A Phase II, Single Arm, Open Label, Study on the Safety, Efficacy, Pharmacokinetics & Pharmacodynamics of Quizartinib + Chemotherapy and as Single-agent After High Dose Therapy in Newly Diagnosed Pediatric FLT3-ITD+ and NPM1wt AML Patients

The CHIP-AML22 Master protocol has the overall aim of increasing the cure rate in newly diagnosed pediatric de novo AML patients, while avoiding unnecessary toxicity. The linked Quizartinib trial (CHIP-AML22/Quizartinib) is a phase II, single arm, open label, study on the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib in combination with chemotherapy and as single-agent after high dose therapy in newly diagnosed pediatric AML patients with a FLT3-ITD mutation and NPM1 wild-type.

开始日期2024-02-06

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

[+1]

NL-OMON53485 / Suspended临床2期

CHIP-AML22/Quizartinib: A phase II, single arm, open label, study on the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib in combination with chemotherapy and as single-agent after high dose therapy in newly diagnosed pediatric FLT3-ITD positive and NPM1 wild type AML patients. (A linked-trial of the CHIP-AML22/Master protocol by the NOPHO-DB-SHIP consortium) - CHIP-AML22/Quizartinib

开始日期2023-10-02

申办/合作机构

Prinses Máxima Centrum Voor Kinderoncologie

NCT04676243 / Withdrawn临床3期IIT

Randomized Study in Newly Diagnosed AML With FLT3-ITD Comparing Daunorubicin/ Cytarabine or Idarubicin/Cytarabine and Quizartinib to Physician's Choice

The orally administered second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is very specific for FLT3, has a high capacity for sustained FLT3-inhibition and an acceptable toxicity profile. Furthermore, single agent quizartinib doubled the response rate as compared to standard of care in a randomized study in r/r-AML. Combination therapy of quizartinib with intensive standard induction chemotherapy has been shown to be safe and moreover, single agent quizartinib maintenance therapy is feasible even after allogeneic HCT.
The efficacy of quizartinib in combination with intensive induction and post-remission therapy including allogeneic HCT and single agent quizartinib as maintenance therapy is evaluated by this protocol. This approach is compared in a randomized manner to the current standard of care.

开始日期2022-05-01

申办/合作机构

Daiichi Sankyo Europe GmbH

100 项与奎扎替尼相关的临床结果

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100 项与奎扎替尼相关的转化医学

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100 项与奎扎替尼相关的专利（医药）

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299

项与奎扎替尼相关的文献（医药）

2024-02-01·Pharmacological Research

Properties of FDA-approved small molecule protein kinase inhibitors: A 2024 update

Review

作者: Roskoski, Robert

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

2024-02-01·Computers in Biology and Medicine

Synergy and antagonism between azacitidine and FLT3 inhibitors

Article

作者: Friedman, Ran ; Yang, Jingmei

Synergetic interactions between drugs can make a drug combination more effective. Alternatively, they may allow to use lower concentrations and thus avoid toxicities or side effects that not only cause discomfort but might also reduce the overall survival. Here, we studied whether synergy exists between agents that are used for treatment of acute myeloid leukaemia (AML). Azacitidine is a demethylation agent that is used in the treatment of AML patients that are unfit for aggressive chemotherapy. An activating mutation in the FLT3 gene is common in AML patients and in the absence of specific treatment makes prognosis worse. FLT3 inhibitors may be used in such cases. We sought to determine whether combination of azacitidine with a FLT3 inhibitor (gilteritinib, quizartinib, LT-850-166, FN-1501 or FF-10101) displayed synergy or antagonism. To this end, we calculated dose-response matrices of these drug combinations from experiments in human AML cells and subsequently analysed the data using a novel consensus scoring algorithm. The results show that combinations that involved non-covalent FLT3 inhibitors, including the two clinically approved drugs gilteritinib and quizartinib were antagonistic. On the other hand combinations with the covalent inhibitor FF-10101 had some range of concentrations where synergy was observed.

