络构建中优势显著，筛选策略包括矩阵筛选（全面检测蛋白组合）和文库筛选（批量筛选提高效率）。已成功应用于酵母、人类等物种的蛋白质组学研究，构建的网络覆盖酵母蛋白质组69%，鉴定出大量人类新蛋白质相互作用。为保障数据可靠性，需通过免疫共沉淀、GST pull-down等生化方法验证，结合GO注释、通路分析等生物信息学手段评估生物学意义。通过网络分析可识别枢纽蛋白、功能模块和信号通路，为疾病机制解析和靶点发现提供线索（图七）。 2.4 其他重要筛选技术：RNAi、TALEN等技术平台2.4.1 RNA干扰技术的原理与局限性 RNAi技术基于双链RNA介导的基因沉默机制，长双链RNA被Dicer酶切割为21-23nt的siRNA，反义链整合入RISC复合体，引导切割互补mRNA实现基因下调。哺乳动物细胞中常用siRNA、shRNA、shRNAmir等试剂避免干扰素反应。但RNAi存在显著局限性：敲除不彻底仅能部分抑制表达，脱靶效应易导致非特异性沉默，细胞类型适用性差异大，沉默效应持续时间短，这些缺陷使其在高精度靶点验证中逐渐被CRISPR技术取代，但仍适用于快速预筛选等场景（图八）。 2.4.2 TALEN技术与其他新兴筛选方法 TALEN技术由TAL效应因子DNA结合域和FokI切割域组成，通过串联重复单元识别任意DNA序列，以二聚体形式发挥作用，特异性高于早期ZFN系统，设计相对简便且应用范围广。但存在构建复杂、筛选通量有限、细胞毒性等问题，限制了大规模应用。其他新兴技术中，化学基因组学结合化学扰动与基因组分析，模拟药物作用模式；DEL技术通过DNA标签连接小分子，实现高通量药物筛选；单细胞多组学在单细胞水平整合多层面信息，揭示细胞异质性，均为靶点验证提供了新路径（图九）。 3. 疾病领域的靶点验证应用案例分析3.1 肿瘤领域：致癌基因、肿瘤抑制基因与免疫检查点验证3.1.1 致癌基因与肿瘤抑制基因的筛选验证全基因组CRISPR-Cas9筛选在肿瘤靶点发现中成效显著。小细胞肺癌研究中，筛选发现NEK9激酶是多西他赛耐药关键调节因子，其敲除可恢复癌细胞药物敏感性，fostamatinib作为NEK9抑制剂在异种移植模型中效果良好；同时鉴定出DHODH酶为从头嘧啶生物合成途径关键靶点，其抑制可显著抑制肿瘤生长。非小细胞肺癌研究中，MDM2被证实为潜在靶点，其过表达与不良预后相关。此外，通过功能缺失筛选发现ZNF24等新肿瘤抑制基因，在肺癌模型中展现抑癌活性；KRAS驱动肺癌研究中，发现NRAS和HRAS具有肿瘤抑制作用，颠覆传统认知（图十）。 3.1.2 药物抗性机制与免疫检查点的发现 CRISPR筛选助力解析肿瘤药物抗性与免疫逃逸机制。神经母细胞瘤研究中，大规模组合筛选发现PRKDC抑制可增强高危细胞对阿霉素的敏感性，在PDX模型中得到验证；EGFR抑制剂抗性研究揭示KEAP1失活通过激活NRF2通路赋予细胞抗氧化能力，导致奥希替尼抗性。免疫检查点领域，CD8 T细胞转移模型的全基因组筛选重现PD-1、Tim-3等经典分子功能，发现Dhx37等新免疫调节基因；肺癌研究中，鉴定出ADAM2通过抑制细胞因子信号和抗原呈递介导免疫逃逸，Tsc2缺失可改善ICB治疗反应，为联合治疗提供依据（图十一）。 3.2 神经退行性疾病：蛋白质聚集与突触功能靶点3.2.1 阿尔茨海默病与帕金森病的靶点发现 CRISPR技术在神经退行性疾病靶点验证中取得突破。阿尔茨海默病研究中，针对关键风险因子ApoE4，合成外泌体递送平台实现CRISPR组分跨血脑屏障递送，在E4-5XFAD小鼠模型中成功实现E4到E3的功能性编辑；TDP-43相关疾病研究中，CRISPR筛选发现TYK2是cdsRNA介导神经细胞死亡的关键调节因子，FDA批准的TYK2抑制剂可挽救细胞毒性。帕金森病研究中，通过遗传学分析结合CRISPR验证，发现IVS11-3C>G等多个新parkin基因突变，丰富了疾病遗传基础认知（图十二）。 3.2.2 亨廷顿病等其他神经退行性疾病的应用 CRISPR技术为亨廷顿病等治疗提供新策略。通过筛选靶向HTT基因剪接元件的碱基编辑器变体，成功开发出外显子跳跃编辑平台，编辑纹状体后可减少HTT蛋白聚集，减轻脑区萎缩；HD基因敲入小鼠的体内筛选，发现多个新的CAG重复序列不稳定性调节因子，为疾病修饰疗法开发提供线索。此外，脊髓性肌萎缩症研究中，CRISPR技术上调SMN2基因表达以缓解症状；额颞叶痴呆研究中，dCas13d系统调控RNA选择性剪接，为RNA处理缺陷相关神经疾病提供治疗路径（图十三）。 3.3 代谢疾病：胰岛素信号与脂质代谢靶点代谢疾病靶点验证聚焦胰岛素信号、脂质代谢等核心机制。人类乳腺细胞多重RNAi筛选鉴定出一批细胞增殖存活关键基因，揭示细胞周期调控网络的核心作用及细胞系特异性通路敏感性，为理解代谢相关细胞生存依赖提供依据。酵母化学基因组学筛选发现多个脂质代谢调节基因与通路，为降脂药物靶点发现提供线索。药物重定位研究中，整合全基因组必需性筛选、网络分析与机器学习，成功预测多种药物新靶点与作用机制，适配代谢疾病多通路关联的特点。此外，CRISPR筛选还发现多个线粒体功能与能量代谢相关新靶点，揭示代谢疾病中的能量调节异常机制（图十四）。 4. 技术应用的多维度视角分析4.1 学术研究视角：基础生物学发现与机制解析学术研究中，靶点验证技术推动基因功能注释、信号通路解析、疾病模型构建等领域发展。全基因组CRISPR筛选实现基因功能系统性注释，已完成数千个人类基因功能鉴定；组合筛选策略助力信号通路网络解析，快速推导mTOR等通路架构；CRISPR技术可在多种模式生物中构建疾病模型，为神经退行性疾病等机制研究提供工具；CRISPRi/CRISPRa等可逆技术实现基因功能动态研究，适配发育生物学时间分辨率需求；多组学整合分析结合CRISPR筛选与单细胞测序、蛋白质组学等技术，从多维度解析基因扰动效应，深化复杂疾病机制认知。4.2 药物开发视角：从靶点发现到临床转化药物开发中，靶点验证技术是基础研究与临床应用的关键桥梁。大规模功能筛选发现DHODH、PRKDC等新药物靶点，突破传统方法局限；通过分析药物处理后的基因表达、信号通路变化，深度解析药物作用机制与副作用成因，支撑药物优化；药物处理条件下的CRISPR筛选揭示EGFR抑制剂等药物的抗性机制，为联合治疗策略开发提供依据；基于基因扰动特征的药物重定位筛选，缩短代谢疾病等领域药物开发周期；结合患者基因组信息与靶点验证技术，实现药物反应精准预测，助力个体化治疗方案制定。4.3 技术服务视角：CRO/CDMO产业发展与技术平台建设靶点验证技术推动CRO/CDMO产业形成专业化服务生态。现代CRO建立涵盖CRISPR、RNAi等技术的高通量筛选平台，配备自动化液体处理系统、高通量测序仪等设备，提供一站式服务；核心竞争力集中于定制化筛选方案设计，根据肿瘤、神经退行性疾病等不同领域需求，优化靶点选择、模型构建等环节；建立严格质量控制体系，通过sgRNA效率验证、脱靶评估等保障服务质量；持续投入技术创新与平台升级，适配单细胞多组学等前沿技术需求；大型CRO构建全球化服务网络，在主要市场建立实验室，提供本地化技术服务与监管支持，适配药物开发全球化趋势。5. 技术瓶颈与挑战深度剖析5.1 技术局限性：脱靶效应、效率与特异性问题靶点验证技术仍面临诸多技术局限。脱靶效应是CRISPR技术核心挑战，Cas9可容忍sgRNA与目标序列错配及小片段插入缺失，增加特异性控制难度，虽开发出高保真Cas9变体、双切口酶等改进策略，但未完全解决。