A Phase 2, Open-label, Multicentre Study Investigating Tolerability and Efficacy of Gilteritinib in Combination With Fludarabine, Cytarabine and Idarubicin (FLAI) as Induction Therapy of Newly Diagnosed Non-M3 FLT3-positive Acute Myeloid Leukemia

The goal of this clinical trial is to evaluate the efficacy of gilteritinib as induction therapy in FLT3-positive adult acute myeloid leukemia patients. The main question it aims to answer is:
Is gilteritinib in combination to chemotherapy able to improve the complete remission rate of FLT3-positive AML?
Participants will receive up to 2 induction cycles with gilteritinib in combination with FLAI (fludarabine, cytarabine, idarubicine) and up to 3 consolidation cycles with gilteritinib and high-dose cytarabine.

开始日期2025-03-01

申办/合作机构

Gruppo Italiano Malattie EMatologiche dell'Adulto

NCT06696183

/ Not yet recruiting临床2期

Sequential Gilteritinib in Combination with Venetoclax and Azacitidine for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) and FLT3 Mutations Ineligible for Intensive Treatment

Explore the best tolerable and efficacious dose of Gilteritinib when combined with standard treatment with Venetoclax and Azacitidine in AML patients with FLT3 mutations which are ineligible for intensive chemotherapy

开始日期2025-01-01

申办/合作机构

Dresden University of Technology

NCT06734585

/ Not yet recruitingN/A

A Comparison Between Gilteritinib in Phase 3 Trials Versus Real-World External Comparator Cohort of Relapsed/Refractory (R/R) FLT3m+ Acute Myeloid Leukemia (AML) Patients After Hematopoietic Stem Cell Transplantation (HSCT)

People with acute myeloid leukemia (AML) are usually treated with chemotherapy. When the cancer comes back (relapse) the next treatment is usually a stem cell transplant. Some people with AML have a changed FLT3 gene which causes leukemia cells to grow faster. This means their cancer may come back more quickly after treatment.
Gilteritinib is approved in many countries to treat people with AML with the changed FLT3 gene whose cancer has come back or have not responded to previous treatment. In some countries, more studies are needed to approve gilteritinib for use.
This study is about people with AML with the changed FLT3 gene. The main aim was to learn if gilteritinib improves how long people stay cancer-free (in remission) after a stem cell transplant. To do this, 2 groups were compared. 1 group were given gilteritinib after a stem cell transplant. This happened in previous studies called the ADMIRAL study and COMMODORE study. The other group received standard of care after their stem cell transplant. They did not receive gilteritinib after their stem cell transplant.
In this study, information about the people who received standard of care after their stem cell transplant will be collected. This study is about collecting information only. The study sponsor (Astellas) will not provide any treatment.
Information will be collected from the people's medical records between 01 Jan 2015 and 31 Dec 2022. The study doctors will collect information from the first relapse, during and after the stem cell transplant. Then, they will record when any of the following happened after the stem cell transplant: the person passed away, their cancer came back, they decided to leave the study or could not be contacted.

开始日期2024-12-31

申办/合作机构

Astellas Pharma Singapore Pte Ltd.

100 项与富马酸吉瑞替尼相关的临床结果

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100 项与富马酸吉瑞替尼相关的转化医学

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100 项与富马酸吉瑞替尼相关的专利（医药）

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410

项与富马酸吉瑞替尼相关的文献（医药）

2025-02-01·CANCER LETTERS

FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia

Article

作者: Chen, Yun ; Zhao, Yuming ; Pei, Han Zhong ; Zhou, Jingfeng ; Zhao, Zhizhuang Joe ; Chen, Chun ; Zhang, Dengyang ; Guo, Yao ; Baek, Suk-Hwan ; Chang, Zhiguang

FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination. STAT5 phosphorylation facilitates its nuclear localization, leading to competitive interactions among STAT5, MDM2, and p53. TKIs blocked STAT5 nuclear entry, amplifying MDM2/p53 binding and subsequent p53 degradation. Additionally, STAT5 overexpression inhibited MDM2-mediated p53 ubiquitination, whereas knock-down of STAT5 destabilizes p53. Co-administration of MDM2 inhibitors stabilizes p53 ubiquitination induced by TKIs, enhancing pro-apoptotic effects on AML cells. Moreover, in mice engrafted with AML cells, gilteritinib treatment results in decreased p53 protein levels and the transcriptional repression of downstream genes in leukemia cells, which are mitigated by the co-administration of MDM2 inhibitors. In conclusion, our study shows that FLT3 TKIs impede STAT5 nuclear translocation, strengthening p53/MDM2 interaction and consequent p53 degradation. This finding reveals a novel mechanism of TKIs resistance and indicates a combination of MDM2 inhibitors with TKIs for AML therapy, offering new insights into effective treatment strategies.

2025-01-01·American Journal of Clinical Oncology

Maintenance Therapy in Acute Myeloid Leukemia

Review

作者: Sabakhtarishvili, Giorgi ; Ansari, Amir ; Tabbara, Imad A.