2024-01-02·ChemMedChem

Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c‐KIT, and RET Anti‐Targets

Article

作者: Dayal, Neetu ; Kempen, Allison L ; Akwata, Desmond ; Sintim, Herman O ; Brauer, Nickolas R

Abstract:

FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely‐related kinases that are important for immune (c‐KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non‐oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti‐targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c‐KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well‐tolerated FLT3 therapeutics for non‐oncology indications or for maintenance therapy for AML.

项与奎扎替尼相关的新闻（医药）

2024-03-27

·CPHI制药在线

一文了解伴FLT3突变急性髓系白血病，3款新型FLT3抑制剂带来新希望

关注并星标CPHI制药在线FLT3是急性髓系白血病（AML）中经常出现的突变基因。当AML患者的FLT3基因发生突变时，他们的疾病预后往往较差，且更容易复发。因此，及时识别FLT3基因的突变情况，并选择恰当的治疗策略，对AML患者的治疗效果具有重要意义。 Fms样酪氨酸激酶3（FLT3）在细胞信号传递路径中起着关键作用，作为一种受体酪氨酸激酶。实际上，AML中出现的最常见的基因突变，其中一个就是在FLT3。这一基因的突变在成人AML患者中约占了30%的比例。其突变形式主要有两种，即FLT3的内部串联重复序列（FLT3-ITD）和酪氨酸激酶结构域（FLT3-TKD）突变。在这些突变中，FLT3-ITD是最常见的，其在AML中的检出率达到了25% [1]。 FLT3突变急性髓系白血病（AML）患者的临床特点通常为年纪偏大、白细胞与血小板计数偏高，以及骨髓原始细胞比例偏高。尽管这些患者的缓解率较低，且治疗后容易复发，但常规化疗的复发率也相对较高，且往往伴随着其他基因突变。特别值得关注的是，一些最常见的共存基因突变包括NPM1、DNMT3A、WT1、TET2、RAS、RUNX1以及PTPN11。对于FLT3-TKD突变，其预后仍然存在争议；相比之下，FLT3-ITD突变具有较强的异质性，预后受其等位基因比率（AR）、插入位点、ITD长度、核型以及其他伴随基因突变如NPM1、DNMT3A、WT1、RUNX1的影响而有所不同。值得关注的是，与NPM1突变同时出现的FLT3-ITD AML的预后相对较好，然而，当与IDH1/2、TET2、DNMT3A、WT1突变同时出现，或者同时合并NPM1和DNMT3A突变时，FLT3-ITD AML的预后则较差。随着对FLT3突变AML发病机制的深入了解、新的检测技术的出现以及FLT3抑制剂的广泛应用，其预后已得到显著改善。因此，根据欧洲白血病网（ELN 2022）的最新指南，所有FLT3-ITD AML现已被归类为中危。 FLT3抑制剂属于酪氨酸激酶抑制剂，通过竞争激酶活性区域的ATP结合位点抑制FLT3蛋白发生磷酸化，进而抑制相关下游生长信号通路（PI3K/Akt、Ras/MAPK和STAT5等）发挥治疗作用。根据FLT3抑制剂与FLT3结合的程度，可将FLT3抑制剂分为第一代和第二代抑制剂和新型FLT3抑制剂。一代FLT3抑制剂索拉非尼索拉非尼是一种能够同时抑制RAF、VEGFR、KIT和FLT3等多个靶点的小分子药物。南方医科大学血液病研究院的刘启发教授领导的研究团队进行了一项临床研究[7]，他们评估了将索拉非尼与维奈克拉、阿扎胞苷和高三尖杉酯碱（简称VAH方案）联合使用，在患有FLT3-ITD阳性的复发/难治性急性髓系白血病（AML）患者中的治疗效果和患者的耐受程度。研究数据表明，患者接受这一治疗方案后的总缓解率高达82.4%。中位随访期为17.7个月，研究尚未观察到中位复合完全缓解（CRc）的持续时间。