PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis

PAR2 Pepducins 作为特发性肺纤维化的新型治疗方法

• 批准号: 9906265
• 负责人: Athan Kuliopulos
• 金额: $ 74.06万
• 依托单位: OASIS PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906265
• 关键词: Acute; Appearance; Biological Assay; Biological Markers; Bone Marrow; Boston; Canis familiaris; Cardiovascular system; Cell Surface Receptors; Cells; Cessation of life; Chemicals; Chronic; Cicatrix; Clinical; Collaborations; Collagen; Data; Death Rate; Development; Diagnosis; Disease; Disease Progression; Dose; Down-Regulation; Drug Exposure; Drug Interactions; Epithelial; Epithelium; Exposure to; Factor VIIa; Feedback; Fibroblasts; Fibrosis; Formulation; G-Protein-Coupled Receptors; Generations; Genetic; Goals; Heart; Hypersensitivity; Inflammation; Inflammatory; Interleukin-6; Interruption; Interstitial Lung Diseases; Kidney; Laboratories; Liver; Liver Fibrosis; Lung; Mediator of activation protein; Medical center; Methods; Modeling; Mus; Mutation; National Heart, Lung, and Blood Institute; Organ; Organ Model; Outcome; PAR-2 Receptor; Pancreas; Pathogenesis; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pirfenidone; Process; Production; Pulmonary Fibrosis; Pulmonary Hypertension; Rattus; Rheumatology; Safety; Series; Signal Transduction; Small Business Technology Transfer Research; Solubility; Specificity; Surface; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Toxicology; Transforming Growth Factor beta; Trichrome stain; Tryptase; Tyrosine Kinase Inhibitor; Validation; Vital capacity; base; clinical candidate; commercialization; comorbidity; design; drug candidate; drug development; effective therapy; efficacy study; healthy volunteer; idiopathic pulmonary fibrosis; indexing; inflammatory marker; inhibitor/antagonist; kidney fibrosis; malignant breast neoplasm; mortality; mouse model; novel; novel therapeutics; outcome forecast; oxygen transport; pharmacokinetics and pharmacodynamics; phase 1 designs; pre-clinical; preclinical study; programs; receptor; respiratory; response; safety study; standard of care; synergism; targeted treatment

Idiopathic pulmonary fibrosis (IPF), the most common of the interstitial lung diseases, occurs in about 128,000 people, with 48,000 new cases diagnosed annually in the US. The typical clinical course is a progressive fibrotic disease characterized by scarring and `honeycombing' of the lungs causing an irreversible loss of the tissue's ability to transport oxygen. Co-morbid pulmonary hypertension is commonly seen in patients with IPF and contributes to a worsening clinical prognosis. IPF ultimately robs a patient of the ability to breathe leading to a mortality rate of 66% at five years following diagnosis. This high death rate corresponds to an unappreciated large number of fatalities per year (n=40,000), about the same yearly rate as deaths due to breast cancer. Current treatments have mainly focused on blocking proliferation of lung fibroblasts. A novel target—Protease-Activated Receptor-2 (PAR2)—has recently been identified as an important mediator in the pathogenesis of IPF. PAR2 is a cell surface receptor that is upregulated in reactive lung epithelium, fibroblasts, and inflammatory cells during progression of IPF, and IPF patients with high expression of PAR2 in the lung have worse survival and clinical indices. Increased pro-coagulant protease (factors VIIa/Xa/TF) activity in the lung, and local inflammatory proteases such as mast cell tryptase trigger aberrant PAR2 signaling and activation of the fibrotic response. The goal of this Oasis fast-track STTR proposal is based on our discovery of a PAR2 inhibitor, OA-235c, as a potent suppressor of aberrant lung fibrotic processes. The cell-penetrating, lipidated inhibitor OA-235c, was developed using our proprietary Pepducin™ technology. Pepducin™ technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely lung. In pre-clinical studies, we show that OA-235c significantly suppresses fibrosis and inflammation in IPF and other fibrotic-organ models. In preliminary toxicology studies, OA-235c was safe and tolerated in dogs, rats, and mice with no evidence of pancreas, liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. Oasis Pharmaceuticals successfully preformulated and produced OA-235c at 98% purity and high chemical and proteolytic stability. Phase 1 (Aim 1) will identify and validate a formulation at 50-100 mg/mL solubility for OA-235c and demonstrate significant suppression of lung fibrosis and determine any drug-drug interactions with the two standard-of-care IPF agents. The goal of Phase 2 (Aim 2) will be to complete the IND Data Package under GLP conditions with GMP OA-235c with submission of the IND to the FDA as the final milestone. Rapid completion of the proposed preclinical and IND-enabling studies would generate a novel drug candidate with an anti-fibrotic mode of action for the potential treatment of IPF in patients.

特发性肺纤维化 (IPF) 是最常见的间质性肺疾病，约有 128,000 人患有特发性肺纤维化 (IPF) 美国每年诊断出 48,000 例新病例，典型的临床病程是渐进的。 以肺部疤痕和“蜂窝状”为特征的纤维化疾病，导致不可逆的肺功能丧失 IPF 患者常见肺动脉高压。 并导致临床预后恶化，最终导致患者丧失呼吸能力。 诊断后五年死亡率高达 66%。 每年有大量未统计的死亡人数（n=40,000），与因 目前的治疗主要集中在阻止肺成纤维细胞的增殖。 靶点——蛋白酶激活受体-2 (PAR2)——最近被确定为该过程中的重要介质。 IPF 的发病机制是一种细胞表面受体，在反应性肺上皮、成纤维细胞中表达上调。 IPF进展过程中的炎症细胞和炎症细胞以及肺中PAR2高表达的IPF患者 生存率和临床指数较差。促凝血蛋白酶（因子 VIIa/Xa/TF）活性增加。 肺部和局部炎症蛋白酶（例如肥大细胞类胰蛋白酶）会触发异常的 PAR2 信号传导， Oasis 快速通道 STTR 提案的目标是基于我们的发现。 PAR2 抑制剂 OA-235c，作为异常肺纤维化过程的有效抑制剂。 脂质抑制剂 OA-235c 是使用我们专有的 Pepducin™ 技术开发的。 技术提供了一个独特的机会来靶向顽固性 G 蛋白偶联的细胞内表面 PAR2 等受体 (GPCR) 具有出色的特异性、效力和长半衰期，具有较长的药物作用 在临床前研究中，我们表明 OA-235c 显着暴露于靶组织，即肺。 在 IPF 和其他纤维化器官模型中抑制纤维化和炎症。 OA-235c 在狗、大鼠和小鼠中是安全且耐受的，没有证据表明胰腺、肝脏、心脏、肾脏、 肺、骨髓或其他器官毒性或高倍数治疗时出现任何实验室异常 Oasis Pharmaceuticals 成功预配制并生产出纯度高达 98% 的 OA-235c。 第 1 阶段（目标 1）将鉴定并验证 50-100 mg/mL 的制剂。 OA-235c 的溶解度并显示出对肺纤维化的显着抑制并确定任何药物-药物 与两种标准护理 IPF 药物的相互作用 第 2 阶段（目标 2）的目标是完成 IND。 符合 GMP OA-235c 的 GLP 条件下的数据包，并向 FDA 提交 IND 作为最终结果 快速完成拟议的临床前和 IND 启用研究将产生一种新药。 具有抗纤维化作用模式的候选者，可用于治疗 IPF 患者。