Anti-Fibrotic Therapy for Scleroderma/SSc

硬皮病/SSc 的抗纤维化治疗

基本信息

批准号：
8655514
负责人：
LATHA PAKA
金额：
$ 158.41万
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/8655514
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.

描述（由申请人提供）：硬皮病（也称为系统性硬化症-SSc）的主要特征是进行性真皮和血管纤维化。其他器官也会受到影响，包括肺、心脏、血管、胃肠道和肾脏。许多患有硬皮病/SSc 的患者也会出现肺功能丧失。硬皮病/SSc 每年影响美国约 400,000 至 900,000 人。 SSc 的死亡率和发病率非常高，并且与相关器官的纤维化程度直接相关。根据一项研究，在美国，硬皮病/SSc 造成的总费用每年达到 15 亿美元。在这项研究中，发病率是主要的成本负担，占总成本的 8.2 亿美元（56%）。硬皮病/SSc 尚无已知的治愈方法，其根本原因仍不清楚，但其归因于自身免疫成分。目前的治疗仅限于控制症状，以改善生活质量并限制长期并发症。硬皮病/SSc 的常见治疗包括免疫抑制剂、抗炎剂、血管扩张剂和抗纤维化剂。皮质类固醇和环磷酰胺等免疫抑制剂的疗效有限，或者有副作用。因此，迫切需要有效且负担得起的治疗策略。硬皮病患者皮肤中血小板衍生生长因子（PDGF）及其受体（PDGFR？和PDGFR？）的表达增加已被证明。此外，通过自身抗体激活 PDGFR 的可能性是自身免疫性纤维化疾病中一个新颖且具有争议性的概念。最近的研究表明，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，在 SSc 患者中过度表达。通过对文献的广泛回顾，我们得出结论，抑制 PDGFR 和 KDR (VEGFRII) 可能是一种有益于硬皮病/SSc 患者的有效的新型治疗策略。我们鉴定出一种小分子受体酪氨酸激酶抑制剂，具有抗 PDGFR 和 KDR 的活性，并在 I 期项目中优化了溶解度。我们对ANG-3070双激酶抑制剂进行了体外和体内表征，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 期计划下拟议的新工作的目标是进一步扩大疗效概况，以确定涉及多种器官纤维化的其他临床前 SSc 动物模型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 患者群体进行临床研究，无论病因如何。我们还将评估 ANG3070 的安全性/毒理学概况，以便组装完整的 IND 临床前数据包，提交给 FDA 以推进人体研究。