Acute myeloid leukemia (AML) poses significant challenges due to its high relapse rates despite initial successful induction chemotherapy. Maintenance therapy aims to prevent disease recurrence, particularly in high-risk patients. This review explores current maintenance treatments, their impacts on patient outcomes, and ongoing studies shaping the treatment landscape for AML. Hypomethylating agents like azacitidine and decitabine have shown promise in improving relapse-free and overall survival, particularly in older patients with AML ineligible for transplantation. Combination regimens involving azacitidine and venetoclax have demonstrated encouraging outcomes post–hematopoietic stem cell transplantation. Targeted therapies, particularly FLT3 inhibitors like midostaurin and quizartinib, have shown significant benefits in improving survival outcomes, especially in FLT3-mutated AML cases. Gilteritinib and sorafenib also exhibit the potential to reduce relapse rates post-transplant. Isocitrate dehydrogenase inhibitors, including ivosidenib and enasidenib, present novel options for postchemotherapy and posttransplantation maintenance. Immunotherapies, such as Wilms tumor 1 peptide-based vaccines and checkpoint inhibitors, are being explored, although results vary. Despite ongoing research, the role of maintenance chemotherapy remains uncertain, with inconsistent outcomes across trials. The approval of oral azacitidine represents a significant advancement, emphasizing the need for further investigation into personalized maintenance approaches. In conclusion, the evolving landscape of maintenance therapy and integrating targeted therapies in AML offers promising avenues for improving patient outcomes.

2025-01-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Identification of inhibitors targeting the FLT3-ITD mutation through 4D-QSAR, in vitro, and in silico

Article

作者: Yan, Hong ; Zhong, Qidi ; Chu, Dongchen ; Zhang, Xiaokun ; Zhang, Yu ; Ji, CuiCui ; Wei, Chaochun ; Wang, Juan

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation is a key target for acute myeloid leukemia (AML) treatment. The second-generation inhibitors such as Gilteritinib still present off-target effects and associated side effects. Therefore, identifying novel FLT3-ITD inhibitors has become a promising strategy for AML treatment. In this study, a 4D-QSAR model was developed based on Gilteritinib and its analogues, and it was found that introducing hydrophobic bulky groups at the piperazine or piperidine of Gilteritinib would enhance the binding affinity to FLT3-ITD. So, three series of targeted compounds (A1-A5, B1-B5 and C1-C5) were designed and synthesized. The antiproliferative activity against MOLM-13 cells was evaluated in vitro. Compound A1 (IC₅₀ = 25.65 nM), with a cubane group at the piperazine position; Compounds B2 (IC₅₀ = 63.38 nM) and C2 (IC₅₀ = 54.96 nM), with a norbornene group at the piperidine position, showed the strongest inhibition in their series. Their IC₅₀ values were comparable to that of the positive control Gilteritinib (IC₅₀ = 22.37 nM). FLT3-ITD was confirmed as the degradation target through a kinase inhibition assay, where the IC₅₀ values were 2.12 nM (Compound A1), 1.29 nM (Compound B2), and 3.06 nM (Compound C2), which were comparable to that of Gilteritinib (IC₅₀ = 0.43 nM). Additionally, molecular docking and molecular dynamics (MD) simulations showed that Compounds A1, B2, and C2 had similar binding modes to that of Gilteritinib with more stable affinities. Overall, these results demonstrated that Compounds A1, B2, and C2 were promising inhibitors for targeting AML with FLT3-ITD mutation.

171

项与富马酸吉瑞替尼相关的新闻（医药）

2025-01-13

·GlobeNewswire-Health Care

ORYZON Announces First Patient Dosed in NCI-Sponsored Iadademstat in Combination With Venetoclax and Azacitidine Clinical Trial in First Line Acute Myeloid Leukemia

