A Randomized Phase II Study of Venetoclax and HMA-Based Therapies for the Treatment of Older and Unfit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML): A MyeloMATCH Treatment Trial

This phase II MyeloMATCH treatment trial compares the usual treatment of azacitidine and venetoclax to the combination treatment of azacitidine, venetoclax and gilteritinib in treating older and unfit patients with acute myeloid leukemia and FLT3 mutations. Azacitidine is a drug that is absorbed into DNA and leads to the activation of cancer suppressor genes, which are genes that help control cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib is in a class of medications called kinase inhibitors. It works by blocking the action of a certain naturally occurring substance that may be needed to help cancer cells multiply. This study may help doctors find out if these different approaches are better than the usual approaches. To decide if they are better, the study doctors are looking to see if the study drugs lead to a higher percentage of patients achieving a deeper remission compared to the usual approach.

开始日期2025-03-03

申办/合作机构

National Cancer Institute

NCT05564390 / Recruiting临床2期IIT

Master Screening and Reassessment Protocol (MSRP) for the NCI MyeloMATCH Clinical Trials

This MyeloMATCH Master Screening and Reassessment Protocol (MSRP) evaluates the use of a screening tool and specific laboratory tests to help improve participants' ability to register to clinical trials throughout the course of their myeloid cancer (acute myeloid leukemia or myelodysplastic syndrome) treatment. This study involves testing patients' bone marrow and blood for certain biomarkers. A biomarker (sometimes called a marker) is any molecule in the body that can be measured. Doctors look at markers to learn what is happening in the body. Knowing about certain markers can give doctors more information about what is driving the cancer and how to treat it. Testing patients' bone marrow and blood will show doctors if patients have markers that specific drugs can target. The marker testing in this study will let doctors know if they can match patients with a treatment study (myeloMATCH clinical trial) that tests treatment for the type of cancer they have or continue standard of care treatment with their doctor on the Tier Advancement Pathway (TAP).

开始日期2024-06-18

申办/合作机构

National Cancer Institute

NCT06235801 / Recruiting临床1/2期IIT

A Phase I/II Study of Gilteritinib and Momelotinib for Patients With Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia

To learn the recommended dose of momelotinib that can be given in combination with gilteritinib to participants with AML.

开始日期2024-05-22

申办/合作机构

The University of Texas MD Anderson Cancer Center

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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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315

项与富马酸吉瑞替尼相关的文献（医药）

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

Effective treatment with Gilteritinib-based regimens for FLT3-mutant extramedullary relapse in acute promyelocytic leukemia

Article

作者: Huang, Dong-Ping ; Hou, Chun-Xiao ; Liu, Shan-Hao ; Jiang, Yi-Zhi ; Chen, Su-Ning ; Chen, Yu

OBJECTIVE:

Extramedullary relapse (EMR) is rare in acute promyelocytic leukemia (APL) and, there is a lack of information on its management. Current practices for EMR in APL are always to adopt strategies from other subtypes of Acute lymphoblastic leukemia (ALL) and Acute myeloid leukemia (AML). Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated a remarkable effect on EMR in FLT3-mutant AML. Therefore, it is worthwhile exploring if FLT3 mutation can be a therapeutic target and assessing the efficacy of Gilteritinib on FLT3-mutant EMR in APL.

METHODS:

We described three cases of FLT3-mutant EMR in APL, comprising two isolated EMR cases and one systemic relapse. The patients underwent treatment with Gilteritinib-based regimens based on FLT3 mutation.

RESULTS:

All three patients achieved complete regression of EMR, and no signs of tumor lysis syndrome during Gilteritinib-based therapy, only patient 1 showed mild granulocytopenia. They all maintained molecular complete remission (mCR) during the follow-up period.

CONCLUSIONS:

The Gilteritinib-based regimen shows a high and sustained therapeutic effect with minimal adverse effects, and provides a valuable experience for further evaluation in EMR APL patients.

2024-03-01·British journal of haematology

Gilteritinib‐based combination therapy in adult relapsed/refractory FLT3‐mutated acute myeloid leukaemia

Article

作者: Xu, Gaixiang ; Feng, Weiying ; Qian, Jiejing ; Pan, Jiajia ; Chen, Nianci ; Wei, Juying ; Shou, Lihong ; Yan, Minchao ; Wang, Huafeng ; Huang, Li ; Mao, Liping ; Zhou, De ; Tong, Hongyan ; Jin, Jie ; Zhou, Yile ; Wu, Gongqiang ; Zeng, Hui ; Fan, Cuihua ; Lou, Yinjun

Summary:

Gilteritinib, a potent FMS‐like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3‐mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib‐based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3‐mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3‐mutated AML, and it may be considered an effective therapy bridge to transplantation.

2024-02-23·Leukemia & lymphoma

Treatment of relapsed or refractory FLT-3 acute myelogenous leukemia with a triplet regimen of hypomethylating agent, venetoclax, and gilteritinib

Article

作者: Nakamura, Ryotaro ; Stein, Anthony ; Pullarkat, Vinod ; Salhotra, Amandeep ; Ball, Brian ; Koller, Paul ; Li, Shanpeng ; Tinajero, Jose ; Palmer, Joycelynne ; Aribi, Ahmed ; Pourhassan, Hoda ; Marcucci, Guido ; Sandhu, Karamjeet ; Ngo, Dat

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35-298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation.

