Delving into the Latest Updates on TM-5614 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

RS5614, TM 5614, TM-5614

+ [1]

Target

PAI-1

Action

inhibitors

Mechanism

PAI-1 inhibitors(Plasminogen activator inhibitor 1 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesSkin and Musculoskeletal Diseases+ [4]

Active Indication

MelanomaPhiladelphia chromosome positive chronic myelogenous leukemiaOsteomalacia+ [5]

Inactive Indication-

Originator Organization

Hamamatsu University School of Medicine

Active Organization

Renascience, Inc.

Hamamatsu University School of Medicine

Inactive Organization

Tohoku University

License Organization

Renascience, Inc.

Daiichi Sankyo Co., Ltd.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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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.

23 Dec 2024·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

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

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.

17 Oct 2024·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

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

Abstract:

Background:

Anti-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.

Methods:

The 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.

Results:

Thirty-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.

Conclusions:

TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma.

100 Deals associated with TM-5614

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 3	Japan	Tohoku University	26 Oct 2020
Melanoma	Phase 3	Japan	Tohoku University	26 Aug 2020
Osteomalacia	Phase 2	Japan	Renascience, Inc.	28 Mar 2022
Rickets, Hypophosphatemic	Phase 2	Japan	Renascience, Inc.	28 Mar 2022
COVID-19	Phase 2	Japan	Renascience, Inc.	-
Interstitial lung disease due to systemic disease	Phase 2	Japan	Renascience, Inc.	-
Non-Small Cell Lung Cancer	Phase 2	Japan	Renascience, Inc.	-
Sarcoma	Phase 2	Japan	Renascience, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


JPRN-jRCT2031190071 (Pubmed) Manual	Phase 2	Philadelphia chromosome positive chronic myelogenous leukemia	33	TM5614	nuixrjnnwi(nwrzlejcuc) = okncwuzjbx mbemzrezam (cfldfteyyx, 18.0 - 51.8)	Positive	23 Sep 2022