Study conducted under the CRADA agreement between NCI and Oryzon MADRID, Spain and CAMBRIDGE, Mass., Jan. 13, 2025 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the first patient has been dosed in a Phase I dose-finding clinical trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with venetoclax and azacitidine in newly diagnosed acute myeloid leukemia (AML), sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. The trial (NCT06514261), titled “Phase 1 Trial of Iadademstat in Combination With Venetoclax and Azacitidine in Patients With Treatment Naive AML”, will evaluate the safety, tolerability, and optimal dose of iadademstat when administered together with the standard-of-care venetoclax and azacitidine in treatment-naïve AML patients. Preliminary efficacy of the triple combination will also be evaluated. This Phase I study will be conducted and sponsored by the NCI, and will be led by Principal Investigator, Dr. Natalie Galanina, from the University of Pittsburgh Cancer Institute. The trial plans to enroll 45 patients and is carried out under a Cooperative Research and Development Agreement (CRADA) that Oryzon has in place with the NCI. Dr. Carlos Buesa, Oryzon’s CEO, added: “We are excited to have the first patient dosed in this study. The trial expands on the findings from our ALICE trial, where combining iadademstat with azacitidine demonstrated robust antileukemic effects in first-line AML, producing deep and durable responses along with a manageable safety profile, including in patients with high-risk prognostic factors that respond poorly to venetoclax plus azacitidine.” In AML, iadademstat is also being evaluated in combination with venetoclax and azacitidine in newly diagnosed AML patients in an investigator-initiated Phase I clinical trial at Oregon Health & Science University (OHSU) Knight Cancer Institute (NCT06357182), and in a company-sponsored Phase Ib clinical trial in combination with gilteritinib in patients with relapsed/refractory AML harboring a FMS-like tyrosine kinase mutation (FLT3mut+) (NCT05546580). About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS (Phase III-ready) and iadademstat in oncology (Phase II). The company has other pipeline assets directed against other epigenetic targets like HDAC-6 where a clinical candidate ORY-4001, has been nominated for its possible development in CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About IadademstatIadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and strong clinical activity in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation & The Lancet Haematology, 2024, 11(7):e487-e498). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations, and in combination with azacitidine and venetoclax in 1L AML in an investigator-initiated study led by OHSU and in a trial under the Cooperative Research and Development Agreement (CRADA) signed with the U.S. National Cancer Institute (NCI) to collaborate on further clinical development of iadademstat in different types of hematologic and solid cancers. Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is in a collaborative Phase II trial with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and in a Phase I/II randomized trial in 1L ED-SCLC in combination with ICI sponsored by NCI and led by the Memorial Sloan Kettering Cancer Center (IND approved). Oryzon is further expanding the clinical development of iadademstat through additional investigator-initiated studies. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. SpainOryzonIR & Media, Europe & US Patricia Cobo/Mario CorderaEmili TorrellSandya von der Weid AtreviaChief Business OfficerLifeSci Advisors, LLC +34 91 564 07 25 +34 673 33 97 65+34 93 515 1313+41 78 680 05 38 pcobo@atrevia.com mcordera@atrevia.cometorrell@oryzon.comsvonderweid@lifesciadvisors.com

