fulacimstat (BAY1142524) / Bayer - LARVOL DELTA

Chymase inhibition by fulacimstat for venous thrombus resolution without increasing bleeding times (ISTH 2025) - "Drugs currently used to support thrombus resolution include anticoagulants like heparin, warfarin or DOACs, and the fibrinolytic agent alteplase (recombinant tPA). In contrast, in fulacimstat-treated hamsters (administered 24h, post-IVC ligation) no pulmonary emboli were observed. Finally, chymase inhibition significantly increased intra-thrombus localised-plasmin activity ex vivo."

Cardiovascular • Hematological Disorders • Pulmonary Embolism • Respiratory Diseases • Thrombosis

Recombinant chymase inhibits fibrinolysis induced by endogenous plasmin in clotted human blood. (PubMed, Front Immunol) - "These in vitro experiments with human whole blood suggest that mast cell-derived chymase impairs blood clot resolution by interfering with the fibrinolytic activity of endogenous intra-clot plasmin. Our findings provide evidence that recombinant mast cell chymase interferes with endogenous plasmin activity in human whole blood clots in vitro and support the potential of chymase inhibitors, such as fulacimstat, as fibrinolytic agents for thrombotic and thromboembolic disorders."

Journal • Cardiovascular • Hematological Disorders • Pulmonary Embolism • Thrombosis

Opening the Door to a New Treatment Paradigm: The Re-emergence of Chymase Inhibitors. (PubMed, J Med Chem) - "Despite a good safety profile, further clinical development of fulacimstat was not pursued due to a lack of efficacy. Recently, a new role of chymase in blood clot biology has been identified, this resparks interest in chymase inhibitors, and positions fulacimstat as a potential innovative option to treat thrombotic conditions."

Journal • Inflammation • Thrombosis

Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution. (PubMed, J Med Chem) - "Chymase inhibitors are now considered as potential profibrinolytic drugs with low bleeding risk and therefore exceptional safety for the treatment of acute thrombosis settings such as stroke, pulmonary embolism, or venous thrombosis. This article describes the chemical optimization journey from a screening hit to the discovery of fulacimstat (BAY 1142524), a selective chymase inhibitor with a good safety profile, as well as its preclinical in vitro and in vivo characterization."

Journal • Preclinical • Cardiovascular • Fibrosis • Hematological Disorders • Myocardial Infarction • Pulmonary Embolism • Respiratory Diseases • Thrombosis

Collagen 4 Alpha 3 (COL4A3) Degradation May Depend on Matrix-Metallo-Protienase 9(MMP9) in Experimental Asthma Exacerbations (ATS 2022) - "Our data suggests that there was no elevated chymase activity during exacerbation after Fulacimstat treatment. MMP9 along with PLAUR was found to be upregulated during exacerbation. Further research is needed to confirm this potential alternative mechanism that might lead to the degradation of COL4A3 in severe type 2 exacerbating asthma."

Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Collagen Type IV • MMP9 • PLAUR

COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy. (PubMed, Eur Respir J) - "C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response."

Journal • Allergic Bronchopulmonary Aspergillosis • Asthma • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Pediatrics • Pulmonary Disease • Respiratory Diseases • Collagen Type IV

Effects of the chymase inhibitor fulacimstat in diabetic kidney disease-results from the CADA DIA trial. (PubMed, Nephrol Dial Transplant) - "Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD."

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial. (PubMed, Clin Pharmacol Drug Dev) - "Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI."

Clinical • Journal • Cardiovascular • Heart Failure • Myocardial Infarction

Effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute myocardial infarction-Results of the Chymase Inhibitor in Adverse Remodeling after Myocardial Infarction (CHIARA MIA) 2 trial. (PubMed, Am Heart J) - "Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction

CADA DIA: A Double-blind Study to Investigate Efficacy, Safety and Tolerability of BAY1142524 in Patients With Type II Diabetes and a Clinical Diagnosis of Diabetic Kidney Disease (clinicaltrials.gov) - P2; N=152; Completed; Sponsor: Bayer; Active, not recruiting ➔ Completed

Clinical • Trial completion

Effects of the chymase inhibitor fulacimstat on adverse cardiac remodelling after acute myocardial infarction - Results of the CHIARA MIA 2 trial (ESC 2019) - "Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study."

CADA DIA: A Double-blind Study to Investigate Efficacy, Safety and Tolerability of BAY1142524 in Patients With Type II Diabetes and a Clinical Diagnosis of Diabetic Kidney Disease (clinicaltrials.gov) - P2; N=139; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting

Enrollment closed

Renal Impairment Study (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Bayer; Active, not recruiting ➔ Completed

Clinical • Trial completion

Long-Term Therapy BAY 1142524, a Chymase-1 Inhibitor, Normalizes Plasma Biomarkers in Dogs With Coronary Microembolization-Induced Heart Failure (ACC 2019) - "In ischemia-induced HF in dogs, CMA1-I normalized plasma A-II, NE, ENDO-1, TNF-α, IL-6, nt-pro BNP and Gal-3. The results are in-line with observations of improved LV function, attenuated LV remodeling and reduced RIF in CMA1-I treated HF dogs."

Biomarker