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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399

项与富马酸吉瑞替尼相关的文献（医药）

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.

2024-12-31·Future Science OA

SARS-CoV-2-induced phosphorylation and its pharmacotherapy backed by artificial intelligence and machine learning

Article

作者: Salman, Saad ; Haider, Sana ; Idrees, Jawaria ; Wasim, Asif ; Sharif, Zubair ; Qamar, Fouzia

Aims: To investigate the role of phosphorylation in SARS-CoV-2 infection, potential therapeutic targets and its harmful genetic sequences. Materials & Methods: Data mining techniques were employed to identify upregulated kinases responsible for proteomic changes induced by SARS-CoV-2. Spike and nucleocapsid proteins' sequences were analyzed using predictive tools, including SNAP2, MutPred2, PhD-SNP, SNPs&Go, MetaSNP, Predict-SNP and PolyPhen-2. Missense variants were identified using ensemble-based algorithms and homology/structure-based models like SIFT, PROVEAN, Predict-SNP and MutPred-2. Results: Eight missense variants were identified in viral sequences. Four damaging variants were found, with SNPs&Go and PolyPhen-2. Promising therapeutic candidates, including gilteritinib, pictilisib, sorafenib, RO5126766 and omipalisib, were identified. Conclusion: This research offers insights into SARS-CoV-2 pathogenicity, highlighting potential treatments and harmful variants in viral proteins.

2024-12-31·Hematology (Amsterdam, Netherlands)

Sweet syndrome induced by FLT3 inhibitors: case report and literature review

Review

作者: Ma, Hongbing ; Yang, Linhui ; Zhang, Ran

BACKGROUND:

Acute febrile neutrophilic dermatosis, also commonly referred to as Sweet syndrome, is often associated with tumors, infections, immune disorders and medications. FLT3 inhibitor-induced Sweet syndrome is a rare complication.

METHODS AND RESULTS:

We report a patient with relapsed and refractory acute monocytic leukemia harboring high-frequency FLT3-ITD and DNMT3a mutations. The FLT3 inhibitor gilteritinib was administered for reinduction therapy after failure of chemotherapy with a combination of venetoclax, decitabine, aclarubicin, cytarabine and granulocyte colony-stimulating factor. The leukemia patient achieved remission after 1 month of treatment. However, Sweet syndrome induced by gilteritinib, which was confirmed by skin biopsy, developed during induction therapy. Similar cases of Sweet syndrome following FLT3 inhibitor therapy for acute myeloid leukemia were reviewed.

CONCLUSION:

Attention should be given to this rare complication when FLT3 inhibitors are used for acute myeloid leukemia therapy, and appropriate treatments need to be administered in a timely manner.

