TM-5614(TM-5614) - 药物靶点：PAI-1_在研适应症：黑色素瘤，费城染色体阳性慢性粒细胞白血病，骨软化_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

PAI-1

作用方式

抑制剂

作用机制

PAI-1抑制剂(纤维蛋白溶酶原激活质抑制物-1抑制剂)

治疗领域

肿瘤血液及淋巴系统疾病皮肤和肌肉骨骼疾病+ [4]

在研适应症

黑色素瘤费城染色体阳性慢性粒细胞白血病骨软化+ [5]

非在研适应症-

原研机构

Hamamatsu University School of Medicine

在研机构

Renascience, Inc.

Hamamatsu University School of Medicine

非在研机构

Tohoku University

权益机构

Renascience, Inc.

Daiichi Sankyo Co., Ltd.

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

11

项与 TM-5614 相关的临床试验

JPRN-jRCT2021230022

/ Recruiting临床2期IIT

A phase II investigator-initiated clinical trial of PAI-1 inhibitor (TM5614) for systemic sclerosis-associated interstitial lung disease under immunosuppressive treatment

开始日期2023-09-06

申办/合作机构-

JPRN-jRCT2031220084

/ Not yet recruiting临床3期IIT

Phase 3, randomized, double-blind study of the efficacy of TM5614 in combination with tyrosine kinase inhibitors in chronic phase chronic myelogenous leukemia patients

开始日期2022-07-29

申办/合作机构-

JPRN-jRCTs031210704

/ Recruiting临床2期IIT

Clinical trials investigating the efficacy and safety of TM5614 for congenital FGF23-related hypophosphatemic rickets / osteomalacia

开始日期2022-03-28

申办/合作机构-

100 项与 TM-5614 相关的临床结果

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100 项与 TM-5614 相关的转化医学

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100 项与 TM-5614 相关的专利（医药）

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11

项与 TM-5614 相关的文献（医药）

2025-03-01·Biomedical Journal

Significance of PAI-1 on the development of skin cancer: optimal targets for cancer therapies

Article

作者: Fujimura, Taku

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that plays a critical role in cancer progression, particularly in skin cancers. PAI-1 is widely recognized for its role in inhibiting fibrinolysis; however, emerging evidence suggests that it also contributes to tumor progression through multiple mechanisms, including tumor angiogenesis, immunomodulation, and stromal cell regulation. In the tumor microenvironment (TME), PAI-1 influences tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), promoting an immunosuppressive environment that supports cancer growth and therapy resistance. Furthermore, PAI-1 has been implicated in the regulation of programmed death-ligand 1 (PD-L1) expression via the JAK/STAT signaling pathway, thereby influencing immune evasion in various skin cancers. The significance of PAI-1 as a therapeutic target has been demonstrated in melanoma and other cutaneous malignancies, where inhibition of PAI-1 has shown promise in overcoming resistance to immune checkpoint inhibitors. Additionally, clinical trials evaluating PAI-1 inhibitors, such as TM5614, highlight its potential as an adjunctive therapy for melanoma and cutaneous angiosarcoma. This review comprehensively explores PAI-1's role in skin cancer progression, its influence on tumor-stromal interactions, and its potential as a therapeutic target.

2024-12-23·British Journal of Dermatology

Decreased interleukin 4 serum levels correlate with plasminogen activator inhibitor-1 inhibitor TM5614 efficacy in patients with malignant melanoma refractory to anti-programmed cell death protein-1 antibodies: post hoc study of the TM5614-MM trial

Article

作者: Amagai, Ryo ; Kambayashi, Yumi ; Maekawa, Masamitsu ; Watanabe, Masahiro ; Kitayama, Chisako ; Tada, Satsuki ; Asano, Yoshihide ; Yamazaki, Emi ; Fujimura, Taku ; Mano, Nariyasu ; Takahashi-Watanabe, Manami

We previously reported that a combination of the PAI-1 inhibitor TM5614 and nivolumab resulted in a 25.9% response rate in patients with anti-PD-1 antibody failure. We therefore comprehensively evaluated the serum levels of chemokines and cytokines in patients enrolled in the protocol per set cohort of the TM5614-MM clinical trial (jRCT2021210029). Our present study revealed significant reductions in IL-4, IL-16 and CXCL2 in the response group treated with TM5614. Our findings suggest that the induction of an antitumour response in our previous clinical trial was due to the activation of tumour-associated macrophages through the blockade of M2 polarization and the reduction of monocytic myeloid-derived suppressor cells in the tumour-bearing host.

2024-10-17·British Journal of Dermatology

A phase II multicentre study of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab for treating anti-programmed cell death 1 antibody-refractory malignant melanoma: TM5614-MM trial

Article

作者: Asano, Yoshihide ; Yoshino, Koji ; Yahata, Takashi ; Matsushita, Shigeto ; Fukushima, Satoshi ; Kato, Hiroshi ; Muto, Yusuke ; Otsuka, Atsushi ; Ishizuki, Shoichiro ; Amagai, Ryo ; Yamazaki, Emi ; Fujisawa, Yasuhiro ; Fujimura, Taku ; Kambayashi, Yumi ; Miyata, Toshio

AbstractBackgroundAnti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma.MethodsThe TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0–4 weeks) and 180 mg once daily (5–8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614.ResultsThirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9–44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort.ConclusionsTM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma.

100 项与 TM-5614 相关的药物交易

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研发状态

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
黑色素瘤	临床3期	日本	Renascience, Inc.	-
费城染色体阳性慢性粒细胞白血病	临床3期	日本	Renascience, Inc.	-
骨软化	临床2期	日本	Renascience, Inc.	2022-03-28
低磷血症佝偻病	临床2期	日本	Renascience, Inc.	2022-03-28
新型冠状病毒感染	临床2期	日本	Renascience, Inc.	-
系统性硬化相关的间质性肺病	临床2期	日本	Renascience, Inc.	-
非小细胞肺癌	临床2期	日本	Renascience, Inc.	-
肉瘤	临床2期	日本	Renascience, Inc.	-

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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


JPRN-jRCT2031190071 (Pubmed) 人工标引	临床2期	费城染色体阳性慢性粒细胞白血病	33	TM5614	襯膚構膚鏇壓簾鏇鬱鹹(製壓夢鹹襯艱艱襯簾艱) = 鑰夢構製廠積蓋簾獵積齋餘膚顧鹹膚廠膚構鑰 (選艱衊觸憲獵壓鹹簾構, 18.0 ~ 51.8)	积极	2022-09-23