Anti-Fibrotic Therapy for Scleroderma/SSc

硬皮病/SSc 的抗纤维化治疗

基本信息

批准号：
8313784
负责人：
LATHA PAKA
金额：
$ 60.63万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313784
关键词：
3-Dimensional Adrenal Cortex Hormones Adverse effects Affect Animal Model Anti-Inflammatory Agents Antibodies Autoimmune Process Bioavailable Biology Blood Vessels Canis familiaris Cessation of life Chronic Clinical Clinical Research Clinical Trials Collagen Cyclophosphamide Data Dermal Disease Dose Drug Design Etiology Fibrosis Goals Grant Growth Factor Heart Histopathology Human Hydroxyproline Immunosuppressive Agents In Vitro Kidney Liver Fibrosis Lung Modeling Molecular Models Morbidity - disease rate Mus No-Observed-Adverse-Effect Level Oral Organ PDGFRB gene Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Pilot Projects Plasma Platelet-Derived Growth Factor Progress Reports Progressive Disease Quality of life Rattus Regimen Research Review Literature Route Safety Schedule Scleroderma Series Severity of illness Skin Small Business Innovation Research Grant Solubility Staging Systemic Scleroderma Testing Therapeutic Therapeutic Intervention Thick Time Toxic effect Toxicogenetics Toxicology Translational Research Treatment Efficacy Treatment Protocols Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factors Vasodilator Agents Water Work base cohort common treatment cost design efficacy testing improved in vivo indium-bleomycin inhibitor/antagonist kinase inhibitor molecular modeling mortality mouse model novel novel therapeutic intervention novel therapeutics patient population pre-clinical programs pulmonary function receptor research study safety study small molecule symptom management

项目摘要

DESCRIPTION (provided by applicant): Scleroderma (also known as systemic sclerosis-SSc) is characterized primarily by progressive dermal and vascular fibrosis. Other organs are affected too, including lung, heart, blood vessels, GI and kidney. Many patients who suffer from scleroderma/SSc also have a loss of pulmonary function. Scleroderma/SSc affects approximately 400,000 to 900,000 people in the USA every year. Mortality and morbidity in SSc are very high and are directly related to the extent of fibrosis in the involved organs. According to one study, the total cost attributed to scleroderma/SSc in the USA reached $1.5 billion annually. In this study, morbidity represented the major cost burden, associated with $820 million (56%) of the total costs. There is no known cure for scleroderma/SSc and the underlying cause remains unknown, though it is attributed to having an autoimmune component. Treatment is currently limited to management of symptoms in order to improve quality of life and limit long-term complications. Common treatments for scleroderma/SSc include immunosuppressive agents, anti-inflammatory agents, vasodilators and anti-fibrotic agents. Immunosuppressive agents such as corticosteroids and cyclophosphamide have demonstrated marginal efficacy, or have side effects. Therefore there is a critical need for effective and affordable therapeutic strategy. Increased expression of both platelet derived growth factor (PDGF) and its receptors (PDGFR? and PDGFR?) have been demonstrated in skin of scleroderma patients. Furthermore, the possibility of PDGFR activation through auto-antibodies is a novel and provocative concept in autoimmune fibrotic diseases. Recent studies have indicated that another growth factor, vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is over expressed in SSc patients. From an extensive review of the literature, we concluded that inhibiting both PDGFR and KDR (VEGFRII) may be an effective novel therapeutic strategy to benefit scleroderma/SSc patients. We identified a small molecule receptor tyrosine kinase inhibitor/s with activity against both PDGFR and KDR and optimized for solubility in Phase I program. We have characterized ANG- 3070 dual kinase inhibitor in vitro and in vivo and found that ANG3070 has significant anti-fibrotic activity in animal models of skin, lung and kidney fibrosis. The objective of the proposed new work under the SBIR Phase II program is to further expand the efficacy profile to identify the optimal dose and therapeutic time window in other preclinical animal models of SSc involving several organ fibrosis. These studies will aid in selecting the dose regimen and selecting SSc patient population for clinical studies regardless of etiology. We will also evaluate the safety/toxicology profile of ANG3070, in order to assemble a complete IND-enabling preclinical data package to submit to FDA for advancing to human studies. PUBLIC HEALTH RELEVANCE: Mortality and morbidity in scleroderma/SSc are very high and are directly related to the extent of fibrosis in the involved organs. A small molecule anti-fibrotc compound will be an effective disease modifying therapy to significantly reduce scleroderma/SSc patient deaths with the devastating effects associated multiple organ fibrosis. Our small molecule represents a novel therapeutic approach for an incurable debilitating disease.

描述（由申请人提供）：硬皮病（也称为全身性硬化性SSC）主要以进行性皮肤和血管纤维化为特征。其他器官也受到影响，包括肺，心脏，血管，GI和肾脏。许多患有硬皮硬皮病/SSC的患者也丧失了肺功能。每年美国的硬皮病/SSC影响美国约40万至90万人。 SSC的死亡率和发病率很高，与所涉及器官的纤维化程度直接相关。根据一项研究，归因于美国硬皮病/SSC的总成本每年达到15亿美元。在这项研究中，发病率代表了主要成本负担，与总成本的8.2亿美元（56％）有关。没有已知的硬皮病/SSC治疗方法，尽管它归因于具有自身免疫成分，但基本原因仍然未知。目前，治疗仅限于症状管理，以改善生活质量并限制长期并发症。硬皮病/SSC的常见治疗方法包括免疫抑制剂，抗炎剂，血管扩张剂和抗纤维化剂。免疫抑制剂（例如皮质类固醇和环磷酰胺）表现出边缘疗效或具有副作用。因此，至关重要的是有效且负担得起的治疗策略。在硬皮病患者的皮肤中，已经证明了血小板衍生因子（PDGF）及其受体（PDGFR？和PDGFR？）的表达增加。此外，通过自身抗体激活PDGFR激活的可能性是自身免疫性纤维化疾病的一种新颖而挑衅的概念。最近的研究表明，在SSC患者中，另一种生长因子血管内皮生长因子（VEGF）是一种有效的血管生成分子。从对文献的广泛回顾中，我们得出的结论是，抑制PDGFR和KDR（VEGFRII）可能是一种有效的新型治疗策略，可使硬皮病/SSC患者受益。我们鉴定了一个针对PDGFR和KDR的活性的小分子受体酪氨酸激酶抑制剂，并在I期计划中进行了优化。我们已经在体外和体内表征了Ang-3070双激酶抑制剂，发现Ang3070在皮肤，肺和肾纤维化动物模型中具有显着的抗纤维化活性。 SBIR II期计划下提议的新工作的目的是进一步扩大功效概况，以确定其他涉及几种器官纤维化的SSC临床前动物模型中的最佳剂量和治疗时间窗口。这些研究将有助于选择剂量方案并选择SSC患者人群进行临床研究，而不论病因如何。我们还将评估ANG3070的安全/毒理学概况，以组装一个完整的成熟临床前数据包，以提交给FDA以促进人类研究。公共卫生相关性：硬皮病/SSC的死亡率和发病率很高，与所涉及器官的纤维化程度直接相关。小分子抗合性化合物将是一种有效的疾病修饰疗法，可显着减少与多器官纤维化相关的毁灭性作用的硬皮病/SSC患者死亡。我们的小分子代表了一种无法治愈的使人衰弱疾病的新型治疗方法。