This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.

开始日期2023-09-13

申办/合作机构

Iterion Therapeutics, Inc.

NCT05755087

/ Recruiting临床1期IIT

Phase Ib Trial of Tegavivint in Patients with Relapsed/Refractory C-MYC Overexpressing Large B-Cell Lymphoma

This phase I trial tests the safety, side effects, and best dose of tegavivint in treating patients with large b-cell lymphomas that has come back (relapsed) or does not respond to treatment (refractory). Tegavivint may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving tegavivint may help control the disease.

开始日期2023-03-06

申办/合作机构

Ohio State University Comprehensive Cancer Center

NCT04780568

/ Recruiting临床1期IIT

A Phase Ib Study of AZD9291 (Osimertinib) and BC2059 (Tegavivint) As First-Line Therapy in Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase Ib trial is to find out the best dose, possible benefits and/or side effects of osimertinib and tegavivint as first-line therapy in treating patients with EGFR-mutant non-small cell lung cancer that has spread to other places in the body (metastatic). Osimertinib and tegavivint may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2022-01-18

申办/合作机构

Ohio State University Comprehensive Cancer Center

100 项与 Tegatrabetan 相关的临床结果

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100 项与 Tegatrabetan 相关的转化医学

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100 项与 Tegatrabetan 相关的专利（医药）

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项与 Tegatrabetan 相关的文献（医药）

2024-05-01·Journal of Medicinal Food

In Vitro and In Vivo Models for the Development of Hair Growth Materials By Regulating the β-Catenin Signaling Pathways

Article

作者: Choi, JeongIn ; Kang, Ha Yeong ; Kim, Min Jeong ; Jung, Sung Keun ; Jang, Sehyeon ; Kim, SeaHyun ; Woo, Min Jeong ; Byun, Sanguine

Although hair loss contributes to various social and economic, research methods for material development are currently limited. In this study, we established a research model for developing materials for hair growth through the regulation of β-catenin. We confirmed that 100 nM tegatrabetan (TG), a β-catenin inhibitor, decreased the proliferation of human hair follicle dermal papilla cells (HFDPCs) at 72 h. In addition, TG-induced apoptosis suppressed the phosphorylation of GSK-3β and Akt, translocation of β-catenin from the cytosol to the nucleus, and the expression of cyclin D1. Interestingly, TG significantly increased the G2/M arrest in HFDPCs. Subcutaneous injection of TG suppressed hair growth and the number of hair follicles in C57BL/6 mice. Moreover, TG inhibited the expression of cyclin D1, β-catenin, keratin 14, and Ki67. These results suggest that TG-induced inhibition of hair growth can be a promising model for developing new materials for enhancing β-catenin-mediated hair growth.

2024-03-01·Leukemia

Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression

Article

作者: Mill, Christopher P ; Kantarjian, Hagop ; Sasaki, Koji ; Kadia, Tapan M ; Davis, John A ; Bhalla, Kapil N ; Sharma, Sunil ; Das, Kaberi ; Horrigan, Stephen ; DiNardo, Courtney D ; Borthakur, Gautam ; Pemmaraju, Naveen ; Fiskus, Warren ; Ruan, Xinjia ; Khoury, Joseph D ; Birdwell, Christine E ; Daver, Naval ; Su, Xiaoping

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.