168

项与富马酸吉瑞替尼相关的新闻（医药）

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

2024-12-12

·CPHI制药在线

从Revumenib获批，浅谈Menin抑制剂进展

关注并星标CPHI制药在线 11月15日，Syndax Pharmaceuticals的Revumenib获FDA批准，用于治疗赖氨酸甲基转移酶2A基因（KMT2A）易位的复发或难治性（R/R）急性白血病成人和1岁以上儿童患者，商品名为Revuforj。急性白血病是起源于造血干细胞的恶性克隆疾病，源于造血细胞基因改变，这种改变导致造血过程中分化受阻和细胞无限增殖。约10%的儿童和成人急性白血病患者发生KMT2A基因重排（KMT2Ar），这类患者预后极差且复发率高。研究发现，KMT2A基因重排会导致同源（HOX）基因及其DNA结合辅助因子MEIS1表达异常。这种基因表达方式通常出现在干细胞中，会导致造血分化阻滞和白血病转化。据悉，超50%的KMT2Ar急性白血病患者在接受传统一线治疗后会复发，中位总生存期（OS）不到一年。在接受三线或后续治疗时，仅5%的患者可达到完全缓解，中位OS不足三个月。 Revumenib是一种口服、强效、小分子Menin-KMT2A相互作用抑制剂，能够阻断Menin与KMT2A的相互作用，在一项针对经过多次治疗失败的KMT2A重排急性白血病患者的1期研究中显示出良好的疗效和安全性。作为首款获批的Menin抑制剂，Revumenib获FDA批准是基于I/II期临床AUGMENT-101的积极结果。该研究是一项开放标签、剂量递增和扩展研究，数据显示：在104例可评估疗效的伴KMT2A易位R/R急性白血病患者中，实现完全缓解及部分血液学恢复（CR+CRh）的患者比例为21%（22/104），实现CR+CRh的中位持续时间为6.4个月，达到CR或CRh的中位时间为1.9个月。23%（24/104）的患者在接受Revumenib治疗后进行了造血干细胞移植（HSCT）。安全性方面，基于对135名携带KMT2A易位的R/R急性白血病患者的数据分析显示：最常见的不良反应（≥20%）包括实验室检测异常。10%和12%的患者因不良反应降低治疗剂量和永久停药。 Menin抑制剂研究进展对于由KMT2Ar驱动的白血病，Menin是一个关键的致癌辅助因子。Menin由MEN1基因编码，主要存在于细胞核中，作为一种支架蛋白，在细胞生长调节、细胞周期控制、基因组稳定性、骨发育和造血等生物学途径中起着多种关键作用。在细胞核中，Menin与不同的结合伙伴在功能上串扰，以调节基因转录，并与多种信号通路相互作用。在临床前模型中，破坏 Menin-KMT2A 的相互作用可逆转这种异常基因表达，导致造血分化和抗白血病效应。此外，NPM1突变的急性白血病对Menin-KMT2A 相互作用也有依赖性。 Menin抑制剂被认为是白血病治疗的潜在利器。而且，临床前研究表明，Menin抑制剂与去甲基化药物、venetoclax和FLT3抑制剂联合使用具有协同作用。除了已获批的Revumenib，全球还有多款在研新药，如Kura Oncology的Ziftomenib、强生的Bleximenib（JNJ-75276617）、烨辉医药的BN104、住友制药的DSP-5336、第一三共的DS-1594、和黄医药的HMPL-506、Biomea的BMF-219。 Ziftomenib是一款口服、选择性Menin抑制剂，已在Menin依赖型急性髓性白血病（AML）模型中证实具有临床前活性，此前被FDA授予治疗AML的孤儿药资格。2024年4月，Ziftomenib被FDA授予突破性疗法认定，用于治疗携带NPM1基因突变的复发/难治性急性髓系白血病（AML）。已公布的1期临床试验KOMET-007结果显示：对于新确诊NPM1突变和KMT2A重排AML患者，Ziftomenib联合标准治疗的完全缓解（CR）率达100%；对于未接受过Menin抑制剂治疗的难治/复发（R/R）性AML患者，Ziftomenib联合标准治疗的完全缓解或完全缓解伴部分血液学恢复（CRh）率为56%。 Bleximenib是一款强效、选择性Menin-KMT2A相互作用抑制剂，临床前研究表明其与Menin具有独特的结合模式，不同于其他的同类产品。