147

项与富马酸吉瑞替尼相关的新闻（医药）

2024-06-23

·药明康德

完全缓解率达100%的CAR-T疗法；延长胰腺癌患者生存期的组合疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. CD19靶向候选CAR-T细胞疗法GLPG5101在1项早期临床试验中治疗5例套细胞淋巴瘤（MCL）患者，客观缓解率（ORR）和完全缓解率（CRR）均为100%。 2. 靶向信号调节蛋白（SIRP）的抗体疗法ELA026治疗初治恶性肿瘤相关噬血细胞性淋巴组织细胞增多症（mHLH）的总缓解率达100%，并提高了此类患者的两个月生存率。 3. 抗体疗法Natrunix联用化疗治疗晚期胰腺癌，在早期临床试验中延长了患者的生存期并改善了化疗的耐受性。药明康德内容团队整理 GLPG5101：公布1/2期临床试验数据 Galapagos公司公布了其CD19靶向候选CAR-T细胞疗法GLPG5101治疗复发/难治性非霍奇金淋巴瘤（NHL）的1/2期临床试验ATALANTA-1的新数据。该细胞疗法从制备到回输到患者体内的中位时间仅需7天。截至2023年12月20日的数据，在研究的第一部分，中位随访时间为13.1个月，接受GLPG5101治疗的16例可评估患者的ORR为87.5%（14/16），CRR为75%（12/16）。71%的患者在数据截止时保持缓解。在研究的第二部分，中位随访时间为4.2个月，15例可评估患者的ORR和CRR均为93.3%（14/15）。100%的患者在数据截止时保持持续缓解。合并两部分的研究结果后根据肿瘤类型进行划分，弥漫性大B细胞淋巴瘤（DLBCL）患者的ORR为78%（7/9），CRR为56%（5/9）；滤泡性淋巴瘤（FL）或边缘区淋巴瘤（MZL）患者的ORR和CRR均为94%（16/17）；套细胞淋巴瘤患者的ORR和CRR均为100%（5/5）。安全性方面，大多数治疗伴发不良事件为1/2级，在研究的第一部分观察到2例3级细胞因子释放综合征（CRS），在研究的第二部分观察到1例3级免疫效应细胞相关神经毒性综合征（ICANS）。 ELA026：公布1b期临床试验的新数据 Electra Therapeutics公司公布了其靶向信号调节蛋白（SIRP）的单克隆抗体ELA026治疗继发性噬血细胞性淋巴组织细胞增生症（sHLH）的1b期研究的最新临床数据。ELA026靶向细胞表面的SIRP，能够靶向清除血液循环中驱动炎症的髓系细胞和T细胞，并且不破坏SIRPα/CD47免疫检查点功能。该疗法旨在治疗伴有异常髓系和T细胞活性的重度炎性疾病。此次公布的结果显示，ELA026在sHLH患者中具有良好的安全性，不良事件可控。在已完成入组的队列1和2中（n=12），ELA026在第4周时的总缓解率为75%，在8例未接受过治疗的mHLH（sHLH的一种亚型）患者中，总缓解率为100%，两个月时的生存率为88%。此类患者在自然史研究中的两个月时的死亡率约为50%。 Natrunix：公布1/2期临床试验数据 XBiotech公司公布了其靶向白细胞介素-1α（IL-1α）的抗体疗法Natrunix联用化疗治疗晚期胰腺癌的1/2期多中心研究的数据。除了能够作为一种抗癌疗法，该公司认为Natrunix还有望改善化疗的耐受性。该研究中采用的化疗方案为ONIVYDE（ON）+5-氟尿嘧啶（5FU）+亚叶酸（LV）。此次公布的结果显示，与安慰剂+化疗组相比，Natrunix+化疗组在24周的治疗周期内发生任何类型的不良事件的数量（297例对比336例）、发生重大不良事件的患者比例（9/33对比12/32）和住院天数（80天对比120天）均明显减少。此外，接受Natrunix+化疗组患者的生存期得到了延长，接受治疗第330天时有8例患者存活，而安慰剂+化疗组没有患者存活超过330天。 ▲患者的生存曲线（图片来源：参考资料[9]） Petrelintide：公布1b期临床试验数据 Zealand Pharma公司公布了其在研长效、潜在“best-in-class”减重疗法petrelintide的1b期试验第二部分的顶线结果。Petrelintide（ZP8396）是一种适合每周一次皮下注射的长效胰淀素类似物，具有中性pH下的化学和物理稳定性。胰淀素在胰腺β细胞中产生，并与胰岛素一起分泌以响应摄入的营养物质。目前的临床或临床前数据表明，petrelintide有潜力实现与GLP-1受体激动剂相当的体重减轻，但具有更好的耐受性，为患者提供更好的用药体验和体重减轻，同时保留患者的肌肉质量。此次公布的结果显示，患者在接受16周高剂量petrelintide治疗后，体重较基线平均减少了8.6%，而安慰剂组仅为1.7%。安全性方面，petrelintide显示良好的耐受性，没有出现严重的不良事件。所有胃肠道（GI）不良事件均为轻度，除了一名受试者在第三次治疗后因中度恶心和呕吐而停止治疗。值得注意的是，没有其他受试者因不良事件停止治疗或报告呕吐，只有两例轻度腹泻报告。恶心在活性组中报告比例为16.7-33.3%，在安慰剂组为16.7%。少数参与者报告了注射部位反应，均为轻度。未观察到患者产生抗药抗体。新闻稿指出，该积极结果支持petrelintide作为GLP-1受体激动剂类药物之外，在体重管理上的另一选择。 Amezalpat（TPST-1120）：公布1b/2期临床试验的新数据 Tempest Therapeutics公司公布了其在研口服、选择性小分子PPAR⍺拮抗剂amezalpat（TPST-1120）在一项全球随机的1b/2期临床试验中获得的积极结果。临床前数据显示，amezalpat可直接杀死肿瘤细胞，并靶向肿瘤微环境中的抑制性免疫通路。这两种类型中的靶向细胞皆依赖脂肪酸代谢，该代谢过程由PPARα转录因子调节。在一项针对接受过多次治疗的晚期实体瘤患者的1期临床试验中，amezalpat单药治疗和与PD-1抑制剂nivolumab联合应用均导致肿瘤缩小及生物标志物的变化。此次公布的结果显示，与标准治疗方案相比，amezalpat与标准治疗方案（抗PD-L1抗体atezolizumab和抗VEGF抗体bevacizumab）联用，在无法切除或转移性肝细胞癌（HCC）患者的一线治疗中，显著提高患者的中位总生存期（OS）达6个月（21个月对比15个月）。此外，按照RECIST v1.1标准评估，amezalpat组的确认客观缓解率（cORR）为30%，对照组为13.3%。安全性方面，amezalpat的耐受性良好，两组之间的安全数据相当。 ▲Amezalpat试验的OS结果（图片来源：参考资料[29]） MB-106：公布1/2期临床试验数据 Mustang Bio公司公布了其在研、可通过门诊给药、靶向CD20的自体CAR-T细胞疗法MB-106治疗华氏巨球蛋白血症（WM）的1/2期临床试验最新数据。该试验中的所有十例患者均曾接受过布鲁顿酪氨酸激酶抑制剂（BTKi）的治疗，并且在接受BTKi治疗期间病情持续恶化。