2022-12-01·Experimental Hematology

TBL1X: At the crossroads of transcriptional and posttranscriptional regulation

Review

作者: Pray, Betsy A ; Alinari, Lapo ; Youssef, Youssef

Over the past 2 decades, the adaptor protein transducin β-like 1 (TBL1X) and its homolog TBL1XR1 have been shown to be upregulated in solid tumors and hematologic malignancies, and their overexpression is associated with poor clinical outcomes. Moreover, dysregulation of the TBL1 family of proteins has been implicated as a key component of oncogenic prosurvival signaling, cancer progression, and metastasis. Herein, we discuss how TBL1X and TBL1XR1 are required for the regulation of major transcriptional programs through the silencing mediator for tetanoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (NCOR)/ B cell lymphoma 6 (BCL6) complex, Wnt/β catenin, and NF-κB signaling. We outline the utilization of tegavivint (Iterion Therapeutics), a first-in-class small molecule targeting the N-terminus domain of TBL1, as a novel therapeutic strategy in preclinical models of cancer and clinically. Although most published work has focused on the transcriptional role of TBL1X, we recently showed that in diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, genetic knockdown of TBL1X and treatment with tegavivint resulted in decreased expression of critical (onco)-proteins in a posttranscriptional/β-catenin-independent manner by promoting their proteasomal degradation through a Skp1/Cul1/F-box (SCF)/TBL1X supercomplex and potentially through the regulation of protein synthesis. However, given that TBL1X controls multiple oncogenic signaling pathways in cancer, treatment with tegavivint may ultimately result in drug resistance, providing the rationale for combination strategies. Although many questions related to TBL1X function remain to be answered in lymphoma and other diseases, these data provide a growing body of evidence that TBL1X is a promising therapeutic target in oncology.

