A Novel Therapeutic for Liver Fibrosis

肝纤维化的新疗法

• 批准号: 8546966
• 负责人: PRAKASH NARAYAN
• 金额: $ 103.81万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546966
• 关键词: Adjuvant; Age; Am 80; Biochemical; Biodegradable microsphere; Blinded; Cicatrix; Cirrhosis; Clinical; Clinical Treatment; Clinical Trials; Collagen; Comorbidity; Data; Deposition; Development; Diagnosis; Diet; Disease; Dose; Drug Design; Drug Formulations; Evaluation; Fibrosis; HRH2 gene; Health; Human; Hydroxyproline; Kidney; Laboratories; Lead; Length; Libraries; Life; Life Style; Liver; Liver Fibrosis; Liver diseases; Marketing; Mechanics; Medical; Metabolic syndrome; Microspheres; Mission; Modeling; Molecular; Molecular Models; Morbidity - disease rate; Mus; Nebraska; Pathway interactions; Patient Selection; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Production; Property; Recombinants; Regimen; Relaxin; Research Personnel; Series; Services; Small Business Innovation Research Grant; Staging; Therapeutic; Therapeutic Effect; Toxicology; Translational Research; Translations; Universities; base; clinically significant; compliance behavior; cost; design; drug candidate; drug efficacy; in vivo; liver transplantation; molecular modeling; mortality; non-alcoholic; novel therapeutics; peptide hormone; phase 1 study; phase 2 study; pre-clinical; preclinical safety; problem drinker; programs; public health relevance; treatment strategy

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.

描述（由申请人提供）：酒精性和非酒精性肝纤维化仍然是肝病学家面临的一个未解决的挑战，因为它可能导致肝硬化和终末期肝病，这是一种危及生命的疾病，需要进行肝移植。目前用于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。由于肝脏疾病通常在显著的瘢痕形成后被诊断，因此迫切需要对抗驱动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的辅助策略。纤维化肝病模型中的大量临床前数据表明内源性肽激素松弛素（H2 R）的胶原分解代谢活性。将这些发现转化为临床治疗方案的过程非常缓慢，这在很大程度上是由于与重组人（rh）H2 R商业生产相关的成本和物流困难。Angion Biomedica利用分子建模和基于药物化学的药物设计，开发了一个单链、短长度的H2 R样肽库，这些肽可以化学合成，并可能提供比rhH 2 R治疗更多的临床商业优势。SBIR I期研究已经从该文库中鉴定出了一种主要的抗纤维化候选药物ANG-4011，其具有优异的药物样性质，并且在肾和肝纤维化的多种临床前模型中具有治疗性，对抗肾和肝中的基质沉积。伙伴合作下 在Kathryn Uhrich教授（Rutgers University，NJ）的国际公认的实验室中，并且代表肽的持续体内递送的里程碑式的一步，我们已经开发了用于ANG-4011的临床相容的、可生物降解的、基于微球的延长释放制剂。拟议的里程碑驱动的SBIR II期研究旨在全面评估我们在肝纤维化临床前模型中的主要候选药物，同时优化其交付。该SBIR II期项目的数据将允许该先导候选药物进入临床前安全性/毒理学组合，并在SBIR IIb期竞争性更新机制的支持下完成。该计划的最终目标是将H2 R样抗纤维化药物用于治疗肝纤维化的临床试验。