他米巴罗汀(Tamibarotene) - 药物靶点：RARα_在研适应症：急性早幼粒细胞白血病，RARα阳性骨髓增生异常综合征，常染色体显性多囊肾病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Amnolake、Retinobenzoic acid、Tamibaro

+ [19]

靶点

RARα

作用机制

RARα激动剂(维甲酸受体α激动剂)

治疗领域

肿瘤血液及淋巴系统疾病其他疾病+ [2]

在研适应症

急性早幼粒细胞白血病RARα阳性骨髓增生异常综合征常染色体显性多囊肾病+ [1]

非在研适应症

晚期肝细胞癌晚期非小细胞肺癌乳腺癌+ [7]

原研机构

Nippon Shinyaku Co., Ltd.

在研机构

Syros Pharmaceuticals, Inc.

Rege Nephro Co. Ltd.初创企业Toko Pharmaceutical Industrial Co. Ltd.

非在研机构

LadRx Corp.R&R, Inc.

Zeria Pharmaceutical Co., Ltd.

最高研发阶段批准上市

首次获批日期

日本 (2005-04-11),

急性早幼粒细胞白血病

最高研发阶段(中国)-

特殊审评孤儿药 (日本)、快速通道 (美国)

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结构

分子式C22H25NO3

InChIKeyMUTNCGKQJGXKEM-UHFFFAOYSA-N

CAS号94497-51-5

关联

31

项与他米巴罗汀相关的临床试验

NCT06289998 / Recruiting临床2期

Phase IIa Clinical Trial of Tamibarotene in Patients With Autosomal Dominant Polycystic Kidney Disease

Clinical trial of tamibarotene in patients with Autosomal Dominant Polycystic Kidney Disease

开始日期2023-12-22

申办/合作机构

Rege Nephro Co. Ltd.初创企业

JPRN-jRCT2011230055 / Suspended临床2期IIT

Phase IIa clinical trial of tamibarotene in patients with Autosomal Dominant Polycystic Kidney Disease

开始日期2023-12-12

申办/合作机构-

NCT06085638 / Withdrawn临床1/2期IIT

Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia

To learn if adding venetoclax to the chemotherapy combination of tamibarotene and azacitidine is more effective than tamibarotene and azacitidine alone in treating higher-risk CMM

开始日期2023-09-14

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与他米巴罗汀相关的临床结果

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100 项与他米巴罗汀相关的转化医学

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100 项与他米巴罗汀相关的专利（医药）

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264

项与他米巴罗汀相关的文献（医药）

2024-08-01·Clinical Immunology

Integrated multi-omics analysis and machine learning developed diagnostic markers and prognostic model based on Efferocytosis-associated signatures for septic cardiomyopathy

Article

作者: Lin, Jibin ; Wang, Boyuan ; He, Shaolin ; Li, Xuelian ; Guo, Xiaopeng ; Wei, Yumiao ; Jiang, Shijiu

Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We used integrated multi-omics analysis to explore the clinical and genetic roles of efferocytosis in SCM. We identified six module genes (ATP11C, CD36, CEBPB, MAPK3, MAPKAPK2, PECAM1) strongly associated with SCM, leading to an accurate predictive model. Subgroups defined by EFFscore exhibited distinct clinical features and immune infiltration levels. Survival analysis showed that the C1 subtype with a lower EFFscore had better survival outcomes. scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from sepsis patients identified four genes (CEBPB, CD36, PECAM1, MAPKAPK2) associated with high EFFscores, highlighting their role in SCM. Molecular docking confirmed interactions between diagnostic genes and tamibarotene. Experimental validation supported our computational results. In conclusion, our study identifies a novel efferocytosis-related SCM subtype and diagnostic biomarkers, offering new insights for clinical diagnosis and therapy.