项与 Tegatrabetan 相关的新闻（医药）

2024-02-25

·药明康德

穿越血脑屏障、降解大脑靶蛋白近90%的口服蛋白降解剂；使75%患者皮炎完全消退的外用凝胶... | 一周盘点

▎药明康德内容团队编辑本期看点1. 可局部外用的小分子BRAF抑制剂LUT014在早期临床研究中的结果积极，75%患有放射性皮炎的乳腺癌患者的皮炎实现完全消退。2. Arvinas公司开发的首个口服PROTAC蛋白降解剂ARV-102在临床前研究中可使大脑深部的目标蛋白LRRK2降解近90%，其1期临床试验已于近期完成了首例患者给药。3. 口服PI3K/mTOR双抑制剂paxalisib联用放射疗法治疗PI3K通路突变实体瘤的脑转移患者，1期临床试验由于结果积极已提前结束。药明康德内容团队整理LUT014：公布1/2期临床试验数据Lutris Pharma于近日公布了其新型小分子BRAF抑制剂LUT014治疗乳腺癌患者放射性皮炎的1/2期临床试验的积极结果。BRAF抑制剂具有矛盾效应，阻断肿瘤细胞中的该通路会导致细胞凋亡和肿瘤缩小，但阻断正常细胞中的该通路会导致MAPK通路激活，细胞开始生长。LUT014利用的正是这种矛盾效应来增强细胞增殖、平衡细胞破坏，这也是放射性皮炎的典型特征。LUT014是一种可局部外用的凝胶，在该研究中的耐受性良好，可能对2级放射性皮炎有效。在该试验的第一部分中，75%（6/8）患者的放射性皮炎获得了完全消退，即改善至0级皮炎。第二部分的研究结果显示，与安慰剂相比，LUT014组患者的临床相关治疗优势约为30%，患者的生活质量也得到了改善。ARV-102：1期临床试验完成首例患者给药Arvinas公司于近期宣布，其开发的首个口服PROTAC蛋白降解剂ARV-102的1期临床试验已完成首例患者给药。ARV-102旨在降解一种大型多结构域支架激酶LRRK2，拟用于治疗神经退行性疾病。LRRK2活性和表达的增加在遗传上参与多种神经疾病的发病机制，包括帕金森病和进行性核上性麻痹。在非人灵长类动物研究中，ARV-102已被证明可以穿过血脑屏障到达大脑深部区域，并使近90%的LRRK2蛋白降解。Paxalisib：公布1期临床试验数据Kazia Therapeutics公司于近期宣布，基于迄今为止观察到的积极的安全性和良好的临床缓解结果，一项由两部分组成的重要1期试验已提前结束。这项由研究者发起的试验评估了paxalisib（一种口服PI3K/mTOR双抑制剂）联用放射疗法治疗PI3K通路突变实体瘤脑转移患者的效果。在这项研究的第一部分中，paxalisib联用放射疗法在所有9名可评估的患者中均显示出潜在的临床活性迹象。该研究的第二部分也被确认达成主要终点，研究人员还在扩展队列中观察到了令人鼓舞的缓解迹象，这部分的详细结果尚待公布。2023年7月，paxalisib联用放射疗法被美国FDA授予了快速通道资格，用于治疗PI3K通路突变实体瘤脑转移患者。OCU410ST：1/2期临床试验完成首个队列给药Ocugen公司于近期宣布，其针对Stargardt病开发的候选基因疗法OCU410ST的1/2期临床试验已完成首个队列的给药。OCU410ST利用腺相关病毒（AAV）递送平台在视网膜递送RORA基因，可调节与Stargardt病相关的通路，例如脂褐素形成、氧化应激、炎症、细胞存活网络等。RCT2100：1期临床试验开始为首批受试者给药ReCode Therapeutics公司于近期宣布，其在研吸入性mRNA疗法RCT2100的1期临床试验中，第一批健康受试者已开始接受治疗。RCT2100使用了新型选择性器官靶向的脂质纳米颗粒（LNP）递送平台，能够将基因药物高度精确地直接递送至与疾病有关的器官、组织和细胞，从而提高疗效和效力。RCT2100旨在将CFTR mRNA递送至靶细胞并指导它们制造CFTR蛋白的功能版本，从而治疗携带CFTR基因I类突变、对目前批准的CFTR调节剂没有反应的囊性纤维化患者，这类患者在囊性纤维化总患者人群中占约10-13%。ALETA-001：1/2期临床试验完成首例患者给药Aleta Biotherapeutics公司于近期宣布，其潜在“first-in-class” CAR-T细胞接合器ALETA-001的1/2期临床试验已完成首例患者给药。ALETA-001拟用于治疗已接受CD19靶向CAR-T细胞治疗且有失败风险的B细胞恶性肿瘤患者。该疗法通过增加CD19抗原密度和恢复癌细胞上丢失的CD19表达，来提高CD19靶向CAR-T细胞疗法的有效性。ALETA-001含有CD19靶蛋白，该靶蛋白进一步与CD20抗体结构域相连，使得CD19+/CD20+癌细胞很容易被已经在患者体内循环的CD19靶向CAR-T细胞识别并杀死。NPX887：1a/b期临床试验完成首例患者给药NextPoint Therapeutics公司于近期宣布，在治疗表达HHLA2（B7-H7）实体瘤患者的1期临床试验中，首例患者已开始接受其靶向HHLA2的全人源单克隆抗体NPX887的治疗。HHLA2是一种独立于PD-L1的新型免疫检查点和肿瘤靶向抗原，在许多癌症中高表达。NPX887旨在通过阻断与HHLA2结合导致的KIR3DL3介导的免疫抑制来防止实体瘤中的免疫逃逸。NPX887被认为可以促进肿瘤微环境中的T细胞和NK细胞的抗肿瘤活性。Tegavivint：启动1b/2a期临床试验的患者招募Iterion Therapeutics公司于近期宣布，其主打产品tegavivint的1b/2a期临床试验正在招募接受过至少一线系统治疗后失败的晚期肝细胞癌（HCC）患者。Tegavivint是一种有效的选择性小分子，能与Wnt/β-catenin通路中的TBL1结合。TBL1与核β-catenin结合会形成活性转录复合物，从而阻止核β-catenin的核降解，并激活Wnt/β-catenin通路中癌基因的转录。Tegavivint通过与TBL1结合，破坏β-catenin与TBL1之间的相互作用来发挥抗癌作用。除HCC外，Iterion公司正在推进针对多种癌症类型的临床项目，包括非小细胞肺癌、弥漫性大B细胞淋巴瘤和小儿实体瘤等。Shigella4V：公布1/2期临床试验数据LimmaTech Biologics公司公布了其候选四价生物结合疫苗Shigella4V（S4V）的1/2期临床试验的积极中期数据。2023年7月，LimmaTech公司从GSK获得了开发的S4V的许可，该疫苗旨在预防志贺菌（Shigella）引起的志贺菌病。志贺菌病是一种严重的传染病，是致命性腹泻疾病的第二大病因，尤其是在中低收入国家的婴儿中。此次公布的来自472名9个月大婴儿的初步数据证实了S4V具有良好的安全性和耐受性，没有报告与疫苗相关的严重不良事件。S4V对四种最常见的病原体血清型（S. flexneri 2a、3a、6和S. sonnei）具有显著的免疫原性。在第一次或第二次注射后，受试者的血清IgG水平均会有统计学意义上的明显增加，具体取决于所使用的剂量和配方。该结果支持进一步开发，LimmaTech公司计划于2024年启动下一项临床试验。