编辑效率存在显著异质性，受染色质状态、sgRNA结构等多种因素影响，预测准确性有待提升，CRISPRi/CRISPRa系统还受启动子结构、细胞类型等因素制约。细胞类型特异性限制明显，原代细胞、终末分化细胞等难以编辑，神经退行性疾病研究中的神经元编辑尤为困难。此外，大规模筛选的通量与成本平衡问题突出，全基因组筛选成本高昂，靶向筛选可能遗漏关键靶点。5.2 成本效益分析：设备投入、时间周期与人力需求靶点验证技术的成本效益受设备、试剂、人力、时间等多因素影响。设备基础设施投入巨大，一套高通量筛选平台需数百万美元，含自动化液体处理系统、高内涵成像仪、测序设备等，且需持续维护升级。试剂成本方面，全基因组CRISPR文库构建需数万美元，通过简化文库设计、采用pooled筛选、共享开源资源等策略可降低成本。人力需求上，需要分子生物学、生物信息学等多领域专业人才，培养周期6-12个月，人才招聘与培训成本高。时间周期优化可提升效益，现代高通量技术将靶点验证流程缩短至2～3个月，降低人力成本并加快研究进展，设备共享与规模化效应进一步降低单位成本。5.3 标准化程度与质量控制体系建设标准化程度不足影响靶点验证结果的可重复性与可比性，完善质量控制体系至关重要。实验流程标准化是基础，需统一细胞培养、转染条件、筛选时间等关键参数，避免实验室间技术差异；数据质量评估需涵盖技术重复一致性、对照表现、sgRNA效率分布等维度，确保筛选系统正常功能；生物信息学分析流程需标准化预处理、统计方法、阈值设定等环节，建立统一数据格式与报告标准；建立sgRNA富集倍数、筛选动态范围、假阳性/阴性率等量化质控指标，为质量评估提供依据；监管机构与行业组织推动的认证认可体系完善，将提升行业整体标准化水平，促进不同研究数据整合比较。5.4 监管要求与伦理考量靶点验证技术应用需应对严格监管与伦理挑战。全球基因编辑监管框架差异显著，美国FDA要求严格的安全性评估，欧洲对生殖细胞编辑实施法律禁止，增加跨国研究难度。临床试验监管要求严苛，CRISPR相关治疗方法需提供详细安全性证据、长期随访计划，对神经系统等敏感组织编辑的监管更为严格。生物安全与环境保护方面，需采取措施防止基因编辑生物意外释放，评估其对生态系统的潜在影响。伦理层面，基因编辑涉及人类遗传信息修改引发广泛关注，国际准则明确生殖细胞编辑禁令，体细胞编辑需严格监管。此外，CRISPR技术专利纠纷、技术转移中的知识产权与出口管制问题，亦制约技术商业化进程。6. 前沿进展与发展趋势展望6.1 2024—2026年技术突破与创新应用 2024—2026年，靶点验证技术呈现多项突破与创新应用。超高通量筛选技术快速发展，声学液滴喷射质谱平台、超密集电化学芯片结合机器学习等技术，实现样本高速处理与精准检测，集成化微生理系统芯片提供更贴近生理状态的筛选环境。CRISPR技术持续创新，紧凑型Cas系统解决递送难题，碱基编辑器与引导编辑器精度提升，Cas12f、Cas14等新型系统丰富工具库。多组学整合分析技术深化，单细胞多组学实现多分子层面同步分析，空间组学揭示基因表达的组织原位分布。AI与机器学习深度融合，应用于sgRNA效率预测、药物反应预测等，提升数据分析与预测能力。新型递送系统取得突破，合成外泌体实现CRISPR组分跨血脑屏障递送，脂质纳米颗粒、病毒载体工程等拓展组织适配范围。6.2 新兴技术融合：AI辅助筛选与单细胞多组学 AI辅助筛选与单细胞多组学的融合重塑靶点验证研究范式。AI辅助筛选已进入实际应用，机器学习算法优化智能文库设计，深度学习模型预测sgRNA效率准确率超85%；自动化数据分析通过聚类算法、预测模型等，从海量数据中识别功能关联与药物反应模式。单细胞多组学技术提供超高分辨率分析能力，单细胞CRISPR筛选结合RNA测序，揭示细胞类型特异性基因功能与药物反应异质性；空间分辨多组学实现组织原位的基因表达与蛋白质分布分析，适配肿瘤微环境、神经回路等复杂研究场景；多模态数据整合构建全面细胞功能图谱，适配复杂疾病多层面调控的机制解析；实时监测技术结合光遗传学CRISPR系统与成像技术，追踪基因扰动的动态效应。6.3 未来发展方向与产业化前景未来5—10年，靶点验证技术将向精准化、智能化、产业化方向演进。技术平台呈现整合化趋势，融合CRISPR编辑、多组学分析等技术形成综合性解决方案；在精准医疗领域深度应用，实现个体化靶点预测、药物反应精准评估与早期诊断标志物发现；自动化与智能化水平持续提升，实现实验操作、数据分析全流程自动化，AI自主优化实验设计与质量监控；监管科学完善与标准化推进，建立成熟监管框架指导技术临床转化；产业生态系统不断完善，形成CRO/CDMO服务、技术设备供应、数据服务等多环节协同的产业格局；国际化合作深化，推动全球技术标准制定与资源共享，促进技术规范化应用。7. 结论与建议靶点验证技术历经革命性发展，从单一基因研究演进为全基因组系统性筛选，从永久性编辑拓展到可逆性调控，为基础生物学研究与药物开发提供核心支撑。CRISPR系列技术成为主流平台，酵母双杂交系统在蛋白质相互作用研究中仍不可替代，各类技术在肿瘤、神经退行性疾病、代谢疾病等领域成功应用。但技术仍面临脱靶效应、效率不均、成本高昂、标准化不足等挑战，临床转化还需应对严格监管与伦理考量。基于发展现状与挑战，提出以下建议：一是加强技术创新投入，聚焦编辑特异性提升、递送效率改善、成本控制等关键瓶颈，重点研发新型CRISPR系统、智能递送平台等前沿技术；二是完善标准化体系建设，建立统一技术标准、质量控制体系与数据规范，推动行业协会牵头制定认证要求；三是推动产学研深度合作，建立技术转移平台与产业联盟，促进技术创新与产业化转化；四是加强人才培养，开设专业课程建立培训体系，培养多学科复合型人才；五是完善监管与伦理规范，加快制定技术监管政策，平衡创新与安全；六是深化国际合作，参与全球标准制定与合作研究，推动技术规范化全球应用。未来，靶点验证技术将持续推动精准医疗发展，为重大疾病挑战提供技术支撑。

基因疗法核酸药物

2026-01-12

·BioSpace

Rigel Provides Business Update and 2026 Outlook

Preliminary fourth quarter 2025 total revenue of approximately $69.8 million, including net product sales of $65.4 million and contract revenues of $4.4 million In the dose escalation phase of the Phase 1b study of R289 in patients with lower-risk MDS, R289 continues to be generally well tolerated. RBC-TI was achieved by 33% (6/18) of evaluable transfusion dependent patients receiving R289 doses ≥500 mg QD, including 40% (2/5) in the 500 mg BID dose group Enrollment in the dose expansion phase of the Phase 1b study is ongoing and Rigel is on track to complete enrollment and select the recommended Phase 2 dose for future clinical studies in