临床1期临床2期孤儿药临床结果

2024-12-17

·安斯泰来中国

安斯泰来CCO Claus Zieler：创新驱动加码中国市场转型聚焦肿瘤创新路径

以下内容转自21世纪经济报道 “以移植和泌尿领域作为基础，我们正在不断加速创新，转型成为以肿瘤为主的创新药企业。近期我们正在中国市场推出两款新的肿瘤药物。”近日，安斯泰来CCO Claus Zieler介绍称，安斯泰来作为一家全球性、前沿性、创新性的制药企业，一直不断地在研发和发明新药方面做出努力，从而满足全球患者未被满足的医疗需求。其实，安斯泰来的理念从公司的名字上便可“窥见一斑”。安斯泰来（Astellas）名称来源于希腊、拉丁及英文中有关“星辰” 的词汇，蕴含着专注研发、以创新及可靠的药物为全人类带来更美好明天的承诺。自1994年进入中国市场，在中国步入“而立之年”的安斯泰来也一直在积极引入创新药。在Claus Zieler看来，中国作为全球人口最多的国家，对创新药物的需求，随着寿命的不断延长和社会老龄化程度的加深而不断增长，呈现出巨大的市场潜力。同时，中国也在加大知识产权尤其是专利保护的力度，这些举措正在持续增强创新药企的信心。此外，中国对医药创新的开放态度，也让新技术和创新药物在这里能够迅速得到接受和推广。基于这些因素，以安斯泰来为代表的跨国企业，都愿意不断将全球创新成果带到中国市场。知识产权保护是推动药物创新可持续发展的关键，而为了更好地支持创新并保护创新成果，Claus Zieler强调，一个社会的医疗保险体系和创新支付手段的协同发展也至关重要。“多元化的支付方式和报销途径是医药行业健康发展的必要条件，这些措施将有助于推动整个行业的持续创新与发展。” 聚焦肿瘤瞄准未被满足的需求从传统的移植和泌尿领域出发，主动创新转型，如今安斯泰来已基本确立以肿瘤治疗为核心的定位。企业内部的积极转型，也渗透于团队运作、科学研究和专业能力的全方位变革。深耕肿瘤领域，是安斯泰来经过深思熟虑后作出的重要决定。一方面，安斯泰来在启动转型时，已积累了一定的肿瘤治疗基础，特别是在前列腺癌领域的创新药物开发上，成功迈出了关键的第一步。 2012年，恩扎卢胺获得美国FDA批准，成为雄激素剥夺治疗和化疗后已扩散的男性前列腺癌患者治疗的药物，2013年该药物在欧洲上市，2019年，恩扎卢胺在中国获批。这一系列的批准标志着安斯泰来在肿瘤治疗领域的持续突破和积累，也为公司转型提供了方向。另一方面，凭借技术优势，安斯泰来敏锐地识别出自身在肿瘤创新药开发领域的潜力。 Claus Zieler解释称，药物开发首先取决于是否存在合适的开发模式（modality），可以通过创新手段实现研发目标。例如，传统的研发方法通常从疾病的发病机制入手，分析基因突变或受体异常等与健康状态的差异，以识别潜在的治疗靶点。在明确其机制后，开发重点是如何作用于机制相应的靶点。传统方法通常通过结合、阻滞或刺激受体等方式来进行干预，然而，安斯泰来却“匠心独具”，选择聚焦一种前沿的开发模式——靶向蛋白降解（TPD），进而引入了一种全新的治疗模式：针对某些无法通过结合解决的问题，不去阻滞靶点，而是直接降解它，将其分解消除。这种高度创新的方法被证明极具成效。 ✦ • ✦ 自TPD这一技术概念于1999年初步形成以来，TPD已经从学术界转移到工业界，跨国药企如安斯泰来、辉瑞、诺华、默沙东等纷纷布局该领域。以TPD中蛋白水解靶向嵌合体(PROTACs)为例，有研报数据显示，在 PROTAC 概念提出 20 年后，截至 2021 年底至少有 15 种不同的靶向蛋白降解剂进入临床，在可以预见的未来将会有更多的临床管线出现。也正是通过聚焦TPD这样的前沿治疗模式，安斯泰来得以在过去十余年完成战略转型，奠定了公司的成功基础，也让安斯泰来一改以往传统的品牌形象，成为充满活力的新锐创新药企。值得注意的是，肿瘤领域一直是全球医药研发的焦点，吸引着无数目光。“肿瘤一直是医疗需求高度未被满足的重要领域之一。随着人类寿命的不断延长和医学的不断进步，感染性疾病不再是死亡的主要原因，取而代之的是肿瘤等慢性疾病。同时，人口老龄化趋势日益明显，这进一步凸显了肿瘤治疗需求的紧迫性和重要性。” 然而，与其他治疗领域相比，肿瘤试验在合格标准、研究终点、研究中心、国家和临床受试者等方面的复杂性明显更高。IQVIA数据显示，自2015年以来，肿瘤治疗药物研发的综合成功率持续下降，至2022年仅为3.5%。因此，布局肿瘤管线的企业需要经过深思熟虑，权衡利弊后做出决定。波士顿咨询指出，逐鹿中国市场的企业需要认识到，中国的疾病谱与其他国家不同——因此需要满足的医疗需求也不一样。例如，中国胃癌和肝癌等发病率高于美国，这些因素代表了独特的本土机遇。这与安斯泰来在“焦点领域”寻找新药机会的观点不谋而合，即持续寻找创造新药的机会，以解决未满足的医疗需求，尤其是高度未被满足的疾病。在整个焦点领域策略中，优先发展项目与后续项目会多维度呈现以患者利益为中心、以临床价值为导向的清晰药物研发路径。受益于此策略，安斯泰来肿瘤管线捷报频传。以安斯泰来的Zolbetuximab为例，这款针对CLDN18.2阳性、不可切除晚期或复发性胃癌的药物是全球首个上市的以CLDN18.2靶点的创新疗法，也是安斯泰来中国首个全球同步研发和同步递交申请的产品。根据国家癌症中心的数据，中国胃癌发病率位居所有恶性肿瘤的第二位，每年新发病例达40至50万，约占全球每年新增患者数量的40%，其中男性发病率为女性的两倍以上。然而，目前胃癌治疗面临药效有限和部分患者无法使用PD-1抑制剂的困境。