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Arvinas Announces First-in-Human Dosing of ARV-102, an Investigational PROTAC® Protein Degrader for Neurodegenerative Disease. Retrieved February 21, 2024, from https://www.globenewswire.com/news-release/2024/02/20/2831684/0/en/Arvinas-Announces-First-in-Human-Dosing-of-ARV-102-an-Investigational-PROTAC-Protein-Degrader-for-Neurodegenerative-Disease.html[2] Monopar Receives Clearance to Proceed with First-in-Human Phase 1 Trial of Novel Radiopharmaceutical MNPR-101-Zr in Advanced Cancers. Retrieved February 21, 2024, from https://ir.monopartx.com/press-releases/detail/81/monopar-receives-clearance-to-proceed-with-first-in-human[3] NextPoint Therapeutics Announces First Patient Dosed in Phase 1a/b Clinical Trial of NPX887, a Novel Therapeutic Targeting HHLA2 to Reactivate Exhausted T and NK Cells in HHLA2+ Solid Tumors. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240220381798/en[4] Iterion Therapeutics Announces First Patient Dosed in Phase 1b/2a Clinical Trial of Tegavivint in Patients with Advanced Hepatocellular Carcinoma Who Have Failed One or More Systemic Treatments. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/iterion-therapeutics-announces-first-patient-dosed-in-phase-1b2a-clinical-trial-of-tegavivint-in-patients-with-advanced-hepatocellular-carcinoma-who-have-failed-one-or-more-systemic-treatments-302065477.html[5] Kazia Therapeutics Reports Early Conclusion of Clinical Trial After Reaching Primary Endpoint. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/kazia-therapeutics-reports-early-conclusion-of-clinical-trial-after-reaching-primary-endpoint-302067134.html[6] ReCode Therapeutics Announces First Participants Dosed in a Phase 1 Healthy Volunteer Clinical Study of Inhaled mRNA-Based Genetic Medicine, RCT2100, for the Treatment of Cystic Fibrosis. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240221731121/en[7] Aleta Biotherapeutics and Cancer Research UK’s Centre for Drug Development Announce First Patient Dosed in ALETA-001 Phase 1/2 Clinical Trial in Patients with Relapsed/Refractory B-Cell Malignancies. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240221259676/en[8] Lutris Pharma Announces Publication of Positive Data From Its Phase 1/2 Trial of LUT014 to Treat Radiation Dermatitis in Patients with Breast Cancer. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/lutris-pharma-announces-publication-of-positive-data-from-its-phase-12-trial-of-lut014-to-treat-radiation-dermatitis-in-patients-with-breast-cancer-302066519.html[9] LimmaTech Biologics Reports Positive Interim Phase I/II Clinical Data on Tetravalent Shigella Bioconjugate Vaccine S4V. Retrieved February 22, 2024, from https://www.businesswire.com/news/home/20240222411799/en[10] ONCOC4 ANNOUNCES FIRST PATIENT WITH ADVANCED PROSTATE CANCER DOSED IN PHASE 1/2 TRIAL OF BIONTECH-PARTNERED BNT316/ONC-392 PROGRAM. Retrieved February 22, 2024, from https://www.oncoc4.com/index.php/blog/news-releases/item/19-oncoc4-announces-first-patient-with-advanced-prostate-cancer-dosed-in-phase-1-2-trial-of-biontech-partnered-bnt316-onc-392-program[11] OCUGEN, INC. ANNOUNCES DOSING COMPLETION OF SUBJECTS WITH STARGARDT IN COHORT 1 OF PHASE 1/2 CLINICAL TRIAL EVALUATING THE SAFETY AND EFFICACY OF OCU410ST. Retrieved February 22, 2024, from https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-dosing-completion-subjects-stargardt-cohort[12] Celcuity Announces First Patient Dosed in Phase 1b/2 CELC-G-201 Clinical Trial of Gedatolisib for the Treatment of Metastatic Castration Resistant Prostate Cancer. Retrieved February 22, 2024, from https://ir.celcuity.com/press-releases/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果放射疗法蛋白降解靶向嵌合体临床1期