患者之前接受过中位9线疗法，只有一例患者在接受MB-106治疗后开始接受额外的抗WM治疗。总体而言，接受MB-106治疗的患者中有90%（9/10）对治疗产生应答，包括3名患者达完全缓解（CR）、2名达非常好的部分缓解和4名部分缓解。此外，1例患者的病情稳定。其中一名获得CR的患者已持续缓解31个月，该患者的免疫球蛋白M（IgM）水平在接受MB-106治疗后迅速降至正常范围，此后一直保持正常。安全性方面，9例患者发生了CRS（5例患者为1级，4例患者为2级），一例患者经历了1级ICANS。尽管剂量增加，但并未观察到3级或4级CRS或2、3或4级ICANS。 NX-594：公布1a/b期临床试验数据 Nurix Therapeutics公司公布了其在研口服BTK降解剂NX-5948治疗复发难治性慢性淋巴细胞白血病（CLL）的1a/b期临床试验的积极数据。NX-5948是一种生物利用度高、可穿越血脑屏障的口服BTK小分子降解剂。 ▲NX-5948的疗效结果（图片来源：参考资料[5]）此次公布的结果显示，NX-594在复发难治性CLL患者身上引起了快速、深度的缓解，ORR达69.2%，这些患者之前曾接受大量治疗并带有BTK抑制剂耐药突变。最早在第一次肿瘤扫描（8周）时就观察到患者出现缓解，许多患者在治疗时间延长后缓解加深。截至4月17日数据截止，所有缓解仍在持续。 ▲一例患者接受NX-5948治疗24周内，脑脊液中的恶性肿瘤细胞消除（图片来源：参考资料[5]） ▲一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退（图片来源：参考资料[2]）此外，一例在进入研究时伴有中枢神经系统受累的CLL患者在接受NX-5948治疗的24周内消除了脑脊液（CSF）中的恶性肿瘤细胞，并在36周时达到接近CR的标准。还有一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退已超过6个月。安全性方面，NX-5948在所有评估剂量下均耐受性良好，最常见的治疗不良事件为紫癜/挫伤、血小板减少和中性粒细胞减少。Nurix预计在2025年启动NX-5948的关键临床试验。 SL-172154：公布1b期临床试验数据 Shattuck Labs公布了其在研疗法SL-172154在1b期剂量扩展临床试验的最新中期数据。SL-172154（SIRPα-Fc-CD40L）是一款在研重定向检查点激动剂（ARC）融合蛋白，旨在同时抑制CD47/SIRPα检查点的相互作用并激活CD40共刺激受体，以增强晚期癌症患者的抗肿瘤免疫反应。此次公布的结果显示，SL-172154与阿扎胞苷（AZA）联用作为高风险骨髓增生异常综合征（HR-MDS）和TP53突变（TP53m）急性髓性白血病（AML）患者的一线疗法时，患者的ORR分别达67%与43%，CRR分别为42%与29%。截至2024年4月23日，SL-172154表现出可控的安全性。输液相关反应（IRRs）是SL-172154治疗过程中最常见的不良事件。 KT-333：公布1期临床试验的新数据 Kymera Therapeutics公布了其在研药物KT-333的1期临床试验的更新数据。KT-333是一种潜在“first-in-class”、强效、高选择性的STAT3靶向小分子降解剂。根据新闻稿，KT-333是靶向未成药转录因子的首个进入临床阶段的降解剂。 ▲KT-333试验临床结果摘要（图片来源：参考资料[3]）此次公布的结果显示，KT-333完成初步临床概念验证，在多种血液恶性肿瘤中展示了抗肿瘤活性。其中，两名经典霍奇金淋巴瘤患者达到CR，1名STAT3突变的NK细胞淋巴瘤患者达到CR。安全性方面，KT-333耐受性良好，主要不良事件为1级和2级，包括口腔炎和疲劳。 ▲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] Shattuck Labs Announces Updated Positive Interim Data from the Phase 1B Dose Expansion Clinical Trial of SL-172154 in Combination with Azacitidine (AZA) in Frontline Higher-Risk Myelodysplastic Syndromes (HR-MDS) and TP53 mutant (TP53m) Acute Myeloid Leukemia (AML) Patients. Retrieved June 21, 2024 from https://www.globenewswire.com/news-release/2024/06/14/2898850/0/en/Shattuck-Labs-Announces-Updated-Positive-Interim-Data-from-the-Phase-1B-Dose-Expansion-Clinical-Trial-of-SL-172154-in-Combination-with-Azacitidine-AZA-in-Frontline-Higher-Risk-Myel.html [2] Kymera Therapeutics Presents New Clinical Data from the Ongoing Phase 1 Trial of STAT3 Degrader KT-333 at EHA Annual Meeting. Retrieved June 21, 2024 from https://www.globenewswire.com/news-release/2024/06/14/2898896/0/en/Kymera-Therapeutics-Presents-New-Clinical-Data-from-the-Ongoing-Phase-1-Trial-of-STAT3-Degrader-KT-333-at-EHA-Annual-Meeting.html [3] Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Hematologic and Solid Tumor Cancers. 