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

• 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
• 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

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.

摘要 这项建议的目标是开发一种适用于口服的新型抗纤维化药物，该药物 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 是最具致残性和致命性的免疫介导的风湿性疾病之一。SSc是一种罕见的疾病，影响 在美国有40,000-150,000人，死亡风险增加五到八倍。这是一个 以血管内皮细胞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(S)。主要受累器官 皮肤、肺、肾脏和血管系统。在SSc患者中，血管内皮细胞损伤 特点是先于炎症和自身免疫反应，刺激组织的进展 纤维化症。早期死亡的主要原因是间质性肺病(ILD)。 常规治疗依赖于宁替达尼(TK抑制剂)和Tocilizumab(IL-6单抗)，以及对症治疗 但这些药物的疗效有限，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病；突出了明显的未满足 医学上需要疾病修正疗法，以防止或减少对主要器官的损害。瞄准 APELIN/APJ信号通路对血管内皮细胞损伤的修复与再生 PATH为SSc患者的治疗提供了独特的新机会(截至今天的血管 内皮修复和再生是SSC药物开发中的一个靶向不足的领域)。这个系统很好地- 作为血管后激活的内源性抗损伤和器官保护机制而建立的 内皮细胞损伤，并在所有受SSc疾病影响的器官中表达。 APIE治疗公司与RTI国际公司合作，已经确定了一种主要的抗纤维化药物 候选药物apelin激动剂APT101，用于治疗肺纤维化。首先，在博莱霉素诱导的肺纤维化中 APT101对小鼠模型的治疗显著抑制了肺组织中胶原的产生(A 肺纤维化进展的标志)，如通过羟脯氨酸检测，和主要终点 学习。其次，APT101在心肌梗死动物研究中显示显著减少纤维化(小鼠和 在体外人类细胞共培养疾病模型中显著降低了生物标记物的反应 肺、皮肤和肾脏纤维性疾病。综上所述，这一证据表明，apeline能的激活 该系统有可能破坏导致SSc进行性纤维化的病原级联反应。我们的目标 对于这一建议，我们在经过验证的SSC模型中获得了临床前数据：1)体内疗效模型，2)体外 人体组织模型。AIMS 1和AIMS 2的结果将为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。