2024-02-20

·PRNewswire

Iterion Therapeutics Announces First Patient Dosed in Phase 1b/2a Clinical Trial of Tegavivint in Patients with Advanced Hepatocellular Carcinoma Who Have Failed One or More Systemic Treatments

HOUSTON, Feb. 20, 2024 /PRNewswire/ -- Iterion Therapeutics, an oncology-focused biopharmaceutical company developing small molecule inhibitors of Transducin beta-like protein 1 (TBL1), a downstream target in the Wnt/beta-catenin signaling pathway, announced today it is actively enrolling a Phase 1b/2a clinical trial of its lead molecule, tegavivint, in patients with advanced hepatocellular carcinoma (HCC) that have failed at least one line of systemic therapy. Activation of the Wnt/beta-catenin pathway is a hallmark of several forms of cancer, including HCC, in which approximately half of patients have tumors with Wnt-activating mutations. Unfortunately, key members of this pathway (including beta-catenin) have either been resistant to conventional drug development or plagued with off-target toxicities. Extensive pre-clinical study results across multiple tumor types suggest that TBL1 is a downstream target that is necessary for Wnt/beta-catenin-activated oncogenesis. TBL1 binds nuclear beta-catenin thus stabilizing the transcription complex necessary to turn on cancer-causing genes. Tegavivint's direct binding to TBL1 displaces beta-catenin and disrupts this complex, allowing the degradation of free nuclear beta-catenin and preventing downstream oncogenic gene transcription. "By targeting TBL1, tegavivint promotes potent inhibition of nuclear beta-catenin oncogenic activity without inducing toxicities observed for other drugs that are upstream in the Wnt-pathway" stated Rahul Aras, Ph.D., President & CEO for Iterion Therapeutics. "HCC is a devastating cancer with a high prevalence of Wnt-activated tumors, and we are committed to developing tegavivint for this patient population that otherwise has very few therapeutic options". HCC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death globally. In 2023, the National Cancer Institute (NCI) estimated 41,210 new HCC cases diagnosed in the US, with 29,380 deaths. The overall prognosis is poor, with a 5-year survival rate of 21.6%. Wnt-activation plays multiple roles in the pathogenesis of HCC by initiating tumorigenesis, promoting metastasis, and enhancing an immunosuppressive tumor microenvironment. Patients with elevated nuclear beta-catenin and TBL1 demonstrate particularly poor outcomes. Despite this, there are no FDA-approved therapies targeting this pathway. "There is a desperate need for novel targeted therapies to address the large unmet clinical need in HCC" expressed Casey Cunningham, M.D., Chief Medical Officer for Iterion Therapeutics. "Tegavivint has demonstrated excellent tolerability and has the potential to address a large portion of this population by directly inhibiting beta-catenin's oncogenic activity". The ongoing clinical trial will enroll approximately 35 patients in dose escalation and optimization cohorts of patients with unresectable locally advanced or metastatic HCC that have failed at least one line of systemic treatment. The study will evaluate safety and clinical efficacy in addition to pharmacokinetic and pharmacodynamic markers to determine a Recommended Phase 2 Dose (RP2D) in HCC. Tegavivint has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 clinical study of patients with desmoid tumors. For more information about this Phase 1b/2a clinical trial of tegavivint in patients with advanced HCC, please visit using the identifier NCT05797805. About Iterion Therapeutics Iterion Therapeutics is a clinical-stage biotechnology company developing novel cancer therapeutics. The company's lead product, tegavivint, is a potent and selective small molecule that binds to Transducin beta-like protein 1 (TBL1), a newly characterized target in the Wnt/beta-catenin pathway. TBL1 binds to nuclear beta-catenin, forming an active transcription complex that prevents nuclear degradation of beta-catenin and activates genes necessary for the Wnt/beta-catenin oncogenic activity. Tegavivint binds to TBL1 and disrupts the interaction between beta-catenin and TBL1, thus promoting the degradation of nuclear beta-catenin and preventing the transcription of Wnt/beta-catenin targeted oncogenes. Iterion is currently advancing multiple clinical programs investigating tegavivint in cancer indications where nuclear beta-catenin overexpression is a known factor. These include Iterion-sponsored programs in hepatocellular carcinoma (HCC), as well as investigator-sponsored programs in non-small cell lung cancer (NSCLC), diffuse large B-cell lymphomas (DLBCL), and pediatric solid tumors. Iterion is the recipient of combined a $18.9 million in Product Development Awards from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information on Iterion, please visit . SOURCE Iterion Therapeutics

