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

治疗系统性硬皮病的新型小分子抗纤维化药物的开发

基本信息

批准号：
10609109
负责人：
Esther M Alegria
金额：
$ 45.24万
依托单位：
APIE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609109
关键词：
APLN gene Adipose tissue Affect Agonist Animals Anti-Inflammatory Agents Antigens Area Autoimmune Responses Biological Assay Biological Markers Bleomycin Blinded Body Weight Cells Cessation of life Chronic Cicatrix Coculture Techniques Collaborations Collagen Cutaneous Data Dermal Development Diagnosis Diffuse Disease Disease model Dose Endothelial Cells Endothelium Extracellular Matrix Face Failure Fibrosis Funding Gene Expression Gene Expression Profiling Goals Grant Hand Heart Histopathology Human Human Characteristics Hydroxyproline Immune Immune response Immunosuppressive Agents Inflammation Injury Interleukin-6 International Interstitial Lung Diseases Kidney Lead Lung Lung Lavage Fluid Measurement Measures Mediating Medical Modeling Monoclonal Antibodies Mus Myocardial Infarction Oral Administration Organ Organ Culture Techniques Orphan Drugs Osmosis Pathogenesis Pathogenicity Pathologist Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physical therapy Production Prognosis Pulmonary Fibrosis Pulmonary Function Test/Forced Expiratory Volume 1 Pump Quality of life Rare Diseases Rattus Research Rheumatism Risk Rodent Model Scleroderma Severity of illness Signal Pathway Skin Skin Tissue Small Business Technology Transfer Research Structure of parenchyma of lung Surrogate Markers System Systemic Scleroderma Systemic Therapy Testing Therapeutic Therapeutic Intervention Thick Tissue Model Tissues Toxic effect Tyrosine Kinase Inhibitor United States Vascular Endothelial Cell Vascular Endothelium Vascular regeneration Weight antifibrotic treatment arm cell injury cell regeneration clinical candidate cytokine disability disorder subtype drug candidate drug development efficacy study endothelial regeneration endothelial repair high risk human tissue idiopathic pulmonary fibrosis improved in vivo loss of function mortality mortality risk mouse model nintedanib novel novel therapeutics pre-clinical prevent primary endpoint receptor regenerative renal damage repaired response response biomarker skin fibrosis small molecule success symptom treatment tocilizumab

项目摘要

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.

抽象的该 STTR 提案的目标是开发一种适合口服给药的新型抗纤维化药物，可用于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病之一。 SSc 是一种罕见疾病，影响美国有 40,000-150,000 人，死亡风险高出五到八倍。它是一个以血管内皮改变为特征的异质性多器官疾病，导致慢性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、肾脏和脉管系统。在 SSc 患者中，血管内皮细胞损伤通常先于炎症和自身免疫反应，刺激进展到组织中纤维化恐惧。早期死亡（诊断后 5 年）的主要原因是间质性肺疾病 (ILD)。治疗常规依赖于尼达尼布（TK 抑制剂）和托珠单抗（IL-6 mAb）以及对症治疗但这些药物的功效有限，并且存在耐受性和/或毒性问题。截至目前，疾病纤维化进展 SSc 的死亡率仍然高于任何其他风湿病；突出明确未满足的问题医学上需要能够预防或减少主要器官损伤的疾病修饰疗法。瞄准通过 Apelinergic System (apelin/APJ) 信号传导修复和再生血管内皮细胞损伤途径为治疗 SSc 患者提供了独特且新颖的机会（截至目前，血管内皮修复和再生是 SSc 药物开发中的一个目标领域）。系统很好—— 被建立为一种内源性抗损伤和器官保护机制，在血管后激活内皮损伤，并在所有受 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药物 apelin 激动剂 APT101，用于治疗肺纤维化。首先，在博来霉素诱导的肺纤维化中使用 APT101 的小鼠模型治疗显着抑制了肺部胶原蛋白的产生（a 肺纤维化进展的标志），通过羟脯氨酸测定检测，以及主要终点学习。其次，APT101 在心肌梗塞动物研究（小鼠和小鼠）中显示出显着减少纤维化大鼠）并显着降低了与以下疾病相关的离体人类细胞共培养疾病模型中的生物标志物反应肺、皮肤和肾纤维化疾病。综上所述，这一证据表明，猿能神经元的激活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，我们将在经过验证的 SSc 模型中获取临床前数据：1) 体内功效模型，2) 体外人体组织模型。目标 1 和 2 的结果将为有关 APT101 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。