Fulacimstat(Fulacimstat) - 药物靶点：chymase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

BAY 1142524、BAY-1142524、BAY1142524

靶点

chymase

作用机制

chymase抑制剂(糜蛋白酶抑制剂)

治疗领域

心血管疾病内分泌与代谢疾病泌尿生殖系统疾病

在研适应症-

非在研适应症

急性心肌梗塞2型糖尿病糖尿病肾病+ [3]

原研机构

Bayer AG

在研机构-

非在研机构

Bayer AG

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)无进展

特殊审评-

结构

分子式C23H16F3N3O6

InChIKeyJDARDSVOVYVQST-MRXNPFEDSA-N

CAS号1488354-15-9

关联

5

项与 Fulacimstat 相关的临床试验

NCT03402438 / Completed临床1期

Investigation of Pharmacokinetics, Safety, and Tolerability of a Single Oral 25 mg BAY 1142524 IR Tablet Dose in Male and Female Subjects With Renal Impairment and in Age-, Gender-, and Weight-matched Healthy Subjects in a Single Center, Non-controlled, Open-label, Observational Design

The study will investigate the pharmacokinetics of BAY1142524 in subjects with mild to severe renal impairment compared to age; weight, and gender-matched healthy subjects.

开始日期2018-02-12

申办/合作机构

Bayer AG

NCT03412006 / Completed临床2期

A Randomized, Double-blind, Multicenter Study to Assess the Efficacy and Safety of a 6 Month Oral Treatment With the Chymase Inhibitor BAY 1142524 at a Dose of 25 mg BID in Comparison to Placebo on Top of Standard of Care in Patients With Type II Diabetes and a Clinical Diagnosis of Diabetic Kidney Disease

The purpose of the trial is the analysis of safety and efficacy of the chymase inhibitor BAY1142524 at a dose of 25 mg BID in comparison to placebo using a 6 months treatment period in type II diabetic patients with a clinical diagnosis of diabetic kidney disease. BAY1142524 or placebo will be given on top of evidence-based standard of care for diabetic kidney disease. Primary objective is the analysis of first signs of efficacy as determined by favourable changes in urinary albumin creatinine ratio. Secondary objective is the analysis of safety and tolerability as evidenced by the incidence and severity of adverse events. 64 valid patients have to complete treatment with verum and 32 valid patients have to complete treatment with placebo.

开始日期2018-02-02

申办/合作机构

Bayer AG

NCT02976467 / Completed临床2期

A Randomized, Double-blind, Multicenter Study to Assess the Safety and Efficacy of a 6 Month Oral Treatment With the Chymase Inhibitor BAY 1142524 at a Dose of 25 mg BID in Comparison to Placebo on Top of Standard of Care in Patients With Reduced Left-ventricular Ejection Fraction (LVEF≤ 45%) After Acute Myocardial Infarction

The purpose of the trial is the analysis of safety and efficacy of the chymase inhibitor BAY1142524 at a dose of 25 mg BID in comparison to placebo using a 6 months treatment period in patients with left-ventricular (LV) dysfunction after myocardial infarction (MI). BAY1142524 or placebo will be given on top of evidence-based standard of care for left-ventricular dysfunction after myocardial infarction. Primary objective is the analysis of first signs of efficacy as determined by favourable changes in functional parameters of adverse cardiac remodelling (i.e. endsystolic and enddiastolic volume index, ejection fraction). Secondary objective is the analysis of safety and tolerability as evidenced by the incidence and severity of adverse events. 30 patients have to complete treatment with verum and 30 patients have to complete treatment with placebo.

开始日期2016-12-30

申办/合作机构

Bayer AG

100 项与 Fulacimstat 相关的临床结果

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100 项与 Fulacimstat 相关的转化医学

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100 项与 Fulacimstat 相关的专利（医药）

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5

项与 Fulacimstat 相关的文献（医药）

2021-12-02·Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association2区 · 医学

Effects of the chymase inhibitor fulacimstat in diabetic kidney disease—results from the CADA DIA trial

2区 · 医学

Article

作者: Strand, Jorma ; Becka, Michael ; Otto, Christiane ; Rossing, Peter ; Avogaro, Angelo ; Kanefendt, Friederike

Abstract:

Background:

The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD.

Methods:

In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care.

Results:

The randomized patients had a mean urine albumin–creatinine ratio (UACR) of 131 mg/g (range: 29–2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% [coefficient of variation (CV) 86%] and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627–1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo.

Conclusions:

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.