由于CLDN 18.2在胃癌、胰腺癌等实体肿瘤中具有高度的选择性及稳定的表达，近年来已成为HER2后的又一个潜力靶点，药物研发路线有单克隆抗体、双特异性抗体、ADC、CAR-T等前沿方向，已成为肿瘤治疗领域的新宠。根据弗若斯特沙利文预测，CLDN18.2抗体市场前景广阔，美国和中国市场预计将在2025至2035年分别从2.52亿美元和2亿美元增长至40.36亿美元和37.44亿美元，复合年增长率（CAGR）分别达到32.0%和33.5%。然而，截至目前，全球仅有安斯泰来的CLDN18.2产品获批上市。因此，Zolbetuximab不仅有望为患者提供全新的治疗选择，也为安斯泰来的营收增长打开了更大的想象空间。此外，安斯泰来治疗尿路上皮癌的药物注射用维恩妥尤单抗已于2024年8月获中国国家药品监督管理局药品审评中心批准。 2022年，中国被新诊断为膀胱癌的患者超过92,000例，其中死亡人数达41,000例。尿路上皮癌是膀胱癌最常见的组织学亚型，约占膀胱癌的90%，对于晚期或转移性尿路上皮癌患者而言，生存率尤其低。因此，注射用维恩妥尤单抗的成功获批也备受关注。在Claus Zieler看来，安斯泰来的药物拥有一个共同的优势，即在患者、监管机构和医疗机构等利益相关方之间建立了高效的沟通渠道。 “当各方清楚地掌握需要了解的信息，医疗专业人士便能作出更合适的处方决策，而患者也能获得更加可及且优化的治疗选择。”Claus Zieler强调。 ✦ • ✦ 创新驱动加码中国布局除上述几款肿瘤药物外，安斯泰来还有一款眼科药物和一款针对女性绝经期潮热症状的治疗药物也在全球推进中，而中国也在这些新药的全球创新研发中扮演着越来越重要的角色。如今，中国已不再仅仅是一个销售市场，而是全球医药健康领域的重要驱动引擎。跨国药企不断深化在华布局，如何推动中国参与早期研究已成为跨国药企绕不开的课题。近年来，多家跨国药企如诺华、诺和诺德、赛诺菲等在华落地新厂区、扩大产能，加大投资力度，而跨国药企每年在中国登记开展的临床试验呈现递增的趋势，并在2022年和2023年保持着高位的临床试验登记量。在全球临床试验开发阶段便将中国纳入试验设计中也成为安斯泰来采取的策略。Claus Zieler表示：“为了加速新药获批上市进程，我们在临床试验的早期阶段便将中国纳入设计，缩短中国与全球新药审批时间的差距。得益于中国的审评审批制度改革，我们与医疗机构的临床试验早期合作得以不断加速，这种合作非常重要。如果没有中国的临床试验参与，就难以研发出真正惠及中国患者的创新药物。所以这种能力也是我们在过去多年以来一直在打造、构建和加强的。” 与此同时，安斯泰来正以更加积极和开放的态度拥抱本土创新。波士顿咨询指出，跨国药企可以利用本土创新者，为中国和全球市场开发新的治疗方法，尤其是当中国开发的疗法弥补了全球在研药缺口，或者中国可以比其他国家更快地让药品进入市场时。因此，引入外部创新已成为跨国药企提升研发效率的重要战略。据统计，2015至2021年间，20家跨国药企获批的138款创新药中，有65%源自外部引进，仅28%为自主研发，其余5%为合作开发。 2023年底，安斯泰来与本土创新企业科望就全新的BiME® (双抗巨噬细胞衔接器)平台及候选药物ES019和另一分子项目达成合作开发及授权许可协议，双方将合作完成两个项目的开发。谈及本土合作的推动，Claus Zieler不无自豪。 “在我们看到有建立合作伙伴关系的可能性时，我们将致力于成为首个或者是首选的合作对象，迅速达成合作并签署协议。” 上述安斯泰来在中国市场的布局，无一不彰显了其对于中国市场未来发展的坚定信心。数据再次证实了这一点。安斯泰来业绩报告显示，得益于恩扎卢胺、吉瑞替尼等肿瘤药在内的产品组合展现的强大潜力，2023财年，安斯泰来中国实现收入885亿日元，同比增长10.6%。在Claus Zieler看来，中国市场的独特性正是安斯泰来在华取得显著成绩的重要基础。一方面，中国作为全球人口最多的国家之一，社会老龄化进程导致医疗服务需求持续增长。这不仅推动了医药市场规模的扩张，也显现出市场对创新药物的强烈需求。无论是庞大的人口基数，还是老龄化带来的医疗挑战，都为创新药的研发和应用带来了巨大的市场潜力。另一方面，药品是一种高度专业性的产品，研发新药需要耗费大量的金钱、人力、时间，而一旦药品被研发出来，其生产和仿制的成本将变得相对低廉。因此，对付出高昂研发成本的创新原研药企进行知识产权保护是创新可持续的关键。因此，许多国家都将新分子和创新药视为专利保护的核心对象，而中国在这一领域的强力举措为安斯泰来等原研药企注入了信心。中国在知识产权保护上已经展现出明确的承诺，不仅对本土企业，也对外资企业一视同仁。而中国对于专利的保护，也让安斯泰来的创新在产品专利期失效之前得到回报。通过这种回报，原研药企才能够继续投入下一批新的创新产品研发当中，形成正向循环。 Claus Zieler举例解释：“安斯泰来近期在中国最高人民法院获得一项专利裁决的支持，这不仅体现了中国对于创新的保护，更强化了我们对中国市场的信任。这样的政策信号对于外资企业规划在华的未来发展至关重要。” 此外，中国文化和公众对创新的开放态度也为创新药物的引入创造了独特优势。中国的医疗专业人士和患者群体对于创新的医疗技术和药物持开放态度，这种接受度在有些国家并不普遍，甚至在某些市场，创新的推广会遇到较大阻力。而在中国，这种开放性无疑是一大亮点。凭借对中国市场的深入理解，Claus Zieler对安斯泰来使命的认知愈加明晰。未来，安斯泰来将继续怀抱对中国市场的深刻理解和对创新的执着追求，利用前沿技术所蕴藏的无限潜力，将前沿创新成果，将科学的进步转化为患者的价值。