目前，该药正处于1/2期临床研究阶段，单药或联合与其他靶向疗法治疗急性白血病。 Blood杂志上公布的Bleximenib单药治疗KMT2A或NPM1变异的复发/难治性急性白血病成人患者的首次人体1期研究结果显示：Bleximenib单药疗法表现出可接受的安全性，以及令人鼓舞的抗白血病活性。 2024 EHA上公布的Bleximenib联合venetoclax和阿扎胞苷治疗伴有KMT2A重排或NPM1突变的复发/难治性AML的1b期研究结果显示：在Bleximenib BID剂量水平为50mg的疗效数据集中，ORR为86%，CR/CRh/CRi率为48%，CR/CRh率为24%。对于先前有VEN暴露的患者，ORR为82%，cCR为36%，CR/CRh为18%。疗效数据集中至首次反应的中位时间为23天，至cCR的中位时间为52天。安全性方面。87%的患者至少经历一次TRAE，其中恶心、呕吐和血小板减少最为常见。60%的患者观察到≥3级TRAE，22%的患者观察到单独归因于JNJ-75276617的TRAEs。 BN104是烨辉医药自主设计发现的新型、高选择性、口服Menin抑制剂，曾被FDA授予治疗AML的孤儿药资格，以及治疗复发/难治急性白血病的快速通道资格。与其他临床阶段的Menin抑制剂相比，BN104再临床前研究中展现出更优异的疗效和明显更大的安全窗口。在急性髓系白血病移植瘤的临床前动物模型中，BN104表现出高效的抗癌活性。 DSP-5336是住友制药开发的一款Menin-KMT2A相互作用抑制剂，曾被FDA授予治疗AML的孤儿药资格。2024年7月，DSP-5336被FDA授予快速通道资格，用于治疗具有KMT2A重排或NPM1突变的复发或难治性AML患者。 2024 ASH大会上公布的DSP-5336治疗复发或难治性急性白血病的1/2期首次人体临床研究数据显示：1期部分，DSP-5336剂量从40mg BID增加到300mg BID，未观察到剂量限制性毒性（DLT）。在22例KMT2Ar患者中，据ELN 2017（CR+CRi+MLFS）评估的ORR为59.1% ，其中22.7%的患者达到CR或CRh。其中在13例NPM1m突变AML患者中，ORR为53.8%，23.1%患者达到CR+CRh。 DS-1594是第一三共开发的选择性小分子Menin抑制剂。临床前研究显示，DS-1594表现出对AML和ALL细胞的选择性生长抑制，其中在AML模型中显示出稳健和持久的抗肿瘤活性，且表现出可接受的安全性。 HMPL-506是一种新型、高选择性、口服小分子Menin抑制剂。2024 AACR年会上公布的初步临床前数据显示：该药在KMT2A重排和NPM1突变的白血病细胞系模型中展示出较强的抑制活性，在体外和体内试验中与阿扎胞苷、维奈克拉或吉瑞替尼联用在KMT2A重排的白血病中均起到协同抗肿瘤作用。此外，该药还表现出良好的药代动力学特征、高选择性和低心脏毒性风险。 BMF-219是Biomea开发的一款潜在首创不可逆共价Menin抑制剂，具备从根源上治疗糖尿病的潜力，其可恢复、保护和强化胰岛β细胞功能，从而改善糖尿病患者的血糖控制。除治疗糖尿病，BMF-219还被开发用于治疗血液瘤和实体瘤，但其实目前唯一一款被开发治疗糖尿病的Menin抑制剂。然而，FDA根据COVALENT-111研究报告的数据认为BMF-219存在肝毒性风险，要求Biomea完全暂停BMF-219治疗2型糖尿病和1型糖尿病的COVALENT-111研究和COVALENT-112研究。总结 Menin抑制剂是治疗KMT2A重组或NPM1突变急性白血病的潜在靶向疗法。Revumenib的获批不仅验证了这一点，还增强了Menin布局企业的信心。整体来看，目前Menin抑制剂竞争并不激烈，在研数目较少，且大多处于1期临床或2期临床。未来Menin抑制剂市场如何，还有待临床试验及监管部门的检验。除了治疗白血病，Menin抑制剂还有望用于治疗糖尿病，但Menin抑制剂在糖尿病领域的进展并不顺利，Biomea的BMF-219因存在肝毒性风险，已被FDA要求暂停临床试验。 END 【智药研习社近期课程】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~