2021-12-01·The European respiratory journal1区 · 医学

COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy

1区 · 医学

Article

作者: Weckmann, Markus ; Sand, Jannie Marie ; Lunding, Lars ; Oliver, Brian George G ; Bahmer, Thomas ; van de Berge, Maarten ; von Mutius, Erika ; Karsdal, Morten Asser ; Wegmann, Michael ; Jonker, Marnix ; Juergens, Uwe R ; Vermeulen, Cornelis ; Hansen, Gesine ; Happle, Christine ; Ulrich-Merzenich, Gudrun ; Rank Rønnow, Sarah ; Duhn, Jannis ; Laumonnier, Yves ; König, Inke ; Rabe, Klaus F ; Dittrich, Anna-Maria ; Burgess, Janette Kay ; Schaub, Bianca ; Faiz, Alen ; Leeming, Diana Julie ; Pech, Martin ; Danov, Olga ; Fuchs, Oliver ; Kopp, Matthias Volkmar ; Zissler, Ulrich ; Sewald, Katherina

Background:

Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).

Objective:

To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.

Methods:

The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test.

Results:

Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5).

Conclusion:

C4Ma3 levels 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.

2020-06-01·American heart journal2区 · 医学

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

2区 · 医学

Article

作者: Avraham Shimony ; Petr Hajek ; Johann Bauersachs ; Ran Kornowski ; Petr Ostadal ; Christiane Otto ; Savina Nodari ; Hans-Dirk Duengen ; Yaron Arbel ; Raymond J. Kim ; Tal Hasin ; Niels Menck ; Friederike Kanefendt ; Jiri Kettner ; Eugenia Nikolsky ; Andres Iniguez Romo ; Mercedes Roque ; Dan Admon ; Gian Carlo Silvio Marenzi ; Vicente Miro Palau ; Hana Linkova ; Felice Achilli ; Bernhard Reimers ; Borja Ibanez ; Jan Fuisting ; Michele Senni ; Michael Becka ; Doron Zahger ; Katia Orvin ; Manuel Martinez Selles ; Sadrack Oumbe Tiam ; Gonzalo Calvo Rojas ; Ivo Podpera

BACKGROUND:

Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI).

METHODS:

In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory.

RESULTS:

Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ± 5.4%, placebo: 4.0% ± 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ± 13.3 mL/m², placebo: 5.1 ± 18.9 mL/m², P = .54), and LVESVI (fulacimstat: 2.3 ± 11.2 mL/m², placebo: 0.6 ± 14.8 mL/m², P = .56) were observed in both treatment arms.

CONCLUSION:

Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.

100 项与 Fulacimstat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15085

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床2期	保加利亚	Bayer AG	2018-02-02
2型糖尿病	临床2期	丹麦	Bayer AG	2018-02-02
2型糖尿病	临床2期	芬兰	Bayer AG	2018-02-02
2型糖尿病	临床2期	以色列	Bayer AG	2018-02-02
2型糖尿病	临床2期	意大利	Bayer AG	2018-02-02
2型糖尿病	临床2期	西班牙	Bayer AG	2018-02-02
2型糖尿病	临床2期	瑞典	Bayer AG	2018-02-02
糖尿病肾病	临床2期	保加利亚	Bayer AG	2018-02-02
糖尿病肾病	临床2期	丹麦	Bayer AG	2018-02-02
糖尿病肾病	临床2期	芬兰	Bayer AG	2018-02-02

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02976467 (CHIARA MIA, Pubmed \| Am Heart J) 人工标引	临床2期	急性心肌梗塞	107	fulacimstat	膚廠鹹淵餘壓願廠窪淵(鑰壓鬱艱顧簾醖築繭構) = 衊鹽窪鬱積襯顧築壓襯繭鑰餘鏇憲衊鏇鬱範獵 (範獵積願齋壓製膚膚憲, 13.3 ) 更多	不佳	2020-06-01
				Placebo	膚廠鹹淵餘壓願廠窪淵(鑰壓鬱艱顧簾醖築繭構) = 膚壓壓積醖繭艱齋壓遞繭鑰餘鏇憲衊鏇鬱範獵 (範獵積願齋壓製膚膚憲, 18.9 ) 更多
NCT02452515 (CHIARA MIA 1, Pubmed) 人工标引	临床2期	左心室功能不全 \| 心肌梗塞	49	Fulacimstat	鏇觸繭糧構觸構築範鹽(網顧鑰鹽範蓋築遞膚窪) = Fulacimstat was safe and well tolerated at all examined doses 鏇夢醖淵獵築蓋憲觸製 (廠觸夢衊鏇構艱遞遞廠 )	不佳	2019-10-01
				Placebo