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Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240614920813/en [21] Cabaletta Bio Reports Positive Initial Clinical Data from Phase 1/2 RESET-Myositis™ and RESET-SLE™ Trials of CABA-201. Retrieved June 21, 2024, from https://www.globenewswire.com/news-release/2024/06/14/2898772/0/en/Cabaletta-Bio-Reports-Positive-Initial-Clinical-Data-from-Phase-1-2-RESET-Myositis-and-RESET-SLE-Trials-of-CABA-201.html [22] ORYZON Presents Preliminary Data From Ongoing Phase Ib FRIDA Trial with Iadademstat Plus Gilteritinib in Relapsed/Refractory FLT3-mut AML Patients at EHA-2024. Retrieved June 21, 2024, from https://www.globenewswire.com/news-release/2024/06/14/2898942/0/en/ORYZON-Presents-Preliminary-Data-From-Ongoing-Phase-Ib-FRIDA-Trial-with-Iadademstat-Plus-Gilteritinib-in-Relapsed-Refractory-FLT3-mut-AML-Patients-at-EHA-2024.html [23] Enlivex Announces Positive Interim Data Readout from a Phase I/II Trial Evaluating Allocetra in End-Stage Knee Osteoarthritis. Retrieved June 21, 2024, from https://www.globenewswire.com/news-release/2024/06/17/2899579/0/en/Enlivex-Announces-Positive-Interim-Data-Readout-from-a-Phase-I-II-Trial-Evaluating-Allocetra-in-End-Stage-Knee-Osteoarthritis.html [24] Cessation Therapeutics Announces Oral Presentation of Preliminary Findings from First-in-Human Study of Anti-Fentanyl Monoclonal Antibody, CSX-1004. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240619579616/en [25] Innate Pharma Shares Updated Results From the Sanofi Developed Blood Cancer Phase 1/2 SAR443579/IPH6101 Trial. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240616126553/en [26] Tempest Unveils New Survival Data for Amezalpat (TPST-1120) in Randomized First-Line HCC Study Demonstrating a Six-Month Improvement over Control Arm. Retrieved June 21, 2024, from https://ir.tempesttx.com/news-releases/news-release-details/tempest-unveils-new-survival-data-amezalpat-tpst-1120-randomized [27] Escend Announces Poster Presentation at the Annual Meeting of the European Hematology Association (EHS) from an Investigator-Initiated Phase I/II study evaluating ES-3000 in Myelodysplastic Syndrome (MDS). Retrieved June 21, 2024, from https://www.prnewswire.com/news-releases/escend-announces-poster-presentation-at-the-annual-meeting-of-the-european-hematology-association-ehs-from-an-investigator-initiated-phase-iii-study-evaluating-es-3000-in-myelodysplastic-syndrome-mds-302177666.html [28] Tubulis Doses First Patient in Phase I/IIa Trial Investigating ADC Candidate TUB-040 in Ovarian Cancer and Lung Adenocarcinoma. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240620456143/en/ [29] Amezalpat (TPST-1120) Randomized 1L HCC Data Updat. Retrieved June 20, 2024 https://ir.tempesttx.com/static-files/8ba2d665-884e-47f7-89c2-adbba73378b2 [30] Mustang Bio Announces Favorable Efficacy and Safety Data from Complete Waldenstrom Macroglobulinemia Cohort of Phase 1/2 Clinical Trial of MB-106, CD20-Targeted Autologous CAR-T Therapy. Retrieved June 18, 2024 from https://ir.mustangbio.com/news-events/press-releases/detail/180/mustang-bio-announces-favorable-efficacy-and-safety-data 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