the second half of 2026 2026 Outlook: Rigel anticipates full-year total revenue of approximately $275 to $290 million, including net product sales of $255 to $265 million, and positive net income for the full year SOUTH SAN FRANCISCO, Calif. , Jan. 12, 2026 /PRNewswire/ -- Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), a commercial stage biotechnology company focused on hematologic disorders and cancer, today provided a business update including preliminary total revenue and net product sales for the fourth quarter of 2025, ongoing activity from the commercial business and development pipeline, and its financial outlook for 2026. "2025 was an excellent year for Rigel, marked by strong commercial execution with record net product sales; significant financial progress, including continued profitability and generation of $77 million in cash; and meaningful clinical advancement of R289 in lower-risk MDS, where we shared encouraging Phase 1b data," said Raul Rodriguez, Rigel's president and CEO. "In 2026, we plan to continue to execute across all areas of the business — driving sustained commercial performance, supporting our expanding clinical programs with a solid financial foundation, delivering preliminary results from the dose expansion phase of our R289 study and continuing to explore opportunities to add new products to our portfolio." Preliminary 2025 Financial Results and Business Update Preliminary Financial Results While Rigel is still determining final results for the fourth quarter of 2025, the company expects to report fourth quarter total revenue of $69.8 million, compared to $57.6 million for the same period of 2024. Rigel expects to report fourth quarter of 2025 gross product sales of $84.5 million. Net product sales are expected to be $65.4 million, compared to $46.5 million for the same period of 2024, including: TAVALISSE ® (fostamatinib disodium hexahydrate) net product sales of $45.6 million compared to $31.0 million for the same period of 2024. GAVRETO ® (pralsetinib) net product sales of $10.2 million compared to $8.1 million for the same period of 2024. REZLIDHIA ® (olutasidenib) net product sales of $9.6 million compared to $7.4 million for the same period of 2024. Contract revenues for the fourth quarter of 2025 are expected to be approximately $4.4 million, consisting of $4.1 million in contract revenues from collaborations and $0.3 million in government contract revenue. Contract revenue from collaborations is expected to include $3.4 million of revenue from Grifols S.A. related to delivery of drug supplies and earned royalties, $0.3 million of revenue from Kissei Pharmaceutical Co., Ltd. related to delivery of drug supplies and $0.2 million of revenue from Medison Pharma Trading AG related to earned royalties. For the full year, Rigel expects to report total revenue of $294.3 million, including net product sales of $232.0 million and contract revenues of $62.3 million, compared to total revenue of $179.3 million in 2024, which included net product sales of $144.9 million and contract revenues of $34.4 million. Expected 2025 contract revenues and total revenue include $40.0 million in non-cash revenue recognized in the second