Soluble epoxide hydrolase is a widely distributed bifunctional enzyme that contains N-terminal phosphatase (N-phos) and C-terminal epoxide hydrolase (C-EH) domains. C-EH hydrolyzes anti-inflammatory epoxy-fatty acids to corresponding diols and contributes to various inflammatory conditions. However, N-phos has been poorly examined. In peritoneal macrophages, the N-phos inhibitor amino-hydroxybenzoic acid (AHBA) seemed to primarily interrupt the dephosphorylation of lysophosphatidates and broadly attenuated inflammation-related functions. AHBA activated intrinsic lysophosphatidate and thromboxane A2 receptors by altering lipid-metabolite distribution; downstream the signaling, phospholipase C was facilitated to dampen intracellular Ca²⁺ stores and AKT kinase (protein kinase B) was activated to presumably inhibit inflammatory gene expression. Our data suggest that N-phos maintains steady-state phospholipid turnover connecting autocrine signaling and is a prospective target for controlling inflammatory responses in macrophages.

30 Mar 2023·International journal of molecular sciences

SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis.

Article

Author: Shibata, Keita ; Yamagishi, Sho-Ichi ; Higashimoto, Yuichiro ; Mori, Yusaku ; Terasaki, Michishige ; Nobe, Koji ; Fukui, Tomoyasu ; Hasumi, Keiji ; Matsui, Takanori ; Ohara, Makoto ; Saito, Tomomi

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe^-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe^-/- mice ex vivo. Although administration of SMTP-44D to Apoe^-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe^-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe^-/- mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.

01 Feb 2022·Stroke

Abstract WMP1: Results From A Phase 2a Study Of TMS-007, An SMTP Family Anti-inflammatory Prothrombolytic, On Patients With Acute Ischemic Stroke Up To 12 Hours After Onset

Author: Tominaga, Teiji ; Wald, Michael ; Hasumi, Keiji ; Nishimura, Naoko ; Niizuma, Kuniyasu ; Hasegawa, Keiko

Approved thrombolytic agents are limited in their use for the treatment of acute ischemic stroke (AIS) due to their benefit-risk profile beyond 4.5 h since last known normal (LKN). TMS-007 is a small molecule, SMTP family member with a novel mode of action: promotion of plasminogen-fibrin binding to enhance physiological thrombolysis while inhibiting inflammation at the site of thrombosis. TMS-007 may extend the treatment time window based on nonclinical pharmacological evidence. We evaluated TMS-007 in a randomized, placebo-controlled, double-blind, dose-escalation phase 2a study. TMS-007 or placebo was administered as a single intravenous infusion at a dose of 1, 3, or 6 mg/kg to AIS patients who were ineligible for t-PA or thrombectomy within 12 h of LKN. The number of patients allocated to placebo and TMS-007 at doses 1, 3, and 6 mg/kg were 38, 6, 18, and 28, respectively. The combined TMS-007 dosing group (Group T; n = 52) was compared with placebo group (Group P; n = 38). The average age was ~72 years old and time since LKN to treatment was ~9 h in both groups (not significantly different). The incidence of symptomatic intracranial hemorrhage (ICH) with worsening NIHSS score of <=4 points per site physician (primary endpoint) was 0% in Group T compared to 3% (n = 1) in Group P. The number of ICH event within 24 h, including symptomatic and asymptomatic, was 6 in Group T and 5 in Group P. Total number of AE was 207 in Group T and 162 in Group P, with gastrointestinal diseases as the most common events in both groups (n = 40 and 32, respectively). TMS-007 was associated with a significant improvement in functional independence at 90 days (secondary endpoint): 40% of patients in Group T achieved a score of 0 or 1 on the mRS, compared to 18% in Group P (p < 0.05). Recanalization, defined by any improvement in arterial occlusive lesion score on magnetic resonance angiography in those with visible occlusion at baseline per central neuroradiologist, occurred in 58.3% (14/24) of Group T compared to 26.7% (4/15) of Group P (odds-ratio, 4.23; 95% CI, 0.99 to 18.07). TMS-007 was generally safe and well tolerated up to 6 mg/kg. TMS-007 may expand the treatment time window for the treatment of AIS. Due to the small study size, more data on efficacy is warranted in patients with visible occlusion.

News (Medical) associated with TMS Co., Ltd.

12 Jan 2024

·firstwordpharma.com

Ji Xing takes Biogen’s clinical stroke candidate off pause

Ji Xing Pharmaceuticals acquired global rights to Biogen’s acute ischaemic stroke treatment on Friday, following a pause in its development last year.The Chinese drug developer, which is mostly focused on cardiovascular diseases, will pay undisclosed upfront and milestone payments for BIIB131, a small molecule plasminogen activator designed to break down blood clots and inhibit local inflammation at the site of thrombosis. Biogen has said this combination could allow for an extended treatment window compared to existing thrombolytic agentsHowever, last April, Biogen decided to pause the initiation of a Phase IIb study of BIIB131 as part of a wider pipeline trim. The company paid $22 million for an option and subsequent licensing of BIIB131 from Japanese drugmaker TMS in 2021.

