Development of Novel Small Molecule Anti-Fibrotic Agent for the Treatment of Systemic Scleroderma

摘要 该STTR提案的目标是开发一种适合口服给药的新型抗纤维化剂， 可以安全有效地治疗系统性硬化症（SSc）或系统性硬皮病患者。SSC 是最致残和致命的免疫介导的风湿性疾病之一。SSc是一种罕见的疾病， 在美国有40，000 - 150，000人，死亡风险高出5到8倍。这是一个 以血管内皮改变为特征的异质性多器官疾病， 炎症和免疫反应导致进行性纤维化和器官衰竭。主要受影响器官 是皮肤、肺、肾和脉管系统。在SSc患者中， 特征性地先于炎症和自身免疫反应，其刺激向组织中的进展。 纤维化疤痕早期死亡（诊断后5年）的主要原因是间质性肺病（ILD）。 治疗常规依赖于NATRA（TK抑制剂）和Tocilizumab（IL-6 mAb）以及对症治疗 但是这些药物的功效有限，并且存在耐受性和/或毒性问题。截至今天，疾病纤维化进展 SSc的死亡率仍然高于任何其他风湿性疾病;突出了明显的未满足的 对疾病修饰疗法的医学需求，其将预防或减少对主要器官的损伤。靶向 通过Apelin能系统（apelin/APJ）信号传导修复和再生血管内皮细胞损伤 该途径为SSc患者的治疗提供了独特和新颖的机会（截至今天，血管性硬化症患者的治疗是一个新的途径）。 内皮修复和再生是SSc药物开发中的一个靶向不足的领域）。系统很好- 作为一种内源性抗损伤和器官保护机制，在血管后被激活， 内皮损伤，并在所有SSc疾病影响的器官中表达。 APIE Therapeutics与RTI International合作，确定了一种领先的抗纤维化药物 候选物，爱帕琳激动剂APT 101，用于治疗肺纤维化。首先，在博莱霉素诱导的肺纤维化中， 用APT 101进行的小鼠模型治疗性处理显著抑制了肺中胶原蛋白的产生（a 肺纤维化进展的标志），如通过羟脯氨酸测定所检测的，以及 study.第二，在心肌梗塞动物研究（小鼠和小鼠）中，APT 101显示出显著减少的纤维化。 大鼠）和显著降低的生物标志物应答， 肺、皮肤和肾纤维化疾病。综上所述，这些证据表明，激活apelinergic 系统有可能破坏导致SSc进行性纤维化的致病级联反应。我们的目标 对于该提案，在经验证的SSc模型中获得临床前数据：1）体内有效性模型和2）离体 人体组织模型目的1和2的结果将为关于APT 101 IND的数据驱动决策提供信息 第二阶段提案的初步指示和后续计划。

ABSTRACT The goal of this STTR proposal is to develop a novel anti-fibrotic agent suitable for oral administration which could be used to safely and effectively treat Systemic Sclerosis (SSc), or Systemic Scleroderma patients. SSc is one of the most disabling and lethal immune-mediated rheumatic disorders. SSc is a rare disease, affecting 40,000-150,000 people in the United States and conferring a five to eight-fold higher risk for mortality. It is a heterogeneous, multiorgan disease characterized by vascular endothelial alterations that results in chronic inflammation and immune responses leading to progressive fibrosis and organ(s) failure. Major impacted organs are skin, lungs, kidneys, and vasculature system. In SSc patients, vascular endothelial cell injury characteristically precedes inflammation and autoimmune responses that stimulates the progression into tissue fibrosis scaring. The leading cause of early death (5 years from diagnosis) is interstitial lung disease (ILD). Treatment routinely relies on Nintedanib (TK inhibitor) and Tocilizumab (IL-6 mAb), and symptomatic treatments but these have limited efficacy, and tolerability and/or toxicity issues. As of today, disease fibrosis progression and mortality rate for SSc remains greater than for any other rheumatic disease; highlighting the clear unmet medical need for disease modifying therapies that will prevent or reduce the damage to major organs. Targeting repair and regeneration of the vascular endothelial cell injury via the Apelinergic System (apelin/APJ) signaling pathway provides a unique and novel opportunity for the treatment of SSc patients (as of today vascular endothelium repair and regeneration is an under targeted area in SSc drug development). The system is well- established as an endogenous anti-injury and organ-protective mechanism that is activated post vascular endothelium injury and is expressed in all SSc disease impacted organs. APIE Therapeutics, in collaboration with RTI International, has identified a lead anti-fibrotic drug candidate, apelin agonist APT101, for the treatment of lung fibrosis. First, in a bleomycin-induced lung fibrosis mouse model therapeutic treatment with APT101 significantly inhibited the production of collagen in the lungs (a hallmark of lung fibrosis progression), as detected via the Hydroxyproline Assay, and primary end point of the study. Second, APT101 showed significantly reduced fibrosis in myocardial infarction animal studies (mice and rats) and significantly reduced biomarker responses in ex-vivo human cell co-culture disease models relevant to lung, skin, and kidney fibrotic diseases. Taken together, this evidence suggests that activation of the apelinergic system has the potential to disrupt the pathogenic cascade responsible for progressive fibrosis in SSc. Our aims for this proposal are obtain preclinical data in validated SSc models: 1) in-vivo efficacy model and, 2) ex-vivo human tissue model. The results from Aims 1 and 2 will inform a data driven decision regarding APT101 IND initial indication and subsequent plans for Phases II proposal.