2024-07-22·British Journal of Cancer

Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade

Article

作者: Owaki, Takayuki ; Ando, Ryota ; Matsukawa, Yoshihisa ; Murakami, Takashi ; Maeda, Motohiro ; Sassa, Naoto ; Yamamoto, Masami ; Ishikawa, Takuya ; Akashi, Tomohiro ; Kato, Katsuhiro ; Tsukamoto, Tetsuya ; Takahashi, Masahide ; Yuguchi, Yuri ; Mii, Shinji ; Kawashima, Hiroki ; Hinohara, Kunihiko ; Enomoto, Atsushi ; Akamatsu, Shusuke ; Iida, Tadashi ; Ishii, Makoto ; Sano, Tomoyasu ; Mizutani, Yasuyuki ; Shiraki, Yukihiro ; Hase, Tetsunari ; Esaki, Nobutoshi ; Miyai, Yuki ; Nomura, Sachiyo

AbstractBackgroundThe proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs.MethodsWe investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models.ResultsHigh infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs.ConclusionOur data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

2024-06-28·Medicine

Identification of shared disease marker genes and underlying mechanisms between rheumatoid arthritis and Crohn disease through bioinformatics analysis

Article

作者: Peng, Peifei ; Shen, Ying

As chronic autoimmune inflammatory diseases, rheumatoid arthritis (RA) and Crohn disease (CD) are closely associated and display a significant positive correlation. However, the underlying mechanisms and disease markers responsible for their cooccurrence remain unknown and have not been systematically studied. Therefore, this study aimed to identify key molecules and pathways commonly involved in both RA and CD through bioinformatic analysis of public sequencing databases. Datasets for RA and CD were downloaded from the GEO database. Overlapping genes were identified using weighted gene co-expression network analysis and differential analysis crossover, and enrichment analysis was conducted for these genes. Protein-protein interaction networks were then constructed using these overlapping genes to identify hub genes. Expression validation and receiver operating characteristic curve validation were performed for these hub genes using different datasets. Additionally, the immune cell correlation, single-cell expression cluster, and the immune cell expression cluster of the core gene were analyzed. Furthermore, upstream shared microRNAs (miRNA) were predicted and a miRNA-gene network was constructed. Finally, drug candidates were analyzed and predicted. These core genes were found to be positively correlated with multiple immune cells that are infiltrated by the disease. Analysis of gene expression clusters revealed that these genes were mostly associated with inflammatory and immune responses. The miRNA-genes network analysis suggested that hsa-miR-31-5p may play an important role in the common mechanism of RA and CD. Finally, tamibarotene, retinoic acid, and benzo[a]pyrene were identified as potential treatment options for patients with both RA and CD. This bioinformatics study has identified ITGB2, LCP2, and PLEK as key diagnostic genes in patients with both RA and CD. The study has further confirmed that inflammation and immune response play a central role in the development of both RA and CD. Interestingly, the study has highlighted hsa-miR-31-5p as a potential key player in the common mechanism of both diseases, representing a new direction in research and a potential therapeutic target. These shared genes, potential mechanisms, and regulatory networks offer new opportunities for further research and may provide hope for future treatment of patients with both RA and CD.