License out/inPhase 2

12 Jan 2024

·www.pharmaceutical-technology.com

Ji Xing acquires Biogen’s BIIB131 for acute ischemic stroke

BIIB 131 is aimed at treating acute ischemic stroke (AIS) patients. Credit: CGN089/Shutterstock.com. Ji Xing Pharmaceuticals has acquired Biogen ’s investigational drug, BIIB 131, aimed at advancing worldwide clinical development to treat AIS. BIIB 131’s mechanism of action focuses on restoring blood flow after an acute stroke, which could lead to improved patient outcomes. The drug, which has shown potential in a Phase II trial in Japan, has both thrombolytic and anti-inflammatory properties, potentially extending the treatment window beyond existing standards. Subjects who received BIIB 131 demonstrated substantially better clinical outcomes at 90 days compared with those who were treated with a placebo. These results were supported by additional safety and angiographic data. The terms of the acquisition include an undisclosed upfront payment as well as payments on meeting milestones and royalty payments on worldwide product sales. Ji Xing Pharmaceuticals CEO and board executive director Sandy Mou stated: “BIIB 131 represents a potential breakthrough for a critical condition (AIS) that has not seen any meaningful pharmacologic innovation for almost 30 years. “We hope to prove that BIIB 131 will significantly improve clinical outcomes for AIS patients around the world. “This acquisition will not only enrich JIXING’s pipeline, but also accelerate the execution of our globalisation strategy.” Ji Xing has also entered a strategic partnership with TMS, following the assignment of an option agreement from Biogen to Ji Xing. This will see TMS and Ji Xing join forces on the global development of TMS-007, another new treatment for AIS. TMS will retain royalty-free rights in Japan, while Ji Xing will spearhead its development and commercialisation in other countries. In a Phase IIa trial of TMS-007 in Japan involving 90 patients with AIS, the small molecule has shown statistically significant difference over placebo on a key efficacy endpoint. The proportion of subjects with a modified Rankin Scale 0-1 (no or minimal symptoms) at day 90 was the efficacy goal. Ji Xing has also licensed exclusive rights for JX09 to TMS in Japan. JX09, an oral treatment for resistant and/or uncontrolled hypertension, is expected to enter Phase I clinical trials in 2024.

Clinical ResultPhase 1Phase 2Acquisition

11 Jan 2024

·pipelinereview.com

JIXING Acquires BIIB131 from Biogen to Treat Acute Ischemic Stroke

Jixing Pharmaceuticals will develop investigational drug globally SHANGHAI, China I January 11, 2024 I Ji Xing Pharmaceuticals (“JIXING”), a clinical-stage biopharmaceutical company committed to bringing innovative medicines to underserved patients with serious and life-threatening diseases, announced today the acquisition of BIIB131 from Biogen, for global clinical development. BIIB131 is an investigational drug for acute ischemic stroke (AIS). Its proposed mechanism of action includes both thrombolytic and anti-inflammatory activities. By restoring critical blood flow following acute stroke, it may benefit more patients over current standard of care by extending the otherwise short treatment window. In the prior Phase 2 clinical trial conducted in Japan, patients treated with BIIB 131 had significantly improved clinical outcomes (proportion of patients with no or minimal neurological deficits) at 90 days, compared to placebo. This was further supported by safety and angiographic findings. "Stroke is a serious threat to global health. BIIB 131 represents a potential breakthrough for a critical condition (AIS) that has not seen any meaningful pharmacologic innovation for almost 30 years. We hope to prove that BIIB 131 will significantly improve clinical outcomes for AIS patients around the world”, said Sandy Mou, Board Executive Director and Chief Executive Officer of JIXING. “This acquisition will not only enrich JIXING’s pipeline, but also accelerate the execution of our globalization strategy.” “We believe that BIIB131 has the potential to change the way we treat acute strokes,” said Roderick Wong, MD, Managing Partner and Chief Investment Officer of RTW Investments, LP. “We would like to thank Biogen and TMS for their ongoing partnership and for their efforts to bring this asset to where it is today.” Under the terms of the agreement, JIXING will acquire the program for an undisclosed upfront with potential milestones and royalties on global sales. JIXING is a biopharmaceutical company headquartered in Shanghai committed to bringing innovative science and medicines to underserved patients with serious and life-threatening diseases in China and around the world. Backed by RTW Investments, LP, JIXING was founded in 2019 and partners with global biotechnology companies to develop and commercialize novel, innovative therapeutics to treat unmet medical needs in cardiovascular and ophthalmic diseases. With a strong and further developing asset pipeline, seasoned management team, and patient-centric focus, JIXING is dedicated to delivering a meaningful and lasting impact on patients. JIXING’s cardiovascular portfolio includes 3 assets in late-stage clinical development (aficamten, etripamil, omecamtiv mecarbil) and 1 in pre-clinical stage (JX09). JIXING's ophthalmology portfolio includes 4 assets in late-stage clinical development (varenicline solution nasal spray/US brand name TYRVAYA, OC-02 nasal spray, JX06/LNZ100, JX07/LNZ101) and 1 asset in pre-clinical stage (JX08). For further information about JIXING, please visit www.jixing.com . SOURCE: Ji Xing Pharmaceuticals

Phase 2Clinical ResultAcquisition

100 Deals associated with TMS Co., Ltd.

100 Translational Medicine associated with TMS Co., Ltd.

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Pipeline

Pipeline Snapshot as of 23 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

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IND Application

Phase 2 Clinical

Current Projects

Drug(Targets)	Indications	Global Highest Phase

TMS-007 ( EPHX2 x PLG )	Acute Ischemic Stroke More	Phase 2
TMS-008 ( PLG )	Cachexia More	IND Application
SMTP-44D ( AGER )	Atherosclerosis More	Preclinical
TMS-009 ( PLG )	Kidney Diseases More	Discovery

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