这些患者的总生存期（OS）平均为18.1个月，无事件生存期（EFS）平均为11.4个月。在接受治疗的患者中，出现3-4级不良事件（AE）的情况包括中性粒细胞减少症、血小板减少导致的贫血、发热性中性粒细胞减少症、肺炎和脓毒症等。其中，有2名患者因治疗相关原因不幸去世。米哚妥林欧洲药品管理局（EMA）和美国食品药品监督管理局（FDA）共同批准了米哚妥林与标准化疗相结合，作为针对FLT3突变成年急性髓系白血病（AML）患者的首选治疗策略。除此之外，对于经历过异基因造血干细胞移植（allo-HSCT）的患者，米哚妥林在维持治疗方面也表现出显著效果，它不仅能够优化患者的预后，而且其安全性也得到了充分验证[8]。这些进展为患有急性髓系白血病（AML）的患者提供了新的治疗选择和更好的康复机会。二代FLT3抑制剂吉瑞替尼（Gilteritinib） 2018年11月28日，美国食品药品监督管理局（FDA）正式批准吉瑞替尼作为治疗FLT3突变型复发或难治性急性髓系白血病（AML）成人患者的药物。随后，在2021年，吉瑞替尼获得中国批准并上市，用以治疗患有复发或难治性FLT3突变型AML的患者[9]。由中国医学科学院血液病医院王健祥教授率领的团队，联合多个国家包括中国、俄罗斯、新加坡、泰国和马来西亚等，开展了一项名为COMMODORE的III期开放、多中心临床试验，对比了吉瑞替尼与挽救性化疗（SC）在治疗FLT3突变复发难治AML患者上的疗效[10]。研究显示，吉瑞替尼组（包含116名患者）的完全缓解（CR）率达到了16.4%，这一数据超过了挽救性化疗（SC）组（包含118名患者，CR率为10.2%）。此外，吉瑞替尼组患者的1年中位总生存期（mOS）也显著长于挽救性化疗（SC）组，分别为9个月和4.7个月（P=0.001 26）。这一研究成果再次确立了吉瑞替尼在针对FLT3突变复发难治AML治疗上的显著优势。奎扎替尼（Quizartinib） 2023年7月20日，美国食品药品监督管理局（FDA）正式批准了奎扎替尼联合标准阿糖胞苷、蒽环类药物的诱导治疗与阿糖胞苷巩固治疗，以及在巩固化疗后单独使用奎扎替尼作为维持治疗，这一治疗方案针对的是新诊断的FLT3-ITD阳性急性髓系白血病（AML）成年患者。这项医疗进展意味着对白血病治疗的一个重要突破，可以为这些患者提供更好的治疗效果和生存率。 QuANTUM-First（NCT02668653）试验是一项双盲随机、安慰剂对照的研究，共纳入了539名新诊断的FLT3-ITD阳性急性髓系白血病患者。通过对奎扎替尼组与安慰剂组之间的对比分析，结果显示，奎扎替尼组在总生存期（OS）上具有显著的统计学意义改善[风险比（HR）0.78，95%置信区间（CI）0.62-0.98，两组比较p=0.0324]。这一数据进一步证明了奎扎替尼在治疗FLT3-ITD阳性急性髓系白血病患者中的疗效和安全性，为这一病症的治疗提供了新的选择。 Crenolanib Richard M. Stone教授的研究团队，隶属于美国丹娜法伯癌症研究所，进行了一项关键性的II期研究[7]，旨在评估在新发现的FLT3突变急性髓系白血病（AML）病患中结合使用Crenolanib的治疗成效。该研究涉及了44名患者（男性占22名），他们的中位数年龄是57岁（年龄范围：19-75岁）。结果显示，总体复合完全缓解（CRc）率高达73%（32/44）。特别是在经过两个周期的治疗后，总CRc率跃升至86%（38/44）。年轻患者的总体缓解率表现尤为突出，达到了90%，且其MRD阴性率高达89%。相较之下，尽管年长患者的总体缓解率为80%，但他们的MRD阴性率相对较低，为45%。此外，值得注意的是，超过70%的年轻患者在接受治疗后的三年时间里仍然存活。这项研究的结果为FLT3突变急性髓系白血病的治疗提供了新的方向，尤其是对于那些年轻的患者，Crenolanib联合治疗方案展现出了显著的效果。新型FLT3抑制剂 Tuspetinib Tuspetinib，这是一种新兴的可口服FLT3抑制剂，凭借其强大的能力，被公认为一种高效的髓系激酶抑制药物。它的作用机制在于能够抑制导致AML细胞增殖异常的多种激酶，这当中就包括了SYK、FLT3、JAK1/2、RSK1/2、突变型KIT和TAK1-TAB1激酶等。一项涉及I/II期的研究[13]对Tuspetinib单独使用（TUS）和与维奈克拉联合使用（VEN/TUS）治疗复发性或难治性AML（R/R AML）的安全性和疗效进行了评估，并确定了II期推荐剂量（RP2D）。该研究的结果表明，Tuspetinib单药治疗的安全性较高，总体完全缓解/完全缓解伴部分血液学恢复（CR/CRh）的比率为36%。