Anti-Fibrotic Therapy for Scleroderma/SSc

描述（由申请人提供）：硬皮病（也称为系统性硬化症- ssc）主要以进行性皮肤和血管纤维化为特征。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的患者也有肺功能丧失。在美国，硬皮病/SSc每年影响大约40万到90万人。SSc的死亡率和发病率非常高，并且与受感器官的纤维化程度直接相关。根据一项研究，美国硬皮病/SSc的总成本每年达到15亿美元。在这项研究中，发病率是主要的费用负担，占总费用的8.2亿美元（56%）。目前还没有治愈硬皮病/SSc的方法，其根本原因仍不清楚，尽管它被认为是由自身免疫成分引起的。目前的治疗仅限于控制症状，以改善生活质量和限制长期并发症。硬皮病/SSc的常用治疗包括免疫抑制剂、抗炎剂、血管扩张剂和抗纤维化剂。免疫抑制剂如皮质类固醇和环磷酰胺已显示出边际疗效，或有副作用。因此，迫切需要有效和负担得起的治疗策略。血小板衍生生长因子（PDGF）及其受体(PDGFR？和PDGFR?)已在硬皮病患者的皮肤中得到证实。此外，PDGFR通过自身抗体激活的可能性在自身免疫性纤维化疾病中是一个新颖而有争议的概念。最近的研究表明，另一种生长因子，血管内皮生长因子（VEGF），一种有效的血管生成分子，在SSc患者中过度表达。通过广泛的文献回顾，我们得出结论，抑制PDGFR和KDR （VEGFRII）可能是一种有效的新型治疗策略，可以使硬皮病/SSc患者受益。我们发现了一种小分子酪氨酸激酶受体抑制剂，对PDGFR和KDR都有活性，并在I期项目中对其溶解度进行了优化。我们在体外和体内对ANG- 3070双激酶抑制剂进行了表征，发现ANG3070在皮肤、肺和肾纤维化动物模型中具有显著的抗纤维化活性。在SBIR II期项目下提出的新工作的目标是进一步扩大疗效，以确定涉及多个器官纤维化的SSc的其他临床前动物模型的最佳剂量和治疗时间窗。这些研究将有助于选择剂量方案和选择SSc患者群体进行临床研究，而不考虑病因。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推进人体研究。

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.