quarter of 2025 resulting from the release of the remaining cost share liability related to the agreement with Lilly for the development and commercialization of ocadusertib. Rigel expects to report cash, cash equivalents, and short-term investments of approximately $154.6 million as of December 31, 2025, compared to $77.3 million as of December 31, 2024. The above information is preliminary, has not been audited, and is subject to change upon the audit of Rigel's financial statements for the fourth quarter and year ended December 31, 2025. Rigel expects to provide complete fourth quarter and full year 2025 financial results in March 2026. Commercial Rigel's commercial portfolio is expected to report preliminary full-year net product sales of $232.0 million, growth of 60% compared to 2024. Clinical Development and Regulatory Rigel continues to advance its Phase 1b clinical study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R289 1 , a potent and selective dual inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1/4) in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (MDS). In October 2025, Rigel announced enrollment of the first patient in the dose expansion phase of the study, where up to 40 patients will be randomized to receive either 500 mg once daily (QD) or twice daily (BID) to determine the recommended Phase 2 dose for future clinical trials. Rigel is on track to complete enrollment of the dose expansion phase of the Phase 1b study and select the recommended Phase 2 dose for future clinical studies in the second half of 2026. The company anticipates sharing preliminary data from the dose expansion phase of the study by the end of 2026. Rigel announced updated data from the dose escalation phase of the ongoing Phase 1b clinical study of R289 at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition in December, indicating that R289 continued to be generally well tolerated in a heavily pretreated R/R lower-risk MDS patient population, the majority of whom were high transfusion burden (HTB) at baseline. Furthermore, red blood cell transfusion independence (RBC-TI ≥8 weeks) was achieved by 33% (6/18) of evaluable transfusion dependent patients receiving R289 doses of at least 500 mg QD and higher. Also at the ASH Annual Meeting, four posters were presented on olutasidenib, which included data that add to the growing body of evidence supporting the benefits of its use in patients with R/R mutated isocitrate dehydrogenase-1 (m IDH1 ) acute myeloid leukemia (AML). In October 2025, the first patient was enrolled in the CONNECT Phase 2 TarGeT-D study evaluating olutasidenib in combination with temozolomide, followed by olutasidenib monotherapy as a maintenance regimen for newly-diagnosed adolescent and young adult patients with a high-grade glioma harboring an IDH1 mutation ( NCT06161974 ). Rigel presented sub-analysis data from the ARROW study evaluating pralsetinib for the treatment of metastatic rearranged during transfection ( RET ) fusion-positive non-small cell lung cancer (NSCLC) at the 2025 North America Conference on Lung Cancer (NACLC) in December. The two poster presentations included efficacy and safety data for patients previously