临床1期

2024-01-18

·CPHI制药在线

FDA批准的癌症新药Nirogacestat，NCCN指南1类推荐

关注并星标CPHI制药在线美国国家综合癌症网络（National Comprehensive Cancer Network，NCCN）日前公布的最新版相关指南显示，基于FDA日前的批准，作为硬纤维瘤患者全身治疗选择的γ分泌酶抑制剂Nirogacestat（Ogsiveo），被授予首选的1类推荐。 Nirogacestat被纳入美国重磅NCCN指南并且1类推荐，成为本药的又一重要里程碑，为临床用药增添新证。NCCN软组织肉瘤指南（2023-12月发布）图片来源：NCCN官网 1.1 Nirogacestat简介 Nirogacestat于2023年11月27日首次美国获批上市，FDA 此前授予该药用于治疗硬纤维瘤的突破性疗法、快速通道和孤儿药资格。根据FDA新闻稿，该药是首个被批准用于治疗硬纤维瘤患者的药物。Nirogacestat结构（二氢溴酸盐）图片来源：FDA批准说明书【公司】Spring Works Therapeutics 【具体适应症】Nirogacestat适用于需要全身治疗的进行性硬纤维瘤成年患者。【作用机制】Nirogacestat是一种γ分泌酶抑制剂，可阻止Notch的蛋白水解激活受体。当失调时，Notch可以激活促进肿瘤生长的途径。【剂型规格】片剂，50mg 【用法用量】建议剂量为150mg，每日两次口服，直到疾病进展或不可接受的毒性。【国内外注册】2023-11-27美国批准；暂未检索其他国家获批上市记录；中国暂无原研和仿制注册/临床进展。 1.2 核心临床情况 Nirogacestat获得FDA批准的主要依据是III期的DeFi (NCT03785964)试验积极结果，该药不仅达到了改善无进展生存期 (PFS) 的主要终点，在次要终点客观缓解率(ORR)和患者报告的结局（PROs）方面也显示出统计学意义和临床意义的改善。研究简介：DeFi试验，一个国际、多中心、在142名患有硬纤维瘤不适合手术的成年患者中进行的随机 (1:1)、双盲、安慰剂对照试验。入组及给药方案：患者被随机接受口服150 mg Nirogacestat或安慰剂，每天两次，直到疾病进展或不可接受的毒性。研究终点：主要终点是PFS；次要终点包括ORR、PROs等。研究结果：有效性方面，Nirogacestat达到了PFS的主要终点，表明与安慰剂相比具有统计显著性改善，疾病进展风险降低了71%。根据RECISTv1.1确认的ORR，治疗组为41%，而安慰剂组为8%；治疗组的完全缓解率为7%，安慰剂组为0%。Nirogacestat主要疗效结果图片来源：FDA批准说明书安全性方面，nirogacestat耐受性良好，安全性可控。任何级别的不良反应（AEs）在治疗组和安慰剂组安全人群中的发生率为69%对72%。治疗组常见的任何级别不良事件包括腹泻（84%）、恶心（54%）、疲劳（51%）和低磷血症（42%）；安慰剂组中常见的任何级别不良事件包括恶心（39%）、疲劳（36%）、腹泻（35%）和呕吐（19%）。 1.3 核心专利情况美国橙皮书收录了该产品的12项专利，涉及化合物/晶型、组合物/制剂及用途等技术领域。Nirogacestat专利情况图片来源：美国OB 注：DS代表该产品的专利，一般包括化合物、晶型/盐；DP代表该产品的组合物/制剂专利；U代表该产品的适应症用途。进一步查看，该产品核心化合物/晶型专利如下：Nirogacestat中美核心专利情况参考来源：OB、欧专局、中国专利局作为最核心及壁垒最高的的化合物专利，最迟于2025年8月18日到期，相关企业可参考关注。 1.4 硬纤维瘤可关注新药硬纤维瘤是一种难以治愈的具有局部侵袭性的软组织肿瘤，可导致严重的发病率。具体来说，硬纤维瘤（侵袭性纤维瘤病、韧带样纤维瘤病、纤维瘤病）是一种源于成纤维细胞的软组织肿瘤，以浸润性生长为主要特征，具有高度复发倾向而无转移行为。