对于FLT3突变型AML患者，这一比率高达50%，而对于FLT3野生型AML患者，这一比率则为25%。这些结果为Tuspetinib在AML治疗中的潜在应用提供了重要的临床依据。 EmavusertibEmavusertib作为一种创新型的FLT3抑制剂，其独特之处在于可以口服使用，为治疗提供了便利。它能够精确地针对IRAK4和FLT3进行作用，表现出令人满意且可管理的安全性。目前，TakeAim Leukemia试验正在深入研究Emavusertib在治疗复发/难治性急性髓性白血病（R/R AML）和高危骨髓增生异常综合征（HR-MDS）方面的安全性、临床疗效以及潜在的生物标志物，为未来的治疗策略提供更为坚实的科学依据。 EP0042 EP0042是一款口服型的药物，它能够有效抑制FLT3和Aurora激酶。研究表明，Aurora激酶在急性髓系白血病（AML）的发病过程中扮演着关键角色，并与FLT3抑制剂耐药性的产生密切相关。因此，EP0042通过同时针对FLT3和Aurora激酶，有望克服对选择性FLT3抑制所产生的获得性耐药性。为了探索EP0042的最佳给药方案，一项I/IIa期研究采用了标准的3+3剂量递增设计，并纳入了复发/难治性AML或骨髓增生异常综合征（MDS）的患者进行临床试验[15]。总结 FLT3抑制剂的研发成功，为那些罹患FLT3突变急性髓性白血病（AML）的患者提供了全新治疗策略。在临床应用中，目前已有一线和二线的FLT3抑制剂可供选用。不仅如此，新型的FLT3抑制剂，如Tuspetinib、Emavusertib和EP0042，也正在接受临床试验的检验，其初步成果显示出了良好的治疗潜力。随着对FLT3突变机制的深入研究以及药物研发的持续进步，我们有理由期待更多高效、精准的靶向治疗药物的出现。这些药物的问世，将为AML患者带来更加显著的治疗效果，帮助他们更好地战胜疾病。参考文献： [1] 邱林，马军. 急性髓系白血病靶向治疗研究进展[J]. 白血病·淋巴瘤， 2022,31(4):197-203. DOI：10.3760/cma.j.cn115356-20220210-00033 . [2] Yu S, Zhang Y, Yu G, Wang Y, Shao R, Du X, et al. Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/ relapsed acute myeloid leukemia with FLT3ITD: A multicenter phase 2 study. J Intern Med.2023;00:1-13. [3] 袁伟，张世忠，主鸿鹄. FLT3抑制剂治疗急性髓系白血病患者研究进展[J].浙江大学学报:医学版, 2022, 51(4):507-514. [4]https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutation [5] Wang JX ， Jiang B ， Li J ，et al. Gilteritinib versus salvage chemotherapy for relapsed/refractory FLT3-mutated acute myeloid leukemia：a phase 3，randomized，multicenter，open-label trial in Asia[J]. Blood， 2021，138Suppl 1：695. doi: 10.1182/blood-2021-145436 .[6] https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia[7] Eunice S. Wang, et al. 2022ASCO.Abstract#7007.[8] Naval Daver, et al. Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML). 2023 ASH. Abstract #162.[9] Eric S Winer, et al. Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation. 2023 ASH. Abstract #2924.