Anti-Fibrotic Therapy for Scleroderma/SSc

描述(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/硬皮病的患者也有肺功能的丧失。硬皮病/硬皮病每年在美国影响大约40万至90万人。SSc的死亡率和发病率非常高，并且与受累器官的纤维化程度直接相关。根据一项研究，在美国，硬皮病/硬皮病造成的总成本每年高达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/硬皮病尚无已知的治愈方法，其根本原因仍不清楚，尽管它被归因于有一种自身免疫成分。目前的治疗仅限于症状管理，以提高生活质量和限制长期并发症。硬皮病/硬皮病的常见治疗方法包括免疫抑制剂、抗炎药、血管扩张剂和抗纤维化药物。免疫抑制剂，如皮质类固醇和环磷酰胺，要么显示出边际疗效，要么有副作用。因此，迫切需要一种有效且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，在自身免疫性纤维化疾病中，通过自身抗体激活PDGFR的可能性是一个新的和具有挑衅性的概念。最近的研究表明，另一种生长因子，血管内皮生长因子(VEGF)，一种强大的血管生成分子，在SSC患者中过度表达。通过广泛的文献回顾，我们得出结论，同时抑制PDGFR和KDR(VEGFRII)可能是一种有效的新的治疗策略，使硬皮病/SSc患者受益。我们确定了一种小分子受体酪氨酸激酶抑制剂/S，它同时具有抗PDGFR和KDR的活性，并在第一阶段计划中对溶解性进行了优化。我们在体内外对Ang-3070双激酶抑制剂进行了表征，发现在皮肤、肺和肾纤维化的动物模型中，ANG3070具有显著的抗纤维化活性。SBIR第二阶段计划下拟议的新工作的目标是进一步扩大疗效范围，以确定涉及多个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给药方案和选择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，以便汇编一个完整的支持IND的临床前数据包，以提交给FDA进行人体试验。 公共卫生相关性：硬皮病/硬皮病的死亡率和发病率非常高，与所涉器官的纤维化程度直接相关。一种小分子抗纤维化合物将是一种有效的疾病修正疗法，可以显着降低硬皮病/硬皮病患者的死亡率，并伴随着与多器官纤维化相关的破坏性影响。我们的小分子代表了一种治疗这种无法治愈的衰弱疾病的新方法。

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.