细胞疗法临床结果免疫疗法临床2期

2024-06-14

·精准药物

PROTACs ｜抗白血病药物研发：现状与展望

鉴于近年来抗白血病 PROTACs 的数量急剧增加，André T. S. Vicented等人对现有信息进行分析和讨论，综述总结了通过降解关键白血病相关靶点来治疗一种或多种不同类型白血病的 PROTACs。 1. 背景介绍白血病作为一组威胁人类健康的恶性血液疾病，其传统治疗方法存在局限性，如治疗抵抗性、副作用、复发和长期后遗症。因此，开发新的治疗方法以改善患者预后是一个迫切的需求。表1最常见的白血病类型近年来，包括靶向蛋白质降解在内的新策略显示出在白血病个性化医疗领域的潜力，特别是PROTACs（蛋白质降解靶向嵌合体），它们通过泛素-蛋白酶体系统有选择性地降解蛋白质，展现出克服传统疗法缺点的潜力，并为白血病治疗提供了新的视角。图1造血和不同类型白血病的起源 2. PROTAC概述 PROTACs是双功能分子，能够利用细胞自身的泛素-蛋白酶体系统（UPS），选择性地促进目标蛋白（POI）的翻译后降解。自2001年Crews实验室首次报告PROTACs以来，过去5年中这一领域的发展迅猛，根据PROTAC数据库（PROTAC-DB），目前已有超过3270种PROTACs被报道。PROTACs分子由三部分组成，一端是能够结合POI的目标配体部分（TLM），另一端是能够招募特定E3连接酶的配体部分（ELM），两者通过连接链（linker）相连。PROTAC进入细胞后，通过TLM端结合POI，ELM端结合E3连接酶，形成稳定的三元复合物，促使POI被非自然地多泛素化，然后被26S蛋白酶体降解。与传统抑制剂相比，PROTACs可以降解没有活性位点的“不可成药”蛋白，并且可以催化机制发挥作用，一个PROTAC分子可以降解多个POI分子。PROTACs作为一种新兴的药物发现工具，为传统抑制剂难以靶向的蛋白质提供了新的治疗策略。泛素-蛋白酶体系统（UPS）和蛋白水解靶向嵌合体（PROTAC）的作用机制 PROTAC 的活性深受所选 TLM、ELM 和连接体组合的影响，因为这三者在确保 POI 与 E3 连接酶之间的理想相互作用方面起着决定性作用，最终导致目标物的多泛素化。图3蛋白水解-靶向嵌合体（PROTAC）的结构和主要构件。PROTAC的结构、主要E3连接酶配体、PROTAC中掺入的接头类型以及接头与靶配体或E3连接酶配体之间的连接点的实例。 3. 针对白血病相关靶点的 PROTACS 目前，文献中报道的众多 PROTACs 能够促进参与不同类型白血病发生和发展的特定靶点的选择性降解。一些有前景的降解剂能够有效地损害靶点，显示出未来治疗一种或多种类型白血病的潜力。BCR-ABL、BCL-XL、布鲁顿酪氨酸激酶（BTK）、含溴结构域蛋白 4（BRD4）、细胞周期蛋白依赖性激酶（CDK6）、FMS 样酪氨酸激酶 3（FLT-3）等蛋白质已被确定为抗白血病 PROTACs 的主要降解靶标。PROTACs通过将目标蛋白（POI）定向到泛素-蛋白酶体系统（UPS）来促进其降解，这种机制相比传统的小分子抑制剂（SMIs）具有优势，减少药物剂量和给药频率，从而减少副作用。图 4 针对白血病相关靶点和主要 E3 连接酶的 PROteolysis-TArgeting Chimeras (PROTACs) 机制 3.1 BCR-ABL BCR-ABL 是一种由染色体易位产生的融合基因蛋白Ph，存常见于慢性髓性白血病（CML）和某些急性淋巴细胞白血病（ALL）中。该蛋白具有组成型酪氨酸激酶作用，可异常激活一系列促进细胞增殖的信号通路，如 Janus 激酶/信号转导和激活转录 5（STAT5）等，这种异常激活会使得细胞内失调，导致白血病细胞过度生成和扩增。 BCR-ABL抑制剂：传统上，针对BCR-ABL的抑制剂如伊马替尼及其衍生物，通过与ATP结合位点竞争来抑制BCR-ABL的激酶活性。然而，这些抑制剂可能因耐药性突变（如T315I）而失效。 BCR-ABL PROTACs：PROTACs通过招募E3泛素连接酶来促进BCR-ABL的多泛素化和随后的蛋白酶体降解，降低癌细胞耐药性。例如，基于dasatinib的PROTAC已显示出对BCR-ABL的有效降解。表 2. 以 BCR-ABL 蛋白为靶标的 PROTACs 的化学结构图 5. 靶向 BCR-ABL 的 PROTAC 的化学结构。(A）BCR-ABL PROTAC 15 的可逆光开关机制。(B）通过招募不常见的E3连接酶靶向BCR-ABL的PROTAC的化学结构。 3.2 BCL-2 family 由一系列促凋亡蛋白和抗凋亡蛋白组成的 B 细胞淋巴瘤 2（BCL-2）家族蛋白在控制细胞生命周期方面发挥着重要作用。促进了肿瘤的产生、发展和抗药性。 BCL-2家族抑制剂：如venetoclax，是针对BCL-2的FDA批准药物，用于治疗CLL和AML。但这些抑制剂可能引起血小板减少等副作用。针对BCL-2家族的PROTACs：PROTACs通过降解BCL-XL等蛋白，并减少副作用。例如，XZ424和DT2216是两种不同的BCL-XL PROTACs，它们通过不同的E3连接酶来促进BCL-XL的降解。表 3. 针对 BCL-XL 蛋白的 PROTACs 的化学结构 3.3 Bruton's tyrosine kinase 属于 Tec 家族的 BTK 在除 T 细胞和成熟浆细胞以外的所有造血细胞中均有表达，并通过参与 B 细胞受体（BCR）信号通路参与 B 细胞的成熟、功能和分化过程。当抗原刺激 BCR 时，会诱导 BTK 磷酸化，进而激活 BTK。 BTK抑制剂：如ibrutinib，通过共价结合BTK的C481位点来抑制其活性。但C481S等突变可导致耐药性。 BTK PROTACs：PROTACs提供了一种非共价结合的降解策略，能够绕过耐药性突变，如使用ibrutinib衍生物作为配体的PROTAC。表 4. 针对 BTK 蛋白的 PROTACs 的化学结构 3.4 BET family 在 BET 家族的各种成员中，有一种 BRD4，它是一种核蛋白，参与组织和调控相关基因（如 c-Myc、BCL-XL、BCL-2）的基因转录。BRD4 蛋白在几种类型的癌症（包括 AML、ALL 和 CML）中经常过度表达和异常激活，因此其作为参与肿瘤进展的一个有希望的靶点进行了广泛研究。 BET抑制剂：如JQ1和OTX015，通过抑制BET家族蛋白来影响基因转录调控。 BRD4 PROTACs：如dBET1和ARV-825，通过降解BRD4来抑制白血病细胞的增殖，且降解效果优于单纯的抑制。图 6. 靶向 BET 家族的 PROTACs 的化学结构。针对白血病 BRD4 蛋白的 PROTACs 结构分析，其中蓝色部分代表 E3 配体，紫色部分代表目标配体，两者通过连接体连接在一起。 