[10] David Taussig, et al. EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Results from an Ongoing Phase I/IIa Dose-Finding/Dose Optimization Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia. 2023 ASH. Abstract #4285. [6] Zhao J , Agarwal S , Ahmad H ,et al.A review of FLT3 inhibitors in acute myeloid leukemia[J].Blood reviews, 2021:100905. [7] 张钰, 邵若洋, 刘启发. FLT3突变急性髓系白血病的全程管理[J].临床血液学杂志,2023,36(5):303-308 [8] DöhnerH, WeiAH, Appelbaum FR, et al. Diagnosis ·and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN [J].Blood,2022,140(12):1345-1377. [9] WANG Z, CAI J, CHENG J, et al. FLT3 inhibitors in acute myeloid leukemia: challenges and recent developments in overcoming resistance[J]. J Med Chem, 2021, 64(6): 2878-2900. [10] 袁伟，张世忠，主鸿鹄. FLT3抑制剂治疗急性髓系白血病患者研究进展[J].浙江大学学报:医学版, 2022, 51(4):507-514. [11] TALLMAN M S, WANG E S, ALTMAN J K, et al. Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2019, 17(6): 721-749. [12] LEVIS M. Midostaurin approved for FLT3-mutated AML[J]. Blood, 2017, 129(26): 3403-3406. [13] SERVE H, KRUG U, WAGNER R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial[J]. J Clin Oncol, 2013, 31(25): 3110-3118. [14] YILMAZ M, KANTARJIAN H M, MUFTUOGLU M, et al. Quizartinib with decitabine +/- venetoclax is highly active in patients (pts) with FLT3-ITD mutated (mut) acute myeloid leukemia (AML): clinical report and signaling cytof profiling from a phase Ⅰb/Ⅱ trial[J]. Blood, 2020, 136(Supplement 1): 19-20. [15] PERL A E, MARTINELLI G, CORTES J E, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML[J]. N Engl J Med, 2019, 381(18): 1728-1740. [16] WANG R, LI Y, GONG P, et al. Arsenic/trioxide and sorafenib induce synthetic lethality of FLT3-ITD acute myeloid leukemia cells[J]. Mol Cancer Ther, 2018,17(9): 1871-1880. [17] YILMAZ M, KANTARJIAN H, SHORT N J, et al. Hypomethylating agent and venetoclax with FLT3 inhibitor "triplet" therapy in older/unfit patients with FLT3 mutated AML[J]. Blood Cancer J, 2022, 12(5): 77.【智药研习社近期课程预告】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~