treated with immunotherapy and for patients from the United States. In the trial, median overall survival (OS) was 44.3 months for the overall patient population. Longer median OS was seen in patients treated in the United States (62.4 months). Rigel presented the first data release for pralsetinib from the TAPISTRY study ( NCT04589845 ) in a poster presentation at the 2026 American Society of Clinical Oncology – Gastrointestinal Cancers Symposium (ASCO-GI) in January. The analysis reported results from the Phase 2 global, open-label, multicohort study, in which the efficacy and safety of pralsetinib was evaluated in a cohort of patients with RET fusion-positive solid tumors, including pancreatic, colorectal, and hepatobiliary cancers. Pralsetinib demonstrated robust and durable activity against RET fusion-positive solid tumors, including gastrointestinal (GI) tumors, and in the efficacy evaluable population showed an overall response rate (ORR) of 67% (26/39). These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition, suggesting the potential therapeutic utility of pralsetinib in these patients. On December 22, 2025, the U.S. Food and Drug Administration (FDA) notified Rigel of the approval of a Prior Approval supplemental New Drug Application, which updated the U.S. Prescribing Information to add a boxed warning regarding serious infections, including opportunistic infections. Rigel previously communicated this risk information to healthcare providers via a Dear Healthcare Provider letter in October 2024. The FDA also notified Rigel that it has met its postmarketing commitment for GAVRETO from its September 2020 accelerated approval to submit the final report for the AcceleRET-Lung study. Publication A paper titled " Olutasidenib for Mutated IDH1 Acute Myeloid Leukemia: Final Five-Year Results from the Phase 2 Pivotal Cohort " was published in November 2025 by Jorge E. Cortes, M.D., Phase 2 trial investigator and Director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, in the Journal of Hematology & Oncology . The publication reports the final 5-year data from the pivotal cohort of the registrational trial evaluating olutasidenib for the treatment of patients with R/R m IDH1 AML, which includes an additional two years of efficacy and safety data. These 5-year data further support the durable responses and manageable safety pro with olutasidenib in patients with R/R m IDH1 AML, including those previously treated with venetoclax-based regimens. 2026 Outlook Rigel anticipates 2026 total revenue of approximately $275 to $290 million, including: Net product sales of approximately $255 to $265 million. Contract revenues of approximately $20 to $25 million. The company anticipates it will report positive net income for the full year 2026, while funding existing and new clinical development programs. Upcoming Investor Event Raul Rodriguez, Rigel's president and CEO, will present a company overview at the 44th Annual J.P. Morgan Healthcare Conference in San Francisco, CA on Wednesday, January 14, 2026 at 3:00 p.m. PT (6:00 p.m. ET). To access the live webcast or archived recording, visit the Investor Relations section of the company's website at . About