3.5 CDK family 细胞周期蛋白激酶(CDKs)家族在细胞活动中发挥重要作用，特别是CDK6。CDK6参与控制细胞周期的G1到S期转换，阻止细胞进入S期所需的基因表达。CDK6在AML和CML等白血病中常被异常激活。 CDK6抑制剂：例如palbociclib，通过竞争性结合CDK6的ATP结合位点来抑制其激酶活性。这些抑制剂主要治疗那些CDK6过度激活或过表达的癌症。然而，由于CDK6在正常细胞中也发挥作用，副作用明显，如中性粒细胞减少症（neutropenia）。 CDK6 PROTACs：与传统的抑制剂相比，CDK6 PROTACs具有减少副作用的潜力，因为它们通过降解CDK6来消除其在细胞周期调控中的作用，从而可能避免了对正常细胞功能的广泛干扰。表 5. 以 CDK6 蛋白为靶标的 PROTACs 的化学结构 3.6 FMS-like tyrosine kinase 3 FLT-3是一种酪氨酸激酶受体，是急性髓细胞性白血病中的致癌驱动因子。20%至30%的新诊断急性髓细胞性白血病患者的FLT-3基因发生突变，例如，（ITD）是最常见的 FLT-3 基因突变类型（FLT-3-ITD），约占所有急性髓细胞白血病病例的 25%，也是一种常见的驱动突变，与急性髓细胞白血病患者的高白血病负荷和不良预后有关。 FLT-3抑制剂: 为了治疗FLT-3突变的急性髓性白血病，开发了多种FLT-3抑制剂，这些药物通过抑制FLT-3的激酶活性来发挥作用。如quizartinib和gilteritinib，已经用于临床治疗FLT-3突变的AML患者，但副作用较大。 FLT-3 PROTACs：是针对FLT-3蛋白的蛋白质降解靶向嵌合体。通过降解FLT-3，可能绕过某些耐药机制，选择性地靶向FLT-3，减少对其他激酶的影响，从而可能减少副作用。FLT-3 PROTACs还可以与其他药物联合使用，以提高治疗效果或克服耐药性。图 7. 靶向 FLT-3 的 PROTACs 的化学结构。针对白血病 FLT-3 蛋白的 PROTACs 结构分析 3.7 MDM2 MDM2是一种E3泛素连接酶，它在细胞内扮演着重要的角色，尤其是在p53蛋白的调控中。MDM2能够结合到p53的N端转录激活域，阻止p53与DNA结合，进而抑制其转录活性。在TP53基因野生型的白血病细胞中，MDM2经常过表达，导致肿瘤抑制蛋白的降解速率增加，最终损害其抗癌功能。 MDM2抑制剂：通过抑制MDM2来稳定p53蛋白，MDM2抑制剂已经在多种癌症治疗中进行了研究，尤其是在那些p53功能受损的癌症中。然而，这些抑制剂可能会触发负反馈机制，减少抑制剂的活性。 MDM2 PROTACs：通过降解MDM2，不仅稳定p53，还可能通过其他机制（如减少MCL-1）增强抗白血病效果。图 8. 靶向 MDM2 的 PROTACs 的化学结构。针对白血病 MDM2 蛋白的 PROTACs 结构分析 3.8 STAT family STAT 家族由七个成员组成，它们共享高度保守的 Src 同源 2（SH2）结构域。其中STAT3 和 STAT5被选为开发 PROTACs 治疗白血病的靶蛋白。 STAT 抑制剂：STAT3/5抑制剂旨在阻止STAT3/5蛋白的活性。由于STAT家族成员在结构上具有高度同源性，开发选择性抑制剂是一个挑战。 STAT3/5 PROTACs：抑制剂相比，PROTACs通过诱导蛋白降解，可能提供更持久和有效的抑制作用。例如，SD-36的PROTAC能够高效降解STAT3，抑制白血病细胞的生长。图 9. 靶向 STAT3/5 的 PROTACs 的化学结构。针对 STAT3/5 蛋白的 PROTACs 对抗白血病的结构分析 3.9 Other antileukemic PROTACs 其他抗白血病PROTACs代表了一类针对白血病治疗中新发现或较少研究靶点的蛋白质降解剂。这些PROTACs通过特异性地降解在白血病发展中起关键作用的蛋白质，如STAT家族蛋白、HDAC6、PBAF复合体亚基、SHP2等，提供了除传统治疗方法之外的新策略。它们利用细胞自身的泛素-蛋白酶体系统来促进这些蛋白质的降解，从而抑制白血病细胞的增殖和存活。图 10. 其他抗白血病 PROTAC 的化学结构。其他抗白血病 PROTAC 的结构分析 4. 挑战与未来展望理想的抗白血病 PROTAC 通过形成稳定的三元复合物（POI-PROTAC-E3 连接酶），对白血病细胞具有选择性细胞毒性活性，能完全、快速、选择性、强效、持久地降解靶标，且 DC50 值尽可能低，从而有效、安全地应用于临床。目前有超过 25 种 PROTACs 正在进行临床试验，研究重点仍是获得具有上述特征的新 PROTACs。然而，新的挑战也引导着最近的 PROTACs 研究取得进展。第一个挑战是扩大可招募的靶点和 E3 连接酶的范围，以及借助硅学工具和人工智能从试错模式转向合理设计 PROTACs。另一个重要问题是评估这些化合物的药代动力学特性以及在体内产生的代谢物的行为。此外，由于PROTACs是大的亲脂性分子，不遵循传统的药物发现规则（如Lipinski的五规则），它们在穿透细胞膜和口服给药方面存在挑战。要进一步的体内研究来评估PROTACs的药效学、毒性和药代动力学特性，这对于评估它们作为未来治疗白血病药物的潜力至关重要。表 7. 小分子抑制剂 (SMI) 和抗白血病 PROTAC 的优缺点尽管未来还有许多挑战，但不可否认的是，PROTACs 已经是一种强大的工具，它将使我们能够大大减少 "无法药物治疗的基因组"，而且作为一种新兴的治疗方式，它有着为未来治疗许多不同疾病的潜力。对于未来的研究方向，旨在通过靶向新的白血病靶点或非传统活性位点来创新。例如，通过光敏开关模块来控制PROTACs的活性，这可能成为未来研究的一个方向。 5. 抗白血病原癌基因的临床试验根据 Clinicaltrials.gov 数据库，目前有 20 多种 PROTACs 正在进行临床试验。BGB-16673、NX-5948 和 NX-2127 降解剂的临床试验包括对 CLL 患者的研究。但是，在 DT2216、ABBV-101 和 AC676 降解剂的临床试验中，并没有说明将对哪种类型的血液癌症进行研究。值得注意的是，大多数正在研究的 PROTACs 都以强制降解 BTK 蛋白为目的。表 6. 临床试验中用于治疗血液恶性肿瘤的 PROTACs 6. 结论 PROTACs 一直是药物研发领域的热门话题，每天都有大量信息涌现。它在白血病治疗领域展现出巨大的潜力和发展前景，但仍需克服设计和优化的挑战，并进行更多的体内研究来验证它们的治疗潜力。参考文献：https://doi-org.libproxy1.nus.edu.sg/10.1002/mco2.575 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体

