Antifibrotic Therapy for Chronic Kidney Disease

描述(申请人提供)：慢性肾脏疾病(CKD)仍然是肾科医生尚未解决的挑战，因为它几乎不可避免地会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。目前实践中的治疗策略中，几乎没有反对导致肾脏疾病的纤维化的分子和细胞程序。目前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前途的靶点。在SBIR第一阶段计划的支持下，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合成了一种高度水溶性、口服生物可用的小分子PDGFR+KDR抑制剂ANG3070。关键和极具说服力的数据表明，ANG3070对实验性CKD具有治疗作用，可减少微量白蛋白尿和尿TGF21，减少肾间质胶原沉积和其他肾脏纤维化指标，并保护肾实质微结构。这项拟议的里程碑驱动的SBIR第二阶段转化研究计划的目标是进行全面的研究性新药(IND)研究，以推动我们的新型口服生物可用小分子疗法在CKD进行临床试验，CKD是尚未满足临床需求的最大市场之一。 公共卫生相关性：一种小分子口服生物活性抗纤药将对慢性肾脏疾病的治疗产生重大的临床影响。

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. PUBLIC HEALTH RELEVANCE: A small molecule orally bioactive antifibrotic will have significant clinical impact in treatment of chronic kidney disease.