ITP In patients with immune thrombocytopenia (ITP), the immune system attacks and destroys the body's own blood platelets, which play an active role in blood clotting and healing. Common symptoms of ITP are excessive bruising and bleeding. Patients suffering with chronic ITP may live with an increased risk of severe bleeding events that can result in serious medical complications or even death. Current therapies for ITP include steroids, blood platelet production boosters (TPO-RAs), and splenectomy. However, not all patients respond to existing therapies. As a result, there remains a significant medical need for additional treatment options for patients with ITP. About NSCLC It is estimated that over 226,000 adults in the U.S. will be diagnosed with lung cancer in 2025. Lung cancer is the leading cause of cancer death in the U.S, with non-small cell lung cancer (NSCLC) being the most common type accounting for 85-90% of all lung cancer diagnoses. 2 RET fusions are implicated in approximately 1-2% of patients with NSCLC. 3 About AML Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that there will be about 22,010 new cases in the United States, most in adults, in 2025. 4 Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow. 5,6 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment. 7 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need. About TAVALISSE ® TAVALISSE (fostamatinib disodium hexahydrate) tablets is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Please click here for Important Safety Information and Full Prescribing Information for TAVALISSE. About GAVRETO ® GAVRETO is indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).* *Thyroid indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Please click here for Important Safety Information and Full Prescribing Information, including Boxed WARNING, for GAVRETO. About REZLIDHIA ® REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 ( IDH1 ) mutation as detected by an FDA-approved test. Please click here for Important Safety Information and Full Prescribing Information, including Boxed WARNING, for REZLIDHIA. To report side effects of prescription drugs to the FDA, visit or call 1-800-FDA-1088 (800-332-1088). TAVALISSE, GAVRETO and REZLIDHIA are registered trademarks of Rigel Pharmaceuticals, Inc. About Rigel Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) is a biotechnology company dedicated to discovering, developing and providing novel therapies that significantly improve the lives of patients with hematologic disorders and cancer. Founded in 1996, Rigel is based in South San Francisco, California. For more information on Rigel, the Company's marketed products and pipeline of potential products, visit . R289 is an investigational compound not approved by the FDA. The American Cancer Society. Key Statistics for Lung Cancer. Revised January 16, 2025. Accessed January 2, 2026: Kato, S. et al. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res. 2017;23(8):1988-1997 doi: 10.1158/1078-0432.CCR-16-1679 The American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Revised March 4, 2025. Accessed January 2, 2026: Patel, A, et al. Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission . 2021 Sep 7;28(7):811-814. doi: Thol F, Ganser, A. Treatment of Relapsed Acute Myeloid Leukemia . Curr. Treat. Options on Oncol. (2020) 21: 66. doi: Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia . Blood (2015) 126 (3): 319-27. doi: Forward Looking Statements Thi s press release contains forward-looking statements relating to, among other things, expected commercial, financial and clinical results, increased projections of financial performance and outlook for 2026, expectations for growing our commercial business , continued enrollment of our R289 study, presentation of study data, expectation of clinical outcomes, continued ability for developing and commercializing TAVALISSE, GAVRETO, REZLIDHIA and R289 domestically and in certain international markets, and expectations for Rigel's partnering and collaboration efforts. A ny statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Forward-looking statements can be identified by words such as "anticipates", "plan", "outlook", "potential", "may", "look to", "expects", "will", "initial", "promising", and similar expressions in reference to future periods. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on Rigel's current beliefs, expectations, and assumptions and hence they inherently involve significant risks, uncertainties and changes in circumstances that are difficult to predict and many of which are outside of our control. Therefore, you should not rely on any of these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward looking statements as a result of these risks and uncertainties, which include, without limitation, the finalization and audit of Rigel's fourth quarter and 2025 fiscal year financial results which could potentially result in changes or adjustments to the selected preliminary financial results and projections presented herein; risks and uncertainties associated with the commercialization and marketing of TAVALISSE, GAVRETO, and REZLIDHIA; risks that the FDA, European Medicines Agency, PMDA or other regulatory authorities may make adverse decisions regarding TAVALISSE, GAVRETO, REZLIDHIA or R289; risks that clinical trials may not be predictive of real-world results or of results in subsequent clinical trials; risks that TAVALISSE, GAVRETO, REZLIDHIA or R289 may have unintended side effects, adverse reactions or incidents of misuses; the availability of resources to develop or market Rigel's product candidates; market competition; as well as other risks detailed from time to time in Rigel's reports filed with the Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the quarter ended September 30, 2025 and subsequent filings. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. Rigel does not undertake any obligation to update forward-looking statements, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise, and expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein, except as required by law. Contact for Investors & Media: Investors: Rigel Pharmaceuticals, Inc. 650.624.1232 ir@rigel.com Media: David Rosen Argot Partners 646.461.6387 david.rosen@argotpartners.com View original content to download multimedia: SOURCE Rigel Pharmaceuticals, Inc.