2024-06-14

·GlobeNewswire-Health Care

ORYZON Presents Preliminary Data From Ongoing Phase Ib FRIDA Trial with Iadademstat Plus Gilteritinib in Relapsed/Refractory FLT3-mut AML Patients at EHA-2024

Data from the first two cohorts demonstrated that combination of iadademstat plus gilteritinib was safe and showed strong antileukemic activityA third cohort is ongoing following FDA’s OPTIMUS guidance MADRID and CAMBRIDGE, Mass., June 14, 2024 (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, today presents preliminary data from its ongoing Phase Ib FRIDA study investigating iadademstat in combination with gilteritinib in relapsed/refractory acute myeloid leukemia (AML) patients harboring a FMS-like tyrosine kinase mutation (FLT3 mut+) at the European Hematology Association (EHA) 2024 congress, being held in Madrid (Spain) on June 13–16. Dr. Amir Fathi, from the Massachusetts General Hospital and Principal Investigator of the study, will present a poster communication entitled “Preliminary results of the FRIDA study: iadademstat and gilteritinib in FLT3-mutated R/R AML”. Dr. Carlos Buesa, Oryzon’s CEO, stated, “We are very excited with these preliminary results, which showed in a mostly refractory patient population a higher-than-expected antileukemic activity in the first two cohorts. We, and others, have previously described the strong synergism of the combination of iadademstat with gilteritinib, and these clinical data confirm this synergism. The observed LSD1 full occupancy data in the first two cohorts outlines that we need to reduce the dose to optimize the marrow recovery and achieve a higher degree of complete responses. With the capability to quantify the levels of LSD1 occupancy, we are in an optimal situation to follow the FDA’s OPTIMUS guidance. The safety profile is so far adequate as expected and recruitment continues.” Summary of the main results reported at EHA-2024 The combination of iadademstat and gilteritinib appears safe and well-tolerated, with no dose limiting toxicities (DLTs) reported in the 28-day DLT evaluation period in the first two cohorts: initial cohort (n=6, iadademstat 100 μg) and DL-1 cohort (n=7, iadademstat 75 μg). There were no unexpected Treatment Emergent Adverse Events (TEAEs).Encouraging antileukemic activity observed, with 9 out of 13 patients (69%) achieving bone marrow (BM) blast clearance in the first cycle. Five out of 13 patients (38%) achieved complete remission (CR), complete remission with partial hematological recovery (CRh) or complete remission with incomplete blood count recovery (CRi). Of note, 11 out of 13 patients were refractory to prior standard regimens including venetoclax, 7+3 and midostaurin. Two patients have undergone hematopoietic stem cell transplantation.Platelet count recovery has been slow in most patients, limiting so far a rapid transition from morphologic leukemia-free state (MLFS) to CR/CRh. Since LSD1 plays a key role in hematopoiesis and both iadademstat doses evaluated in the first two cohorts (starting dose and DL-1) showed full LSD1 target engagement (≈90%), lower doses are being investigated with the aim of maintaining efficacy and improving platelet recovery, in accordance with the FDA’s Optimus Project requiring to identify the minimum safe and biologically active dose.FRIDA is currently accruing patients to the third cohort, DL-2 (iadademstat 75 μg, 3 weeks treatment per cycle). Two patients have been enrolled, with no reported DLTs to date.Pharmacokinetic (PK) data support there is no drug-drug interaction between iadademstat and gilteritinib. FRIDA (NCT05546580) is an escalation/expansion, open-label, single arm, multicenter Phase Ib trial to establish the safety, tolerability, and the recommended Phase II dose (RP2D) of the combination of iadademstat with gilteritinib. The study has been designed according to the FDA’s Project Optimus and consists of 2 parts: a dose finding part to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic and emerging activity of the combination, and to determine the pharmacologically-active dose (i.e., the minimum safe and biologically active dose) of iadademstat in combination with gilteritinib, and an expansion part at the specific dose(s) selected to evaluate the activity of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. The trial is conducted in the US and plans to accrue up to approximately 45 patients. Oryzon is further expanding the clinical development of iadademstat in AML through an Investigator-initiated study (IIS) led by Oregon Health & Science University (OHSU). This trial is a Phase Ib dose-finding study to evaluate iadademstat in combination with the SoC, venetoclax and azacitidine, in first line AML patients and is expected to begin enrolling patients in the coming weeks. In addition, in neuroendocrine tumors, in the context of the CRADA agreement between Oryzon and the NIH, the NCI is sponsoring a randomized Phase I/II trial in 1L extensive disease small cell lung cancer combining iadademstat with immune checkpoint inhibitors. The IND for this trial was recently approved by the FDA. A copy of the EHA-2024 poster is available here. About Oryzon Founded 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 and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets like HDAC-6, where ORY-4001 has been nominated as clinical candidate for the treatment of certain neurological disorders such as 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 Iadademstat Iadademstat (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 efficacy data in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation). 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. 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 being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and the company is preparing a new trial in combination with immune checkpoint inhibitors (ICI) in SCLC. Oryzon has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Cancer Institute (NCI) to collaborate on potential further clinical development of iadademstat in different types of solid and hematological cancers; a first trial in combination with ICI in SCLC has recently received FDA IND approval. In total iadademstat has been dosed so far to more than 130 cancer patients in four clinical trials. 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. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Mario CorderaEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 673 33 97 65+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.commcordera@atrevia.cometorrell@oryzon.com

