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A first-in-human study of the anti-inflammatory profibrinolytic TMS-007, an SMTP family triprenyl phenol
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  • Takashi Moritoyo,
  • Naoko Nishimura,
  • Keiko Hasegawa,
  • Ishii Shinya,
  • Kenji Kirihara,
  • Munenori Takata,
  • Akiko Kishi-Svensson,
  • Yumi Umeda-Kameyama,
  • Shuichi Kawarasaki,
  • Ryoko Ihara,
  • Chie Sakanaka,
  • Yurie Wakabayashi,
  • Kuniyasu Niizuma,
  • Teiji Tominaga,
  • Tsutomu Yamazaki,
  • Keiji Hasumi
Takashi Moritoyo
The University of Tokyo Hospital

Corresponding Author:[email protected]

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Naoko Nishimura
TMS Co., Ltd.
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Keiko Hasegawa
TMS Co., Ltd.
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Ishii Shinya
The University of Tokyo Hospital
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Kenji Kirihara
The University of Tokyo Hospital
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Munenori Takata
The University of Tokyo Hospital
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Akiko Kishi-Svensson
The University of Tokyo Hospital
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Yumi Umeda-Kameyama
The University of Tokyo Hospital
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Shuichi Kawarasaki
The University of Tokyo Hospital
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Ryoko Ihara
The University of Tokyo Hospital
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Chie Sakanaka
The University of Tokyo Hospital
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Yurie Wakabayashi
The University of Tokyo Hospital
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Kuniyasu Niizuma
Tohoku University Graduate School of Medicine
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Teiji Tominaga
Tohoku University Graduate School of Medicine
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Tsutomu Yamazaki
The University of Tokyo Hospital
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Keiji Hasumi
Tokyo University of Agriculture and Technology
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Abstract

Background: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action mediated by soluble epoxide hydrolase inhibition contributes to the efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window while reducing hemorrhagic transformation. Aims: To evaluate the safety, pharmacokinetics, and pharmacodynamics of TMS-007 in healthy volunteers. Methods: A randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. There were 6 cohorts planned, but 5 were completed. In each cohort (n = 8), individuals were randomized to receive one of 5 doses of TMS-007 (3, 15, 60, 180, or 360 mg; n = 6) or placebo (n = 2). Results: TMS-007 was generally well-tolerated, and no serious adverse events attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed in brain MRI analysis, and no bleeding-related responses in laboratory testing were found. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor 2-antiplasmin levels were unchanged after the TMS-007 dosing. A slight increase in the plasma level of plasmin-α2-antiplasmin complex, an index of plasmin formation, was observed in some subjects who received 360 mg of TMS-007 (≈ 6 mg kg−1). Conclusions: TMS-007 is generally well-tolerated and exhibits favorable pharmacokinetic profiles that warrant further clinical development.
23 Sep 2022Submitted to British Journal of Clinical Pharmacology
26 Sep 2022Submission Checks Completed
26 Sep 2022Assigned to Editor
30 Sep 2022Reviewer(s) Assigned
14 Oct 2022Review(s) Completed, Editorial Evaluation Pending
17 Oct 2022Editorial Decision: Revise Minor
15 Nov 20221st Revision Received
16 Nov 2022Submission Checks Completed
16 Nov 2022Assigned to Editor
16 Nov 2022Review(s) Completed, Editorial Evaluation Pending
17 Nov 2022Editorial Decision: Revise Minor
24 Nov 20222nd Revision Received
24 Nov 2022Submission Checks Completed
24 Nov 2022Assigned to Editor
24 Nov 2022Review(s) Completed, Editorial Evaluation Pending
05 Dec 2022Editorial Decision: Accept
Jun 2023Published in British Journal of Clinical Pharmacology volume 89 issue 6 on pages 1809-1819. 10.1111/bcp.15651