2024-12-12

·GlobeNewswire-Health Care

Aptose Announces Publication of Preclinical Data in AACR Journal Demonstrating Tuspetinib’s Unique Mechanism of Action and Synthetic Lethality on AML Cells When Combined with Venetoclax

Peer-reviewed publication details unique TUS mechanism of action TUS+VEN combination synthetic lethality overcomes resistance to VEN Tuspetinib prolongs survival in multiple AML models resistant to other drugs Findings suggest TUS will demonstrate broad antileukemic activity across AML patients TUS+VEN+AZA Triplet Frontline Therapy in Newly Diagnosed AML Patients Now Enrolling SAN DIEGO and TORONTO, Dec. 12, 2024 (GLOBE NEWSWIRE) -- Aptose Biosciences Inc. (“Aptose” or the “Company”) (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated targeted agents to treat hematologic malignancies, today announced the publication of preclinical data for Aptose’s lead hematology compound tuspetinib (TUS) in Cancer Research Communications, a journal of the American Association for Cancer Research (AACR), available online now (link). The publication, entitled “Preclinical development of tuspetinib for the treatment of acute myeloid leukemia,” is the first preclinical profiling of tuspetinib, a well-tolerated, once daily, oral kinase inhibitor currently in clinical development for treatment of acute myeloid leukemia (AML). The publication defines TUS activities on select oncogenic signaling targets, demonstrates enhanced activity and safety of TUS when combined with other agents, and illustrates synthetic lethality when combined with venetoclax (VEN). Pharmacokinetic and toxicology studies revealed that TUS is readily absorbed and achieves plasma concentrations sufficient to inhibit the target kinases, it has a plasma half-life that supports once daily dosing, and it demonstrates a favorable safety profile. Aptose is now enrolling newly diagnosed AML patients in a Phase 1/2 clinical study to receive the tuspetinib + venetoclax + azacitidine (TUS+VEN+AZA) triplet combination (NCT03850574). Clinical studies in patients with relapsed or refractory AML receiving TUS single agent or the TUS+VEN combination have been completed. “The non-clinical findings presented in the publication suggest that TUS will demonstrate favorable safety and a breadth of antileukemic activity across AML patient populations with a diversity of adverse mutations, and the initial clinical data is bearing that out,” said William G. Rice, Chairman, President and Chief Executive Officer. “We are eager for the next set of data in our triplet combination trial of TUS+VEN+AZA.” Key findings: Tuspetinib inhibits a defined cluster of oncogenic signaling kinases operative in AML TUS inhibits SYK, JAK1/2, RSK2, mutant KIT, and wild type and mutant forms of FLT3TUS potently killed AML lines (GI50 = 1.3 to 5.2 nM) and Ba/F3 cells expressing wildtype (GI50 = 9.1 nM) or various mutant forms of FLT3 (GI50 = 2.5 – 56 nM)TUS dampens stroma-induced activation of FLT3-ITD signaling in AML cells TUS prolongs survival in multiple AML models Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3 mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax or 5-azacytidine TUS combines effectively with other classes of agents to kill AML cells with mutations in RAS and other difficult-to-treat adverse mutationsTUS was 2.1-15-fold and a 4.5-13-fold more potent than gilteritinib at blocking fibrinogen and immunoglobulin-mediated activation of SYK in KG-1a cellsThe most notable observation was the marked and unexpected synthetic lethal vulnerability to venetoclax and two MCL1 inhibitors in the TUS-resistant cells About Aptose Aptose Biosciences is a clinical-stage biotechnology company committed to developing precision medicines addressing unmet medical needs in oncology, with an initial focus on hematology. The Company's small molecule cancer therapeutics pipeline includes products designed to provide single agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The Company’s lead clinical-stage, oral kinase inhibitor tuspetinib (TUS) has demonstrated activity as a monotherapy and in combination therapy in patients with relapsed or refractory acute myeloid leukemia (AML) and is being developed as a frontline triplet therapy in newly diagnosed AML. For more information, please visit www.aptose.com. Forward Looking Statements This press release may contain forward-looking statements within the meaning of Canadian and U.S. securities laws, including, but not limited to, statements relating to the therapeutic potential of tuspetinib, its clinical development and safety profile, including that it combines effectively with other classes of agents and will demonstrate a favorable safety profile and a breadth of antileukemic activity across an AML patient population with a diversity of adverse mutations, as well as statements relating to the Company’s plans, objectives, expectations and intentions and other statements including words such as “continue”, “expect”, “intend”, “will”, “should”, “would”, “may”, and other similar expressions. Such statements reflect our current views with respect to future events and are subject to risks and uncertainties and are necessarily based upon a number of estimates and assumptions that, while considered reasonable by us are inherently subject to significant business, economic, competitive, political and social uncertainties and contingencies. Many factors could cause our actual results, performance or achievements to be materially different from any future results, performance or achievements described in this press release. Such factors could include, among others: our ability to obtain the capital required for research and operations and to continue as a going concern; the inherent risks in early stage drug development including demonstrating efficacy; development time/cost and the regulatory approval process; the progress of our clinical trials; our ability to find and enter into agreements with potential partners; our ability to attract and retain key personnel; changing market conditions; inability of new manufacturers to produce acceptable batches of GMP in sufficient quantities; unexpected manufacturing defects; and other risks detailed from time-to-time in our ongoing quarterly filings, annual information forms, annual reports and annual filings with Canadian securities regulators and the United States Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should the assumptions set out in the section entitled “Risk Factors” in our filings with Canadian securities regulators and the United States Securities and Exchange Commission underlying those forward-looking statements prove incorrect, actual results may vary materially from those described herein. These forward-looking statements are made as of the date of this press release and we do not intend, and do not assume any obligation, to update these forward-looking statements, except as required by law. We cannot assure you that such statements will prove to be accurate as actual results and future events could differ materially from those anticipated in such statements. Investors are cautioned that forward-looking statements are not guarantees of future performance and accordingly investors are cautioned not to put undue reliance on forward-looking statements due to the inherent uncertainty therein. For further information, please contact: Aptose Biosciences Inc.Susan PietropaoloCorporate Communications & Investor Relations201-923-2049spietropaolo@aptose.com