临床2期临床结果临床1期孤儿药免疫疗法

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	L01XE54	DB12141

研发状态

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适应症	国家/地区	公司	日期
FLT3阳性急性髓性白血病	欧盟	Astellas Pharma Europe Ltd.	2019-10-24
FLT3阳性急性髓性白血病	冰岛	Astellas Pharma Europe Ltd.	2019-10-24
FLT3阳性急性髓性白血病	列支敦士登	Astellas Pharma Europe Ltd.	2019-10-24
FLT3阳性急性髓性白血病	挪威	Astellas Pharma Europe Ltd.	2019-10-24
急性髓性白血病	日本	Astellas Pharma, Inc.	2018-09-21

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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	卢森堡	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

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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


EHA2024	N/A	复发性急性髓细胞白血病 \| 难治性急性髓细胞白血病 FLT3 mutations	59	Gilteritinib monotherapy	鬱醖襯鬱齋餘廠醖簾顧(鹹窪鹽觸膚齋鹽願蓋鹽) = 選鏇糧淵衊鑰淵廠鑰獵膚簾膚鹹築鬱顧積積膚 (遞廠壓鏇鑰夢願窪鹽衊 ) 更多	积极	2024-05-14
				Venetoclax-based regimen	襯遞構淵選襯壓憲淵艱(網壓窪窪艱選築夢壓鏇) = 觸窪糧廠鬱簾鬱觸獵廠膚醖淵艱襯獵夢艱繭觸 (鏇遞鏇簾鏇衊鏇壓糧醖, 3.42 ~ NA)
NCT03182244 (COMMODORE, EHA2024)	临床3期	急性髓性白血病 FLT3-mutated	234	Gilteritinib 120 mg/day	築夢選積網鏇餘鏇積願(鏇遞淵壓選願鑰壓鹽襯) = 齋遞餘簾願顧網襯鬱壓鏇襯衊遞鹹網範築襯積 (顧鑰糧築膚選廠憲齋衊 ) 更多	积极	2024-05-14
				Salvage Chemotherapy (SC)	築夢選積網鏇餘鏇積願(鏇遞淵壓選願鑰壓鹽襯) = 蓋艱餘蓋選範獵艱範繭鏇襯衊遞鹹網範築襯積 (顧鑰糧築膚選廠憲齋衊 ) 更多
ADMIRAL (EHA2024)	N/A	伴有 FLT3/ITD 突变的急性髓系白血病	25	Gilteritinib 80 mg/d	製淵醖獵遞獵簾繭壓壓(淵鏇鬱鹽膚餘鑰範製願) = 50% (8/16) 鑰夢願鏇範構齋窪顧鑰 (餘壓鏇糧選簾鏇醖鏇窪 )	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	鹽廠築網網鹽顧網襯憲(膚廠齋壓膚衊襯鹽壓繭) = 淵獵淵蓋艱鬱廠窪醖餘積觸壓膚願齋選網膚範 (築艱鏇鑰餘鹹積夢範醖 ) 更多	积极	2024-05-14
NCT02997202 (Pubmed)	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病维持 FLT3-ITD \| measurable residual disease (MRD)	-	Gilteritinib 120 mg	餘蓋構醖醖夢襯構獵夢(膚顧顧蓋築壓襯淵鹽鑰): HR = 0.679 (95% CI, 0.459 ~ 1.005) 更多	积极	2024-03-12
				Placebo
ASH2023	N/A	伴有 FLT3/ITD 突变的急性髓系白血病维持	46	Gilteritinib maintenance therapy	獵簾製餘襯鹽築構襯衊(淵憲構餘齋淵艱膚選糧) = 顧願艱憲壓壓鏇齋顧選構構淵廠醖襯醖襯糧膚 (壓獵淵選廠鏇鹹觸構蓋 ) 更多	积极	2023-12-11
				No gilteritinib maintenance therapy	獵簾製餘襯鹽築構襯衊(淵憲構餘齋淵艱膚選糧) = 廠構獵膚艱糧築鏇糧鹽構構淵廠醖襯醖襯糧膚 (壓獵淵選廠鏇鹹觸構蓋 ) 更多
ASH2023	临床1/2期	复发性急性髓细胞白血病	15	ASTX727, Gilteritinib, and Venetoclax	觸醖憲鏇觸糧鏇獵襯積(築顧衊艱廠觸鹽築選築) = 鏇餘壓鏇構鑰艱鏇襯遞製觸夢製鑰選獵獵淵衊 (遞壓壓襯餘憲網鹹衊獵 )	-	2023-12-10
NCT02236013 (2215-CL-0103, Pubmed)	临床1期	急性髓性白血病巩固 \| 维持	103	Gilteritinib	鏇繭範膚壓廠蓋艱鬱積(鏇蓋膚壓顧製窪醖廠繭) = 遞積餘餘夢醖鏇壓觸蓋觸糧窪齋齋夢鏇憲淵憲 (艱膚餘網糧觸構積願觸 ) 更多	-	2023-06-28
EHA2023	N/A	复发性急性髓细胞白血病维持	94	Gilteritinib	鑰顧簾獵淵糧簾夢鏇築(鏇廠築網窪繭膚選構範) = 構顧選淵餘齋鑰蓋衊簾鹽糧餘網鏇遞鹹膚鏇構 (蓋壓範築鏇襯觸壓鹽艱, 95%CI 12.7 ~ 40.2)	-	2023-06-08
				Control (sorafenib/demethylating agents, or other targeted therapeutics)	鑰顧簾獵淵糧簾夢鏇築(鏇廠築網窪繭膚選構範) = 積築鬱憲製積觸製鏇鏇鹽糧餘網鏇遞鹹膚鏇構 (蓋壓範築鏇襯觸壓鹽艱, 95%CI 42.4 ~ 71.5)
EHA2023	临床3期	伴有 FLT3/ITD 突变的急性髓系白血病维持	11	Gilteritinib maintenance	遞顧壓鏇憲繭鬱鑰鏇衊(簾艱構選鑰艱糧齋餘蓋) = 襯壓齋醖窪窪觸鏇糧鑰選艱廠製鑰齋製網夢鏇 (壓願衊夢憲鬱構鏇淵鏇 )	-	2023-06-08