Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction—Results of the CHIARA MIA 1 Trial

Background Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life‐threatening cardiovascular disease in North America. Post‐DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT. It has recently been shown that mast cells play a crucial role in a DVT murine model. The underlying mechanism involved in the prothrombotic properties of mast cells, however, has yet to be identified. Methods and Results C57BL/6 mice and mouse mast cell protease‐4 (mMCP‐4) genetically depleted mice (mMCP‐4 knockout) were used in 2 mouse models of DVT, partial ligation (stenosis) and ferric chloride–endothelial injury model of the inferior vena cava. Thrombus formation and impact of genetically repressed or pharmacologically (specific inhibitor TY‐51469) inhibited mMCP‐4 were evaluated by morphometric measurements of thrombi immunochemistry (mouse and human DVT), color Doppler ultrasound, bleeding times, and enzymatic activity assays ex vivo . Recombinant chymases, mMCP‐4 (mouse) and CMA‐1 (human), were used to characterize the interaction with murine and human plasmin, respectively, by mass spectrometry and enzymatic activity assays. Inhibiting mast cell–generated mMCP‐4, genetically or pharmacologically, resolves and prevents venous thrombus formation in both DVT models. Inferior vena cava blood flow obstruction was observed in the stenosis model after 6 hours of ligation, in control‐ but not in TY‐51469–treated mice. In addition, chymase inhibition had no impact on bleeding times of healthy or DVT mice. Furthermore, endogenous chymase limits plasmin activity in thrombi ex vivo. Recombinant mouse or human chymase degrades/inactivates purified plasmin in vitro. Finally, mast cell–containing immunoreactive chymase was identified in human DVT. Conclusions This study identified a major role for mMCP‐4, a granule‐localized protease of chymase type, in DVT formation. These findings support a novel pharmacological strategy to resolve or prevent DVT without affecting the coagulation cascade through the inhibition of chymase activity.

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“…Future studies may require the use of novel orally available chymase inhibitors, such as fulacimstat (BAY‐1142524). 18 , 47 , 48 , 49 …”

Section: Discussionmentioning

confidence: 99%

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Lapointe

Vincent

Giguère

et al. 2023

JAHA

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“…Currently, only 1 phase II clinical trial has been registered to assess the safety of chymase inhibition following myocardial infarction ( Table 1 ). 58 …”

Section: Attenuating Specific Innate Immune Responsesmentioning

confidence: 99%

Immunomodulation of Myocardial Fibrosis

Sikking

Stroeks

Marelli‐Berg

et al. 2023

JACC: Basic to Translational Science

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“…For these reasons it can be a potential new target for post-MI therapy. Fulacimstat is an orally existing chymase inhibitor which has a multi-functional anti-remodeling effect that reduces LV disfunction after myocardial infarction ( 9 ).…”

Section: Interstitiummentioning

confidence: 99%

New Targets in Heart Failure Drug Therapy

Correale

Tricarico

Fortunato

et al. 2021

Front. Cardiovasc. Med.

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Despite recent advances in chronic heart failure management (either pharmacological or non-pharmacological), the prognosis of heart failure (HF) patients remains poor. This poor prognosis emphasizes the need for developing novel pathways for testing new HF drugs, beyond neurohumoral and hemodynamic modulation approaches. The development of new drugs for HF therapy must thus necessarily focus on novel approaches such as the direct effect on cardiomyocytes, coronary microcirculation, and myocardial interstitium. This review summarizes principal evidence on new possible pharmacological targets for the treatment of HF patients, mainly focusing on microcirculation, cardiomyocyte, and anti-inflammatory therapy.

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Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction—Results of the CHIARA MIA 1 Trial

Cited by 17 publications

References 19 publications

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Immunomodulation of Myocardial Fibrosis

New Targets in Heart Failure Drug Therapy

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