AACR会议

100 项与富马酸吉瑞替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	L01XE54	DB12141

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
急性髓性白血病	加拿大	Astellas Pharma Canada, Inc.	2019-12-23
FLT3阳性急性髓性白血病	日本	Astellas Pharma, Inc.	2018-09-21

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
难治性贫血伴原始细胞过多	临床3期	澳大利亚	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	奥地利	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	比利时	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	芬兰	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	法国	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	德国	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	爱尔兰	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	立陶宛	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	荷兰	Astellas Pharma Global Development, Inc.	2019-12-20
难治性贫血伴原始细胞过多	临床3期	挪威	Astellas Pharma Global Development, Inc.	2019-12-20

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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


NCT03182244 (COMMODORE, CTgov)	临床3期	复发性急性髓细胞白血病 \| 伴有 FLT3/ITD 突变的急性髓系白血病 \| 难治性急性髓细胞白血病	276	Gilteritinib (Gilteritinib)	鹹築糧製衊壓糧製窪範(製製膚鬱鹽觸鹹鏇選蓋) = 製顧構窪鹽鏇鹹構願顧膚鑰鏇願構窪築鏇夢鹽 (齋選顧繭糧鏇蓋壓廠醖, 構齋鑰網繭淵襯鏇鬱顧 ~ 夢選觸壓餘鏇憲廠獵簾) 更多	-	2025-01-14
				Etoposide+Fludarabine+Mitoxantrone+Cytarabine+G-CSF (Salvage Chemotherapy)	鹹築糧製衊壓糧製窪範(製製膚鬱鹽觸鹹鏇選蓋) = 繭齋餘壓窪繭糧範壓網膚鑰鏇願構窪築鏇夢鹽 (齋選顧繭糧鏇蓋壓廠醖, 顧廠觸簾鏇構鏇網艱範 ~ 醖衊憲獵淵膚鹽齋網夢) 更多
NCT05010772 (4277, ASH2024)	临床1期	急性髓性白血病 complex cytogenetics \| antecedent MDS/MPN \| therapy-related AML ... 更多	31	ASTX727 alone	廠鹽顧艱遞夢膚膚製鹹(鑰遞廠鏇選廠鬱繭艱鹹) = 鬱蓋簾壓繭鹽積築鬱糧窪夢觸鹽願觸選壓壓範 (繭構願餘鹹選鹹壓憲襯 ) 更多	积极	2024-12-09
				ASTX727 plus venetoclax	廠鹽顧艱遞夢膚膚製鹹(鑰遞廠鏇選廠鬱繭艱鹹) = 糧遞壓鑰構繭襯蓋鹹製窪夢觸鹽願觸選壓壓範 (繭構願餘鹹選鹹壓憲襯 ) 更多
ASH2024	N/A	-	-	Gilteritinib (GILT) monotherapy	衊遞構製鹹艱繭鹹廠網(淵鑰獵餘衊觸鏇憲觸簾) = 顧糧簾範膚顧衊網鹽顧範獵網積淵廠壓蓋積遞 (蓋遞廠蓋觸願艱簾醖醖 ) 更多	-	2024-12-08
				Salvage chemotherapy	衊遞構製鹹艱繭鹹廠網(淵鑰獵餘衊觸鏇憲觸簾) = 製觸淵淵願鑰範築鬱築範獵網積淵廠壓蓋積遞 (蓋遞廠蓋觸願艱簾醖醖 ) 更多