疾病主要特点如下：（1）罕见：5-6例/100,0000人/年；（2）好发年龄：30-40岁；（3）发病部位：腹壁、腹腔内、腹外；（4）肿瘤本身病程差异较大；（5）近年来整体治疗方式变化较大。硬纤维瘤目前的治疗主要包括随诊观察、手术切除、放疗/化疗治疗以及靶向药物治疗。靶向药物作为近年来的新兴治疗手段，在硬纤维瘤的治疗中也取得了一定的疗效。硬纤维瘤在研新药情况参考来源：美国临床试验登记网、公开平台等；图形自制 BMS-986115是由百时美施贵宝研发的一种小分子药物，是一种γ-分泌酶抑制剂。目前该药物最高研发阶段为临床三期，用于治疗硬纤维瘤。此前，该药获FDA授予快速通道认定，用于治疗进展性硬纤维瘤。 Endoxifen是由Jina Pharmaceuticals Inc研发的一种小分子药物，是一种ERs调节剂。目前该药物最高研发阶段为临床三期，用于治疗躁狂症。该药物的硬纤维瘤正在开展I期试验。 Tegatrabetan是由艾尔建研发的一种小分子药物，是一种Wnt信号途径抑制剂和CTNNB1抑制剂。目前该药物最高研发阶段为临床二期，用于治疗肝细胞癌；I期包括硬纤维瘤、实体瘤、非霍奇金淋巴瘤、肝胚细胞瘤、骨肉瘤、黑色素瘤、结直肠癌、卵巢上皮癌、神经母细胞瘤、肾母细胞瘤、胰腺癌、胰腺导管癌、尤因肉瘤和子宫内膜癌。 1.5 γ分泌酶抑制剂后继者 Notch信号通路在生物体的早期发育中程序性地操控细胞的命运和组织的分化。γ分泌酶抑制剂，可阻断Notch受体的蛋白水解激活。当失调时，Notch可以激活有助于肿瘤生长的通路。随着γ分泌酶结构的解析和在体内功能的研究进展，其作为癌症和阿尔兹海默症的潜在治疗靶点吸引了跨国制药巨头的目光，有多个γ分泌酶抑制剂进入了临床阶段。 BMS-986115与Nirogacestat同机制同适应症，亦是一种γ-分泌酶抑制剂，用于治疗硬纤维瘤。 Osugacestat是由百时美施贵宝和葛兰素史克研发的一种小分子γ-分泌酶抑制剂，目前该药物最高研发阶段为临床二期，用于治疗三阴性乳腺癌和腺样囊性癌。 BMS-932481是由百时美施贵宝研发的一种一种小分子γ-分泌酶抑制剂。目前该药物最高研发阶段为临床一期，用于治疗阿尔茨海默病。γ分泌酶抑制剂在研新药情况参考来源：美国临床试验登记网、公开平台等；图形自制 Nirogacestat，作为首个获批上市且目前唯一的硬纤维瘤药物，目前又被纳入重磅NCCN指南1类推荐，为硬纤维瘤患者带来新的治疗希望。无论是治疗同领域还是机制药物，Nirogacestat的进度都遥遥领先同类药物，期待该药后续市场表现和解决未满足的临床需求。作者简介：药丸，中国药科大学硕士毕业，具有法律及药学教育背景，拥有法律资格证和专利代理师资格证，致力研究药学和专利，做一颗有价值的药丸。参考资源： 1-NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 3.2023. 2024-01-12访问；https://www.nccn.org/patients/guidelines/content/PDF/sarcoma-patient.pdf 2-https://www.onclive.com/view/nccn-adds-nirogacestat-to-guidelines-for-patients-with-soft-tissue-sarcoma 3-Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140 4-硬纤维瘤诊疗的国际专家共识及其解读 5-γ-分泌酶小分子抑制剂和调节剂的作用机制研究 6-Nirogacestat获批说明书 7-Nirogacestat美国OB智药研习社2月课程预告来源：CPHI制药在线声明：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~