临床2期临床结果临床1期ASCO会议

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

评价

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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


ASH2025	N/A	免疫性血小板减少症	30	Fostamatinib	選廠顧選網廠鏇願鏇襯(願蓋選襯齋構夢鹽構遞) = shorter Lag Time (LT) in thrombin generation associated with PS content of microparticles (MPs) in relapsed patients 觸糧蓋製蓋蓋積積築範 (願鑰壓顧壓簾鹹積膚獵 )	积极	2025-12-06
ASH2025	N/A	免疫性血小板减少症	164	Fostamatinib	遞顧鏇糧糧餘鹽積夢壓(餘糧壓觸觸糧遞襯窪顧) = 積鑰淵獵蓋餘憲鏇壓鬱憲網簾築鏇憲鬱壓網鏇 (範壓顧鹹鑰鏇襯鹽膚鏇 ) 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	鹽憲鹹願糧襯夢蓋鏇顧 = 淵襯構艱構艱夢醖壓襯艱顧齋繭鬱積衊鹹積繭 (鑰築構憲鹹壓夢齋鑰鹽, 窪蓋糧築餘襯獵鏇鏇觸 ~ 壓簾鏇獵築窪遞構淵醖) 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)	鹹糧範鬱顧蓋製構廠廠 = 選製網製艱選壓鑰齋襯積顧醖鹽餘壓鑰夢製鏇 (積簾範鬱鹽製構夢廠積, 鑰鏇鏇簾鏇衊憲願顧窪 ~ 範顧壓獵淵襯壓艱夢遞) 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)	鹹糧範鬱顧蓋製構廠廠 = 遞構壓簾壓選壓憲範簾積顧醖鹽餘壓鑰夢製鏇 (積簾範鬱鹽製構夢廠積, 簾憲壓衊鑰築繭繭範衊 ~ 餘憲製廠鏇製膚餘淵夢)	-	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	齋構鏇襯鹹鹹艱簾憲膚(簾齋糧遞選壓鬱鑰夢衊) = 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 鹽襯齋醖淵鹹鹹製鹽範 (鏇衊獵廠簾遞窪鹽顧範 ) 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	鹽糧鏇範選簾窪築範廠(構鑰醖鏇範網構繭夢夢) = n=13, 22% 鹽鹽製憲醖夢築醖觸壓 (憲鹽襯膚積窪醖壓壓繭 ) 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	鏇選餘遞選衊糧餘壓窪(積夢蓋積獵鹹鹽鑰鏇顧) = 顧築壓積蓋齋蓋壓窪願糧襯顧衊醖簾淵齋繭顧 (憲夢觸構願選廠餘窪構 ) 更多	积极	2024-12-09
2555Early Treatment Use of Fostamatinib (ASH2024)	N/A	免疫性血小板减少症二线	157	Fostamatinib	構鏇醖鏇憲鑰範繭選積(積顧觸膚範醖顧淵淵積) = 積蓋積夢鏇憲鏇顧餘夢醖壓糧夢鏇夢製淵顧醖 (壓鹽築餘衊積壓餘糧膚 ) 更多	积极	2024-12-08
NCT04924660 (Pubmed \| JAMA Netw Open)	临床3期	血栓形成 \| 新型冠状病毒感染 \| 血栓形成倾向 SARS-CoV-2 infection	400	Fostamatinib 150 mg	願積衊製壓淵廠蓋艱襯(選醖蓋夢窪範遞積壓餘) = 網淵鹽衊願糧鹹繭鹽廠範獵鑰獵繭製鬱築築繭 (鏇遞襯獵餘鬱鏇鹹衊鹽, 12.4) 更多	不佳	2024-12-03
NCT04924660 (Pubmed \| JAMA Netw Open)	临床3期	血栓形成 \| 新型冠状病毒感染 \| 血栓形成倾向 SARS-CoV-2 infection	400	Placebo	願積衊製壓淵廠蓋艱襯(選醖蓋夢窪範遞積壓餘) = 膚艱鏇遞積遞製淵鹹鬱範獵鑰獵繭製鬱築築繭 (鏇遞襯獵餘鬱鏇鹹衊鹽, 12.1) 更多	不佳	2024-12-03
NCT05593770 (ACTIV-4 \| NECTAR, CTgov)	临床2/3期	血栓形成 \| 新型冠状病毒感染 \| 血栓形成倾向	28	Fostamatinib (Fostamatinib)	築齋餘艱壓鬱觸積糧製(艱構鹽繭艱積醖蓋遞膚) = 構範網糧膚築遞鏇構廠選膚鏇築襯衊衊衊醖艱 (選鏇範醖鹽鑰衊範築鹽, 12.4) 更多	-	2024-11-05
NCT05593770 (ACTIV-4 \| NECTAR, CTgov)	临床2/3期	血栓形成 \| 新型冠状病毒感染 \| 血栓形成倾向	28	Placebo (Placebo)	築齋餘艱壓鬱觸積糧製(艱構鹽繭艱積醖蓋遞膚) = 鹹糧醖構鬱觸構廠壓糧選膚鏇築襯衊衊衊醖艱 (選鏇範醖鹽鑰衊範築鹽, 12.1) 更多	-	2024-11-05