临床结果

2024-03-26

·Pharmaceutical Technology

Edgewood secures $20m in Series A for clinical development of cancer therapy

The global market for AML therapies is expected to be worth $6.62bn in 2031, according to a GlobalData report. Image Credit: LALAKA / Shutterstock. Massachusetts-based company Edgewood Oncology has raised $20m in Series A to advance the clinical development of its lead cancer therapy BTX-A51. The Series A funding round was led by US-based venture fund Alta Partners. Edgewood Oncology expects the funds to finance multiple clinical trials into 2026. BTX-A51 is a multi-kinase inhibitor of casein kinase 1 alpha (CK1α) and cyclin-dependent kinases 7 and 9 (CDK7 and CDK9). Edgewood acquired the rights to the therapy from the Hebrew University of Jerusalem in 2023. Edgewood is evaluating BTX-A51 in an open-label Phase I/II trial (NCT04243785) as a monotherapy and in combination with a chemotherapeutic, azacitidine, in patients with relapsed/refractory acute myeloid leukaemia (r/r AML). In Phase Ia, the BTX-A51 monotherapy showed a favourable safety profile along with encouraging antileukemic activity. The combination cohort started enrolment in December 2023. The cohort is expected to enrol up to 30 participants. The cohort aims to evaluate the response rate, safety, toxicity, and pharmacokinetics of the combination therapy of BTX-A51 and azacytidine in patients with r/r AML. See Also: Oncology in 2024: The clinical trial trends reshaping the role of CROs Avenzo Therapeutics secures $150m to progress oncology pipeline The global market for AML therapies is expected to be worth $6.62bn in 2031, according to a GlobalData report . The AML therapy pipeline consists of more than 200 drugs in early development, with the majority of drugs in development being enzyme inhibitors, according to GlobalData Pharma Intelligence Center. GlobalData is the parent company of Pharmaceutical Technology . Edgewood is also investigating BTX-A51 as a treatment for solid tumours and non-Hodgkin lymphoma, open-label Phase I trial (NCT04872166). The study expects to enrol up to 116 participants and is estimated to be completed in May 2027. The company also plans to initiate a Phase II trial evaluating BTX-A51 in breast cancer patients with a genetically defined profile in Q2 2024. Advances in AML therapies include Daiichi Sankyo ’s Vanflyta (quizartinib). In November 2023, the European Commission (EC) approved Vanflyta as an add-on therapy for newly diagnosed fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) positive AML in adults. In September 2023, Mendus’s cancer vaccine, vividencel, received fast-track designation from the US Food and Drug Administration (FDA). A month later, Sellas Life Sciences Group’s CDK9 inhibitor, SLS009, received an orphan drug designation from the FDA. AML therapies in early development include Aptose Biosciences ’ tuspetinib. The company started the Phase I/II APTIVATE trial evaluating the drug’s pharmacodynamics, tolerability, safety, and pharmacokinetics in r/r AML patients in January. In September 2023, Foghorn Therapeutics dosed the first patient in the Phase I trial evaluating the combination therapy of FHD-286 and chemotherapy in patients with r/r AML.

临床1期孤儿药快速通道上市批准疫苗

2024-03-12

·Pharmaceutical Technology

MHRA authorises Daiichi Sankyo quizartinib for AML for marketing

Daiichi Sankyo’s quizartinib is indicated for use as a first-line treatment in adults with acute myeloid leukaemia. Credit: Nemes Laszlo / Shutterstock.com. The UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation to Daiichi Sankyo for quizartinib (Vanflyta) for use as a first-line treatment in adults with acute myeloid leukaemia (AML) with a FLT3-ITD mutation. The decision allows for the oral administration of quizartinib in combination with chemotherapy – a significant development in the treatment of AML. Taken once daily, quizartinib targets tyrosine kinases to hinder the growth of abnormal bone marrow cells. The treatment duration and dosage are determined by the prescribing physician and may continue post-chemotherapy. The approval is backed by a double-blind, randomised, placebo-controlled Phase III clinical trial in 539 adult subjects aged between 18 and 75 years with newly diagnosed FLT3-ITD positive AML. See Also: MHRA approves Marinus’ ganaxolone for CDKL5 deficiency disorder Innovent’s ROS1 TKI is one step closer to winning the Chinese NSCLC market The study demonstrated a statistically significant improvement in overall survival (time from randomisation to death from any cause) for patients who received quizartinib. Patients receiving quizartinib had a median overall survival of 31.9 months compared to 15.1 months for those receiving a placebo. Abnormal liver enzymes, low blood platelet and white blood cell levels, anaemia, diarrhoea, nausea, stomach pain and headache were the most common side effects linked to the trial. MHRA Healthcare Quality and Access interim executive director Julian Beach stated: “ Our key priorities are keeping patients safe and enabling their access to high quality, safe and effective medical products. “We’re assured that the appropriate regulatory standards for the approval of this medicine have been met. As with all medicines, we will keep its safety under close review.” In another development, the MHRA also gave marketing authorisation to Pfizer for etrasimod (Velsipity) for the treatment of moderately to severely active ulcerative colitis. Etrasimod is prescribed as a long-term treatment and should be initiated only under a doctor’s supervision. The approval is supported by two clinical studies, ELEVATE UC 52 and ELEVATE UC 12, indicating its efficacy for patients where standard treatments were inadequate. The UK National Institute for Health and Care Excellence (NICE) has also published a final guidance recommending etrasimod for ulcerative colitis. With the NICE recommendation, more than 25,000 people in England will be eligible to receive the treatment. The latest development comes after the MHRA approved Marinus Pharmaceuticals ’ ganaxolone, marketed as Ztalmy, an anti-seizure medication for cyclin-dependent kinase-like 5 (CDLK5) deficiency disorder .

