Anti-Fibrotic Therapy for Scleroderma/SSc

硬皮病/SSc 的抗纤维化治疗

• 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
• 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

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的患者也有肺功能丧失。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/SSc的总成本每年达到15亿美元。在这项研究中，发病率代表了主要的成本负担，与8.2亿美元（56%）的总成本。硬皮病/SSc没有已知的治愈方法，其根本原因仍然未知，尽管它归因于具有自身免疫成分。目前的治疗仅限于控制症状，以提高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。免疫抑制剂，如皮质类固醇和环磷酰胺已证明边际疗效，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？（PDGFR）已经在硬皮病患者的皮肤中得到证实。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的一个新的和挑衅性的概念。最近的研究表明，另一种生长因子，血管内皮生长因子（VEGF），一种有效的血管生成分子，在SSc患者中过度表达。从广泛的文献综述中，我们得出结论，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。我们鉴定了一种对PDGFR和KDR均具有活性的小分子受体酪氨酸激酶抑制剂，并在I期项目中优化了溶解度。我们已经在体外和体内表征了ANG- 3070双重激酶抑制剂，并且发现ANG-3070在皮肤、肺和肾纤维化的动物模型中具有显著的抗纤维化活性。SBIR II期计划下拟议的新工作的目标是进一步扩大疗效特征，以确定涉及几个器官纤维化的SSc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患者人群进行临床研究，无论病因如何。我们还将评估ANG 3070的安全性/毒理学特征，以便组装一个完整的IND支持临床前数据包提交给FDA，以推进人体研究。