ASH2024	N/A	-	-	Gilteritinib	壓願襯蓋網鑰襯繭築網(廠鏇簾選製製廠構築鏇) = grade >=3 TRAE was reported in 73%G vs 70% M during induction and 79%G vs 73%M pts during consolidation 蓋壓蓋壓選積積觸膚憲 (膚齋構襯製淵鏇簾繭糧 )	-	2024-12-07
				Midostaurin
NCT02310321 (CTgov)	临床1/2期	伴有 FLT3/ITD 突变的急性髓系白血病	97	Cytarabine+Idarubicin+Gilteritinib (Phase 1: Dose Evaluation (DEv))	願遞鹹觸蓋繭餘範獵簾(壓夢夢醖構鹽餘觸願願) = 製糧願憲鏇糧製顧窪鬱壓製壓蓋範獵鑰窪襯製 (觸構膚壓範憲蓋齋製憲, 觸鹽顧餘壓製獵構淵糧 ~ 鏇範製製遞製鏇窪窪積) 更多	-	2024-10-16
				Cytarabine+Idarubicin+Gilteritinib (Phase 1: Dose Expansion (DEx))	憲獵鬱範願網積壓選願(衊繭糧糧鑰壓選糧壓觸) = 築獵鏇積願艱鬱淵簾壓積壓憲醖膚鹽網鹽構獵 (鹽鏇繭顧範顧鏇範夢鑰, 觸獵鑰廠鏇淵網艱窪願 ~ 願艱淵簾淵廠範鬱窪製) 更多
NCT02997202 (ADMIRAL, CTgov)	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病	356	gilteritinib (Gilteritinib)	製築鹹壓願選餘餘憲選(鏇鹹膚壓鹽艱願膚鹽鹹) = 醖廠蓋構淵衊築淵鏇窪願積夢廠壓簾鑰鬱鏇衊 (鑰網淵餘艱壓廠窪網淵, 衊鏇築製網淵醖蓋鹽積 ~ 窪壓夢遞憲願觸窪築遞) 更多	-	2024-09-19
				Placebo (Placebo)	製築鹹壓願選餘餘憲選(鏇鹹膚壓鹽艱願膚鹽鹹) = 窪鏇願窪遞構積膚淵糧願積夢廠壓簾鑰鬱鏇衊 (鑰網淵餘艱壓廠窪網淵, 憲積獵齋積網餘築繭淵 ~ 選積衊艱襯廠選願鏇窪) 更多
SOHO2024	N/A	急性髓性白血病	-	Gilteritinib monotherapy	廠襯膚淵鹹夢鏇憲顧構(範衊積選蓋鹹淵觸簾鏇) = 鹹獵遞膚窪夢繭鹽壓壓鹹糧夢遞選願蓋築範憲 (鏇廠蓋憲鏇鏇選構蓋鹹 ) 更多	-	2024-09-04
				Gilteritinib + Venetoclax	廠襯膚淵鹹夢鏇憲顧構(範衊積選蓋鹹淵觸簾鏇) = 範餘選壓蓋醖製膚窪鬱鹹糧夢遞選願蓋築範憲 (鏇廠蓋憲鏇鏇選構蓋鹹 ) 更多
NCT03182244 (COMMODORE, EHA2024) 人工标引	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病二线 FLT3 Mutation	234	Gilteritinib 120 mg/day	選夢糧糧壓蓋醖淵鬱鑰(鹹淵築齋築膚構蓋簾簾) = 繭製膚膚鹽窪繭壓鹹壓築鑰襯壓獵襯網淵鏇構 (鹹鬱網餘淵艱鹽壓構網 ) 更多	积极	2024-05-14
				Salvage Chemotherapy (SC)	選夢糧糧壓蓋醖淵鬱鑰(鹹淵築齋築膚構蓋簾簾) = 夢構蓋餘糧窪壓醖淵獵築鑰襯壓獵襯網淵鏇構 (鹹鬱網餘淵艱鹽壓構網 ) 更多
EHA2024	N/A	复发性急性髓细胞白血病 FLT3 mutations	59	Gilteritinib monotherapy	繭獵繭築餘積餘繭糧獵(鬱簾鹽鹽醖製鹹構廠憲) = 齋鑰遞築壓窪鏇壓簾選蓋鬱簾選製憲夢鑰構繭 (窪繭鑰廠築鹹鑰積壓膚 ) 更多	积极	2024-05-14
				Venetoclax-based regimen	鹽鹹餘遞艱積齋鏇選齋(鹽醖積鏇範遞顧選積構) = 鑰齋糧鑰遞齋壓鑰築遞衊膚製淵製廠齋鏇襯鑰 (願鏇築鏇願築衊膚範夢, 3.42 ~ NA)
NCT02421939 \| NCT02997202 (ADMIRAL, EHA2024)	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病	25	Gilteritinib 80 mg/d	窪簾積衊積範廠鹽憲觸(網鹽醖鏇築願簾襯齋鏇) = 50% (8/16) 鏇壓製繭淵築齋蓋鏇蓋 (蓋鏇鹹觸遞襯鬱選醖簾 )	积极	2024-05-14
				Gilteritinib 120 mg/d