A Novel Therapeutic for Liver Fibrosis

描述(申请人提供)：酒精性和非酒精性肝纤维化仍然是肝病学家尚未解决的挑战，因为它可能导致肝硬变和终末期肝病，这是一种危及生命的情况，需要进行肝移植。目前治疗肝纤维化的治疗策略包括改变饮食、生活方式和/或药物以减轻疾病的根本原因。由于肝脏疾病的诊断通常是在显著的疤痕形成之后进行的，因此迫切需要辅助策略来反对导致肝脏疾病的纤维化的分子和细胞程序，并激活基质降解途径。在纤维性肝病模型中，临床前数据的优势表明内源性多肽激素Relaxin(H2R)具有胶原分解代谢活性。将这些发现转化为临床方案的过程缓慢得令人痛苦，这在很大程度上是因为与商业生产重组人(Rh)h2R相关的成本和Logistic a困难。利用分子建模和基于药物化学的药物设计，Angion Biomedica开发了一个单链、短长度的H2 R样多肽库，可以通过化学合成，并有可能提供比rhH2 R疗法更多的临床商业优势。SBIR I期研究已经从该库中确定了一种主要的抗纤维化候选药物Ang-4011，它具有出色的类药物特性，对多种肾脏和肝脏纤维化的临床前模型具有治疗作用，与肾脏和肝脏的基质沉积相反。与 作为新泽西州罗格斯大学Kathryn Uhrich教授的国际知名实验室，我们为Ang-4011开发了一种临床兼容、可生物降解的微球缓释配方，这标志着多肽在体内持续递送方面迈出了里程碑式的一步。拟议的里程碑驱动的SBIR第二阶段研究旨在对我们在肝纤维化临床前模型方面的领先候选进行全面评估，同时优化其交付。来自SBIR第二阶段计划的数据将允许这一主要候选者进入临床前安全/毒理学电池，该电池将在SBIR第二阶段竞争更新机制的支持下完成。该计划的最终目标是将一种类似于H2 R的抗纤维化药物带入治疗肝纤维化的临床试验。

DESCRIPTION (provided by applicant): Alcoholic and non-alcoholic liver fibrosis remains an unsolved challenge for the hepatologist as it can lead to cirrhosis and end-stage liver disease, a life-threatening condition that necessitates liver transplantation. Current therapeutic strategies for the treatment of liver fibrosis include changes in diet, life-style and/or medications to allevate the underlying cause of disease. Since liver disease is typically diagnosed following significant scar formation, adjuvant strategies that oppose the molecular and cellular program of fibrosis that drives liver disease and activate matrix degrading pathways are urgently required. A preponderance of preclinical data in models of fibrotic liver disease speaks to collagen catabolizing activity of endogenous peptide hormone Relaxin (H2R). Translation of these findings into clinical regimen has been painfully slow in large part due to the costs and logistica difficulties associated with commercial production of recombinant human (rh) H2R. Using molecular modeling-and medicinal chemistry-based drug design, Angion Biomedica has developed a library of single chain, short length H2R-like peptides that can be chemically synthesized and potentially offer multiple clinico-commercial advantages over rhH2R therapy. SBIR Phase I studies have identified a lead antifibrotic candidate, ANG-4011, from within this library, that has excellent drug-like properties and is therapeutic in multiple preclinical models f renal and hepatic fibrosis, opposing matrix deposition in kidney and liver. In partnership with the internationally recognized laboratory of Prof. Kathryn Uhrich (Rutgers University, NJ), and representing a landmark step in sustained in vivo delivery of peptides, we have developed a clinically compatible, biodegradable, microsphere-based extended release formulation for ANG-4011. The proposed milestone-driven SBIR Phase II study is designed to make a comprehensive evaluation of our lead candidate in preclinical models of liver fibrosis while optimizing its delivery. Data from this SBIR Phase II program will allow for entry of this lead candidate to the preclinical safety/toxicology battery to be completed under the aegis of the SBIR Phase IIb competing renewal mechanism. The ultimate objective of this program is to bring an H2R-like antifibrotic to clinical trials for treatment of liver fibrosis.