92

项与他米巴罗汀相关的新闻（医药）

2024-11-15

·佰傲谷BioValley

Ⅲ期临床失败，触发贷款违约

近日，Syros Pharmaceuticals公司宣布，tamibarotene治疗新诊断RARA基因过表达高危骨髓增生异常综合征（HR-MDS）患者的III期临床SELECT-MDS-1未能达到主要终点目标，与对照组相比，Tamibarotene+Azacitidine联合疗法未能显著提高某些MDS患者的完全缓解率。 tamibarotene是全司押注希望的管线，先前公司停止在新诊断RARA过表达AML患者招募已经大大刺激了市场的神经，经历了70%的大跌。 MDS是tamibarotene目前推的最快的适应症，Syros指望着靠着这个临床成功来摆脱财务困境。 SELECT-MDS-1临床的失败再次加剧了市场的失望情绪，该临床结果公布后，公司股价急剧下跌，跌幅高达92%。希望管线破灭 tamibarotene是一款口服视黄酸受体α (RARα)激动剂，最早日本由Nippon Shinyaku公司开发，2005年6月就已在日本被批准上市，用于治疗急性早幼粒细胞白血病。视黄酸受体α是一种核受体，由RARA基因编码，大约50%的MDS患者和30%的AML患者表现出RARA基因的过表达。当RARA的表达量超过其严格控制的天然配体时，骨髓中的细胞可能无法分化成健康的髓细胞，从而导致血液恶性肿瘤。 Tamibarotene通过与过表达的RARA结合，帮助恢复髓细胞分化。2023年，Tamibarotene获得了FDA快速通道指定，用于治疗RARA过表达的高风险MDS患者。 SELECT-MDS-1主要评估Tamibarotene+Azacitidine对比Azacitidine+安慰剂在新诊断RARA过表达高危骨髓增生异常综合征（HR-MDS）患者中的安全性和有效性。结果显示，接受Tamibarotene+Azacitidine治疗的患者CR率为23.8%，而对照组（Azacitidine+安慰剂）的CR率为18.8%，虽然CR率前者更高，但是没有达到统计学显著差异。公司首席执行官Conley Chee在一份声明中表示了对这一结果的深感失望，公司将停止SELECT-MDS-1临床试验，在完成对后期临床数据的审查后评估下一步方案。此外，Tamibarotene在另一项适应症—AML中的临床疗效更加不理想。针对40名新诊断RARA过表达AML患者的预先设定分析结果显示(SELECT-AML-1)，Tamibarotene三联疗法组患者的CR/CRi率不及对照组（65% VS 70%)，公司认为在最终分析中，Tamibarotene三联疗法组显示出优势的可能性不大。在2024年8月，Syros宣布计划停止SELECT-AML-1的患者招募。该消息公布后，公司股价暴跌70%。从公司两次的股价反应看出，Tamibarotene连个临床试验挫折对公司打击之大，尤其是公司把已经十分紧张的资金都押注Tamibarotene上。 35%的裁员重组 Syros Pharmaceuticals由知名风险投资公司Flagship Pioneering孵化，成立于2011年，专注于基因调控疗法的开发。2022年9月收购了TYME公司后在纳斯达克交易市场上市。在公司去年重组前，共有8条管线在研，包括共2个临床后期管线和6个早期临床/临床前管线。然而去年，两个合作方的相继离开给公司打击很大。 2023年7月和8月，辉瑞（镰状细胞病和β-地中海贫血）和Incyte（骨髓增殖性肿瘤）相继终止与公司的合作协议，里程碑款项已经泡汤。同时公司Syros财务状况也堪忧，截至2023年9月30日，现金、现金等价物和有价证券为1.12亿美元。去年10月，Syros进行了重组来消减开支，临床前管线一律砍掉，只剩下Tamibarotene在内的三条管线在研，其中还暂停了SY-2101在急性早幼粒细胞白血病的临床开发。作为重组的一部分，还裁员了35%，公司的首席执行官、首席科学官也在此次人事变动之列。触发违约条款更加雪上加霜的是，SELECT-MDS-1临床失败还构成与Oxford Finance LLC贷款协议的违约。早在2020年，公司与Oxford Finance LLC签订了一项贷款和担保协议，该协议中协定了一些违约条款，其中就包括SELECT-MDS-1未达到临床主要终点。 Tamibarotene的失败也基本阻断了公司的再融资能力，2025年11月1日起，公司就要开始偿还本金。截至2024年9月30日，Syros现金及其现金等价物只有0.58亿美元。参考出处 https://www.biospace.com/drug-development/syros-crashes-over-90-on-late-stage-mds-fail-loan-default https://ir.syros.com/press-releases/detail/311/syros-reports-third-quarter-2024-financial-results-and https://www.nasdaq.com/press-release/syros-reports-third-quarter-2023-financial-results-and-provides-a-corporate-update 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

临床3期临床失败临床结果并购

2024-11-13

·EndPoints

Syros' shares plummet as blood cancer drug fails again

Syros Pharmaceuticals’ share price nosedived after its last drug candidate flunked a trial in hematological malignancies for the second time in recent months. In a 190-participant Phase 3 trial, the biotech’s tamibarotene plus azacitidine led to a 23.8% complete response rate in people with newly diagnosed higher-risk myelodysplastic syndromes and RARA gene overexpression versus 18.8% for azacitidine plus placebo. The result was not statistically significant with a p-value of 0.2084, according to a Tuesday release . Syros’ share price $SYRS was down 80% premarket Wednesday. The trial failure triggers a default event under the terms of Syros’ secured loan facility with Oxford Finance. The biotech plans to stop the trial, analyze the data and “evaluate the next steps,” CEO Conley Chee said in the release. The study flop comes just three months after an August disappointment for a tamibarotene triplet regimen in a Phase 2 study of newly diagnosed, unfit patients with acute myeloid leukemia and RARA gene overexpression. Tamibarotene is a retinoid acid receptor alpha agonist. “Tamibarotene’s demise brings to an end Syros’ last clinical program,” TD Cowen analysts said in a Wednesday note, adding the company is likely to end all development of the drug. The biotech previously stopped work on two other clinical candidates, SY-2101 and SY-5609, although it said on an earnings call last month it is looking for licensing opportunities for the latter. The company reported $58.3 million in cash and equivalents as of the end of September.