上市批准临床3期临床结果

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外链

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研发状态

适应症	最高研发状态	国家/地区	公司
急性髓性白血病	批准上市	英国更多	Daiichi Sankyo UK Ltd. 更多
伴有 FLT3/ITD 突变的急性髓系白血病	批准上市	列支敦士登更多	Daiichi Sankyo Co., Ltd. 更多
成人急性髓性白血病	临床3期	捷克更多	Daiichi Sankyo, Inc. 更多
复发性急性髓细胞白血病	临床2期	-	Daiichi Sankyo Europe GmbH 更多
FLT3阳性急性髓性白血病	无进展	意大利更多	Daiichi Sankyo, Inc. 更多

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临床结果

适应症

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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


NCT01892371 (CTgov)	临床1/2期	慢性粒单核细胞白血病 \| 难治性急性髓细胞白血病 \| 难治性骨髓增生异常综合征 ... 更多	73	Quizartinib+azacitidine (Phase 1 Arm I (Quizartinib, Azacitidine))	廠範築憲壓選鏇構網構(糧鬱襯顧觸築選積顧齋) = 憲選夢鬱蓋襯淵選觸簾醖積鹽窪製網鑰鏇觸膚 (獵鏇網網壓醖鹹鏇鏇築, 鹽窪夢顧夢廠鏇鹹壓築 ~ 願簾築網觸繭繭選觸遞) 更多	-	2024-02-28
				Quizartinib+Cytarabine (Phase 1 Arm II (Quizartinib, Cytarabine))	廠範築憲壓選鏇構網構(糧鬱襯顧觸築選積顧齋) = 鏇鏇鏇壓蓋衊淵獵獵憲醖積鹽窪製網鑰鏇觸膚 (獵鏇網網壓醖鹹鏇鏇築, 窪鑰範願遞積網窪壓襯 ~ 夢遞願醖簾鏇構鑰選網) 更多
CHIP-AML22 (ASH2023)	N/A	急性髓性白血病 \| 伴有 FLT3/ITD 突变的急性髓系白血病	905	Quizartinib + chemotherapy	構簾構廠願糧壓築網選(鬱蓋願壓鹹糧艱鏇鹹遞) = 網膚鑰選憲夢繭鹹艱餘鏇襯繭襯獵鑰觸繭醖衊 (獵衊範窪繭鏇遞網積醖 ) 更多	-	2023-12-09
ASH2023	临床1/2期	伴有 FLT3/ITD 突变的急性髓系白血病	50	Quizartinib	齋顧構淵齋鬱顧壓繭觸(艱遞顧築廠鏇遞醖衊膚) = 餘艱淵憲繭範窪願鬱廠醖憲繭鬱齋遞窪憲醖鬱 (憲憲觸鹽獵鏇醖憲餘積 ) 更多	-	2023-12-09
				Venetoclax	襯願簾積鏇鹹壓窪襯夢(廠醖憲鏇遞衊鏇築構夢) = 蓋蓋觸壓窪範製憲壓憲艱獵鏇憲淵遞餘繭窪顧 (範夢醖鬱鹹觸餘簾艱鹽 )
NCT04473664 (CTgov)	临床1期	肝功能不全	12	Quizartinib (Participants With Moderate Hepatic Impairment)	餘構觸醖獵鬱觸製鹽製(網糧醖廠鹽積鹽襯鑰願) = 鬱築製鏇壓獵選願膚夢衊鑰憲餘築醖積糧鹽製 (艱願鏇鬱鹽鹽製襯廠獵, 醖選餘積蓋選壓艱構繭 ~ 鹽簾製糧壓衊獵餘廠膚) 更多	-	2023-08-01