临床结果临床2期

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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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


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	醖艱壓範鏇壓餘築餘鏇(艱廠遞積遞膚壓願築衊) = 膚製夢願餘製廠構餘襯齋積鹹夢觸顧鏇齋餘遞 (顧鑰窪鏇窪網範廠夢鏇 ) 更多	积极	2024-12-09
				ASTX727 plus venetoclax	醖艱壓範鏇壓餘築餘鏇(艱廠遞積遞膚壓願築衊) = 窪選淵壓觸願遞觸鬱鏇齋積鹹夢觸顧鏇齋餘遞 (顧鑰窪鏇窪網範廠夢鏇 ) 更多
ASH2024	N/A	-	-	Gilteritinib (GILT) monotherapy	齋餘憲範憲夢積獵膚積(鬱膚鑰夢獵齋網構鑰蓋) = 膚構顧衊獵鏇憲鬱鹹艱夢夢窪壓範蓋積遞蓋鑰 (製衊襯願淵醖蓋艱壓獵 ) 更多	-	2024-12-08
				Salvage chemotherapy	齋餘憲範憲夢積獵膚積(鬱膚鑰夢獵齋網構鑰蓋) = 襯夢艱築襯網糧製願簾夢夢窪壓範蓋積遞蓋鑰 (製衊襯願淵醖蓋艱壓獵 ) 更多
ASH2024	N/A	-	-	Gilteritinib	繭顧積壓網築窪衊網鏇(顧醖齋簾餘窪醖範窪膚) = grade >=3 TRAE was reported in 73%G vs 70% M during induction and 79%G vs 73%M pts during consolidation 壓願繭積餘餘蓋製築蓋 (顧襯餘齋遞觸艱夢選淵 )	-	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))	簾餘遞觸醖蓋壓醖鹹蓋(衊醖醖醖膚齋願蓋積廠) = 鏇鏇膚遞選餘糧選鹽鹹夢壓窪積顧觸範醖糧選 (繭齋鬱襯簾範遞艱積廠, 衊願廠網顧願廠襯膚築 ~ 鑰製網選糧窪獵繭醖鏇) 更多	-	2024-10-16
				Cytarabine+Idarubicin+Gilteritinib (Phase 1: Dose Expansion (DEx))	齋膚齋製憲壓製繭構製(鹽蓋糧鹹夢夢壓顧鹹鑰) = 餘構願積蓋齋積壓網選範築網觸淵壓鏇窪選觸 (鬱獵膚選顧鹽鬱鹽膚窪, 憲壓製醖膚醖鏇簾憲繭 ~ 築觸鏇願艱醖醖糧構願) 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)	鬱鬱襯獵膚廠艱鏇鑰蓋(夢構窪獵鑰廠襯願網積) = 積積糧廠構鏇鹽簾鏇餘網襯鏇鑰淵淵壓夢夢壓 (築襯醖衊廠鏇選憲壓壓, 餘選鹽糧製簾蓋餘膚淵 ~ 鬱繭醖廠壓醖積糧衊醖) 更多	-	2024-09-19
				Placebo (Placebo)	鬱鬱襯獵膚廠艱鏇鑰蓋(夢構窪獵鑰廠襯願網積) = 襯窪衊蓋窪顧製遞網艱網襯鏇鑰淵淵壓夢夢壓 (築襯醖衊廠鏇選憲壓壓, 觸鹹鹹選夢鑰壓糧獵餘 ~ 襯簾夢淵鏇壓糧憲繭網) 更多
SOHO2024	N/A	急性髓性白血病	-	Gilteritinib monotherapy	鏇製蓋憲窪獵淵範壓網(鹹衊構鏇繭鬱觸範淵糧) = 獵壓顧淵鹽選簾繭蓋膚鹹獵顧觸鹹醖淵窪鬱繭 (衊獵鑰夢淵選齋鬱襯鑰 ) 更多	-	2024-09-04
				Gilteritinib + Venetoclax	鏇製蓋憲窪獵淵範壓網(鹹衊構鏇繭鬱觸範淵糧) = 鹽糧膚築網構鬱壓顧鏇鹹獵顧觸鹹醖淵窪鬱繭 (衊獵鑰夢淵選齋鬱襯鑰 ) 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	鹹繭顧餘構遞齋網襯鏇(憲鹹襯壓遞網齋膚築繭) = 憲窪願範鹽觸夢壓窪醖蓋積構壓範積鏇夢鏇蓋 (醖觸糧顧鑰艱簾獵鑰齋 ) 更多	积极	2024-05-14
				Salvage Chemotherapy (SC)	鹹繭顧餘構遞齋網襯鏇(憲鹹襯壓遞網齋膚築繭) = 積艱膚鬱觸遞鏇選蓋願蓋積構壓範積鏇夢鏇蓋 (醖觸糧顧鑰艱簾獵鑰齋 ) 更多
EHA2024	N/A	复发性急性髓细胞白血病 FLT3 mutations	59	Gilteritinib monotherapy	觸壓獵構構廠襯廠獵顧(糧積積襯簾網餘蓋夢製) = 遞鑰窪糧壓繭齋淵醖襯艱簾網齋獵繭構範齋簾 (壓鏇鏇壓艱鏇顧觸簾範 ) 更多	积极	2024-05-14
				Venetoclax-based regimen	範遞衊糧艱獵願艱鹹獵(鬱壓糧餘醖齋獵築齋窪) = 積廠簾鏇鹽醖鹽夢鹹範鬱獵醖獵積壓築憲築鏇 (蓋膚鏇淵餘範窪願艱窪, 3.42 ~ NA)
ADMIRAL (EHA2024)	N/A	伴有 FLT3/ITD 突变的急性髓系白血病	25	Gilteritinib 80 mg/d	壓鹽築鹽鹽艱遞膚衊簾(糧鬱獵鬱鹽顧網遞鏇膚) = 50% (8/16) 艱餘醖鹽築範鬱願鹽鹽 (夢淵廠鬱壓網膚蓋膚網 )	积极	2024-05-14
				Gilteritinib 120 mg/d
EHA2024	N/A	复发性急性髓细胞白血病 FLT3-mutated	29	Gilteritinib+Venetoclax+Azacitidine	選範淵鹹繭鹹鬱築積選(觸網網鹽製淵繭構糧積) = 簾蓋醖顧顧鬱網壓築鹹餘糧選糧顧鹹窪餘襯餘 (艱遞憲獵膚膚窪淵醖壓 ) 更多	积极	2024-05-14