临床3期临床2期临床失败

2024-11-13

·Firstwordpharma

Another study failure puts brakes on Syros’ tamibarotene in blood cancers

After flunking a mid-stage study in front-line acute myeloid leukaemia three months back, Syros Pharmaceuticals’ oral retinoic acid receptor alpha (RARα) agonist, tamibarotene, has hit yet another and a potentially terminal roadblock. This time, the investigational therapy in combination with azacitidine failed to meet the primary endpoint of a late-stage study involving patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) harbouring RARA gene overexpression – triggering a loan default for the company with Oxford Finance LLC.“We are deeply disappointed by this outcome, particularly for the HR-MDS patients who are seeking a new treatment option for this challenging disease,” said CEO Conley Chee, adding that while Syros will terminate the trial, it will continue to review exisiting data and chart out a further course of action.The Phase III SELECT-MDS-1 study assessed the efficacy and safety of tamibarotene plus azacitidine versus placebo plus azacitidine in RARA-overexpressed patients with HR-MDS, the main goal being the complete response (CR) rate in the first 190 participants. Results showed the tamibarotene plus azacitidine arm demonstrated a CR rate of 23.8% in the initial 190 patients, compared with the placebo plus azacitidine arm’s 18.8%, with no statistically significant difference between the groups. Meanwhile, the safety analysis of all enrolled 245 patients showed the tamibarotene combination was generally well-tolerated, with an adverse event profile comparable to previous studies.Facing financial troubles in the wake of failed deals with Incyte and Pfizer in 2023, the company cut 35% of its workforce last October and discontinued most clinical programmes, including SY-2101 for acute promyelocytic leukaemia, to focus on its lead asset, tamibarotene.

临床3期临床结果财报

100 项与他米巴罗汀相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01418	他米巴罗汀	L01X	DB04942

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
急性早幼粒细胞白血病	日本	Toko Pharmaceutical Industrial Co. Ltd.	2005-04-11

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
RARα阳性骨髓增生异常综合征	临床3期	波兰	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	奥地利	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	匈牙利	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	捷克	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	加拿大	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	意大利	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	德国	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	西班牙	Syros Pharmaceuticals, Inc.	2021-02-08
RARα阳性骨髓增生异常综合征	临床3期	法国	Syros Pharmaceuticals, Inc.	2021-02-08
银屑病	临床2期	日本	-	-

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临床结果

适应症

分期

评价

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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