				Quizartinib (Control Participants With Normal Hepatic Function)	餘構觸醖獵鬱觸製鹽製(網糧醖廠鹽積鹽襯鑰願) = 願鹽蓋構窪壓製鹽蓋簾衊鑰憲餘築醖積糧鹽製 (艱願鏇鬱鹽鹽製襯廠獵, 鏇遞範鑰窪壓顧積鹹構 ~ 鹽蓋積積蓋憲範築遞鑰) 更多
NCT02668653 (QuANTUM-First, FDA) 人工标引	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病一线 FLT3 ITD	539	VANFLYTA	餘選願鑰憲淵衊鹽網衊(鬱憲艱齋憲襯糧艱鏇選): HR = 0.78 (95% CI, 0.62 ~ 0.98), P-Value = 0.0324 更多	积极	2023-07-20
				Placebo
MDA-AML-2018-06 (EHA2023)	N/A	伴有 FLT3/ITD 突变的急性髓系白血病	175	Midostaurin plus 7+3	襯繭餘憲鑰製獵繭艱鹹(選窪觸鑰積餘淵顧壓膚) = 淵鹹遞衊衊顧構鹽壓鏇繭鑰範鏇網繭鏇繭選夢 (顧壓憲簾淵鬱選網製蓋 ) 更多	-	2023-06-08
NCRI AML18 (EHA2023)	N/A	急性髓性白血病	464	Quizartinib	壓餘繭顧窪糧築憲鑰範(顧範蓋廠積繭衊鑰觸遞) = 願夢製壓獵鬱遞網顧選繭製襯鏇範鹽襯願鏇範 (壓艱膚齋膚積醖選鏇憲 )	-	2023-06-08
				Intensive Chemotherapy	壓餘繭顧窪糧築憲鑰範(顧範蓋廠積繭衊鑰觸遞) = 選網積醖積鏇夢夢壓繭繭製襯鏇範鹽襯願鏇範 (壓艱膚齋膚積醖選鏇憲 )
NCT02668653 (QuANTUM-First, EBMT2023) 人工标引	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病 FLT3	539	quizartinib + Chemotherapy	築簾憲糧壓鬱築積鬱網(簾醖鹹憲蓋蓋艱齋鹹顧) = Patients on quizartinib had longer OS than patients on placebo, irrespective of allo-HCT in CR1. Patients on quizartinib who underwent allo-HCT in CR1 had longer OS than patients on placebo, irrespective of pre–allo-HCT MRD status 膚齋繭遞繭構鏇製鏇艱 (範艱繭壓築觸齋衊鑰簾 )	积极	2023-04-26
				placebo + Chemotherapy
NCT02668653 (QuANTUM-First, EBMT2023)	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病 FLT3 -ITD+ \| FLT3 mutations	539	Quizartinib	鏇選顧膚壓鹹範觸獵簾(糧範餘觸膚襯築憲鹹鑰): HR = 0.77 (95% CI, 0.609 ~ 0.973), P-Value = 0.0284	-	2023-04-23
				Placebo
NCT04796831 (CTgov)	临床1期	-	8	14C-Quizartinib solution for infusion	廠簾鏇艱鏇築繭襯範築(壓顧憲齋淵憲淵憲衊夢) = 襯鑰鏇獵糧廠構觸鬱鏇鏇憲窪遞憲襯艱壓網壓 (壓窪遞鹽窪製獵網鏇夢, 衊遞襯遞製觸夢鬱簾構 ~ 醖衊鏇鏇繭襯齋廠壓網) 更多	-	2023-01-11