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Antifibrotic Therapy for Chronic Kidney Disease

慢性肾脏病的抗纤维化治疗

基本信息

批准号：
8517104
负责人：
PRAKASH NARAYAN
金额：
$ 100.3万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517104
关键词：
Adjuvant Adverse effects Angiotensin II Angiotensin Receptor Animal Model Bioavailable Biology Caring Chronic Chronic Kidney Failure Clinical Clinical Trials Collagen Comorbidity Complement Data Dependence Development Diabetic Nephropathy Dose Drug Design Drug Kinetics End stage renal failure Enzyme Inhibitor Drugs Enzyme Inhibitors Fibrosis Goals Hydroxyproline In Vitro Investigational Drugs Investigational New Drug Application Kidney Kidney Diseases Life Marketing Metabolic syndrome Microalbuminuria Modeling Molecular Molecular Models Nephrectomy Oral Outcome PDGFRB gene Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Platelet-Derived Growth Factor Pre-Clinical Model Rattus Receptor Protein-Tyrosine Kinases Regimen Renal Replacement Therapy Safety Schedule Small Business Innovation Research Grant Therapeutic Therapeutic Index Time Toxicology Translational Research Tyrosine Kinase Receptor Inhibition United States Food and Drug Administration Urine Vascular Endothelial Growth Factors Water base design drug candidate drug discovery drug efficacy inhibitor/antagonist interstitial molecular modeling novel pre-clinical programs response safety study small molecule

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) remains an unsolved challenge for the nephrologist, as it almost inevitably leads to end-stage renal failure, a life-threatening condition that necessitates renal replacement therapy. Few, if any, of the currently practiced therapeutic strategies oppose the molecular and cellular program of fibrosis that drives renal disease. There is now mounting evidence that certain receptor tyrosine kinases including platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are promising targets for development of anti-fibrotic strategies. Under the aegis of the SBIR Phase I program and harnessing a drug discovery engine comprising molecular modeling, rational drug design, medicinal chemistry and in vitro biology, Angion Biomedica has synthesized a highly water soluble, orally bioavailable, small molecule PDGFR+KDR inhibitor, ANG3070. Critical and highly compelling data indicate that ANG3070 is therapeutic in experimental CKD, reducing microalbuminuria and urine TGF21, decreasing renal interstitial collagen accumulation and other markers of renal fibrosis and preserving renal parenchymal microarchitecture. The goal of this proposed milestone driven SBIR Phase II translational research program is to conduct the comprehensive gamut of Investigational New Drug (IND)-enabling studies required to advance our novel, orally bioavailable, small molecule therapeutics to clinical trials in CKD, one of the largest markets of unmet clinical need.

描述（由申请人提供）：慢性肾脏疾病（CKD）对于肾病专家来说仍然是一个未解决的挑战，因为它几乎不可避免地导致终末期肾功能衰竭，这是一种危及生命的疾病，需要肾脏替代治疗。很少，如果有的话，目前实践的治疗策略反对导致肾脏疾病的纤维化的分子和细胞程序。越来越多的证据表明，包括血小板衍生生长因子（PDGF）和血管内皮生长因子（VEGF）在内的某些受体酪氨酸激酶是开发抗纤维化策略的有希望的靶点。在SBIR I期项目的支持下，利用包括分子建模、合理药物设计、药物化学和体外生物学在内的药物发现引擎，Angion Biomedica合成了一种高水溶性、口服生物利用度的小分子PDGFR+KDR抑制剂ANG3070。关键且高度令人信服的数据表明，ANG3070对实验性CKD具有治疗作用，可减少尿微量白蛋白和尿TGF21，减少肾间质胶原积累和其他肾纤维化标志物，并保留肾实质微结构。这个里程碑式的SBIR II期转化研究项目的目标是开展全面的研究性新药（IND）研究，以推进我们的新型口服生物可利用小分子疗法在CKD的临床试验，CKD是最大的未满足临床需求的市场之一。