孤儿药临床3期上市批准临床结果突破性疗法

100 项与 Tegatrabetan 相关的药物交易

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研发状态

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
晚期肝细胞癌	临床2期	加拿大	Iterion Therapeutics, Inc.	2023-09-13
晚期肝细胞癌	临床2期	美国	Iterion Therapeutics, Inc.	2023-09-13
急性髓性白血病	临床2期	美国	Iterion Therapeutics, Inc.	2023-04-10
复发性弥漫性大B细胞淋巴瘤	临床1期	美国	Ohio State University Comprehensive Cancer Center	2023-03-06
复发性高级别 B 细胞淋巴瘤伴 MYC 和 BCL2 或 BCL6 重排	临床1期	美国	Ohio State University Comprehensive Cancer Center	2023-03-06
难治性高级别 B 细胞淋巴瘤	临床1期	美国	Ohio State University Comprehensive Cancer Center	2023-03-06
EGFR突变的非小细胞肺癌	临床1期	美国	Ohio State University Comprehensive Cancer Center	2022-01-18
转移性非小细胞肺癌	临床1期	美国	Ohio State University Comprehensive Cancer Center	2022-01-18
侵袭性纤维瘤病	临床1期	加拿大	Iterion Therapeutics, Inc.	2018-07-15
侵袭性纤维瘤病	药物发现	美国	Iterion Therapeutics, Inc.	2018-07-15

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临床结果

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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


NCT04851119 (PEPN2011, AACR2023) 人工标引	临床1/2期	实体瘤 \| 侵袭性纤维瘤病 \| 淋巴瘤	13	overall	(製鏇齋衊衊襯鏇網糧製) = at least possibly related to treatment included anemia (2) and lymphopenia (2). A single patient had a grade 3 QT prolongation requiring cessation of tegavivint after cycle 3. 廠築鏇簾築鹽鏇壓廠積 (糧窪築憲簾壓襯夢淵遞 ) 更多	积极	2023-04-14
NCT04851119 (PEPN2011, AACR2023) 人工标引	临床1/2期	实体瘤 \| 侵袭性纤维瘤病 \| 淋巴瘤	13	Tegavivint 5 mg/kg		积极	2023-04-14
NCT03459469 (AACR2022) 人工标引	临床1期	侵袭性纤维瘤病	17	BC2059	(觸顧醖窪鹽積齋艱獵範) = 壓窪鹽壓網夢願構鑰夢築艱簾遞積築醖窪壓製 (範築願構餘蓋鑰鹽網襯 ) 更多	积极	2022-06-15
NCT03459469 (ASCO2022) 人工标引	临床1期	侵袭性纤维瘤病	24	BC2059	(願壓製蓋觸衊範蓋獵築) = 築蓋鹹顧鹹鑰夢鬱壓願選蓋鹹積壓襯衊艱構餘 (糧襯鏇選構鹹醖遞窪選 ) 更多	积极	2022-06-02