NCT04797780 (SELECT-MDS-1, Company_Website) 人工标引	临床3期	高危骨髓增生异常综合征	190	Tamibarotene in combination with azacitidine	(遞築窪鬱選鑰夢鬱衊積) = 網廠蓋鏇壓選齋艱鹽醖獵齋夢獵艱鏇鏇繭鏇襯 (襯糧顧鹹鬱壓鹽衊艱積, 16.7 ~ 32.2) 未达到	不佳	2024-11-12
				Placebo and azacitidine	(遞築窪鬱選鑰夢鬱衊積) = 積遞醖膚蓋遞淵窪齋淵獵齋夢獵艱鏇鏇繭鏇襯 (襯糧顧鹹鬱壓鹽衊艱積, 10.1 ~ 30.5) 未达到
SELECT-AML-1 (NEWS) 人工标引	临床2期	RARA阳性急性髓性白血病	19	tamibarotene+venetoclax+azacitidine	(選觸顧廠選艱艱獵獵範) = 膚膚蓋製餘製網艱膚繭鑰衊製艱鹹簾淵襯鹽鏇 (網醖製壓鏇廠鹹願餘衊 ) 更多	积极	2023-12-07
				venetoclax+azacitidin	(選觸顧廠選艱艱獵獵範) = 鹽鏇齋願構憲遞簾獵鏇鑰衊製艱鹹簾淵襯鹽鏇 (網醖製壓鏇廠鹹願餘衊 ) 更多
NCT02807558 (Pubmed)	临床2期	急性髓性白血病	51	Tamibarotene plus azacitidine	餘鑰鹹鏇範糧鑰窪蓋遞(鹹醖繭顧醖糧獵網顧衊) = hematologic AEs were comparable to single agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine 顧襯顧製網鬱網構獵築 (遞獵築簾壓鏇顧獵窪膚 ) 更多	-	2022-12-07
NCT04905407 (SELECT-AML-1, ASH2022) 人工标引	临床2期	RARA阳性急性髓性白血病一线 RARA	6	Venetoclax+Azacitidine+Tamibarotene	(鑰夢鑰範餘襯餘構鬱憲) = occurring in more than one patient was febrile neutropenia 積獵鹽壓廠鏇選範觸齋 (淵襯網遞製網鹽顧醖獵 ) 更多	积极	2022-11-15
				Venetoclax+Azacitidine
NCT04905407 (SELECT AML-1, EHA2022)	临床2期	RARA阳性急性髓性白血病	80	Tamibarotene/Venetoclax/Azacitidine	蓋簾獵餘窪簾窪積壓膚(築淵壓廠餘範鏇顧願顧) = 網鏇繭選鏇餘選衊鹽鹹顧鹹廠觸淵顧艱願餘壓 (鹽簾憲獵醖選積獵淵願 )	-	2022-05-12
NCT02807558 (ASH2020) 人工标引	临床2期	RARA阳性急性髓性白血病一线 RARA	51	Azacitidine+SY-1425 (RARA+)	(遞觸範築鬱艱鑰膚糧廠) = febrile neutropenia (27%), pyrexia (12%), pneumonia (12%), and sepsis (10%). 衊壓願齋鏇夢繭積窪蓋 (襯選蓋顧廠襯醖鹹襯願 ) 更多	积极	2020-11-05
				Azacitidine+SY-1425 (RARA-)
NCT02807558 (ASH2020) 人工标引	临床2期	复发性急性髓细胞白血病 RARA Positive	28	Azacitidine+SY-1425	(獵選憲鹽艱鹽蓋範顧鬱) = 壓廠願艱繭遞夢淵衊遞構壓窪憲憲範襯觸顧齋 (廠獵繭窪製齋遞廠廠獵 ) 更多	积极	2020-11-05
NCT02807558 (ASH2018) 人工标引	临床2期	急性髓性白血病 \| 骨髓增生异常综合征	10	azacitidine+SY-1425	(鑰構觸簾願鏇構淵壓觸) = febrile neutropenia (44%), and hypertriglyceridemia, pruritus, abdominal pain and peripheral edema (33% each). 壓夢齋鏇構製膚願窪獵 (鏇選艱繭顧遞遞艱網選 )	积极	2018-11-29
				daratumumab+SY-1425
NCT02807558 (EHA2017)	临床2期	急性髓性白血病 \| 骨髓增生异常综合征	155	SY-1425 and azacitidine	鹽遞遞醖獵蓋網蓋願壓(築網壓鏇鹹鹹築築願鏇) = 積獵鑰遞齋鹹顧築襯齋壓鏇鑰鑰鹹襯鑰壓憲淵 (淵遞壓鬱鏇鏇繭範鬱淵 )	-	2017-05-18
not provided (EULAR2016)	临床2期	狼疮性肾炎	23	ATRA 10 mg/day	鹹衊築膚鹽窪構鹹構鬱(簾遞鏇蓋餘鑰選觸艱遞) = 衊網顧築廠願壓襯鑰餘膚襯憲醖願鹽鹹蓋簾膚 (製衊網顧觸觸糧夢鏇壓 ) 更多	积极	2016-06-08
				AM80 4 mg/day	鹹衊築膚鹽窪構鹹構鬱(簾遞鏇蓋餘鑰選觸艱遞) = 夢鹽醖衊觸選簾襯膚艱膚襯憲醖願鹽鹹蓋簾膚 (製衊網顧觸觸糧夢鏇壓 ) 更多