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部疾病，发生在约128,000中 人们每年在美国诊断出48,000例新病例。典型的临床课程是进步的 纤维化疾病的特征是肺部疤痕和“蜂窝”，导致不可逆转的损失 组织运输氧气的能力。联合性肺动脉高压通常在IPF患者中看到 并有助于令人担忧的临床预后。 IPF最终抢劫了患者的呼吸能力 诊断后五年的死亡率为66％。这个高死亡率对应于 每年没有批准的大量死亡（n = 40,000），年龄与死亡率相同 乳腺癌。目前的治疗主要集中在阻断肺成纤维细胞的增殖。小说 靶标 - 致激活的受体2（PAR2） - 最近被确定为重要的介体 IPF的发病机理。 PAR2是一种细胞表面受体，在反应性肺上皮，成纤维细胞中上调， IPF进展过程中的炎症细胞和肺中PAR2高表达的IPF患者 生存和临床指数较差。促凝蛋白酶（因子VIIA/XA/TF因素）在 肺和局部炎症蛋白酶，例如肥大细胞胰蛋白酶触发异常PAR2信号传导和 纤维化反应的激活。这个绿洲快速轨道sttr提案的目标是基于我们发现的 PAR2抑制剂OA-235C，是异常肺纤维化过程的有效抑制剂。细胞穿透， 使用我们的专有Pepducin™技术开发了脂化抑制剂OA-235C。 pepducin™ 技术提供了一个独特的机会，可以瞄准固联的顽固性G蛋白的细胞内表面 受体（GPCR），例如具有独特特异性，效力和长期衰老的PAR2，并具有延长药物 暴露于靶组织，即肺。在临床前研究中，我们表明OA-235C显着 抑制IPF和其他纤维化模型中的纤维化和注射。在初步毒理学研究中， OA-235C在没有胰腺，肝脏，心脏，肾脏的狗，大鼠和小鼠中安全且耐受性 肺，骨髓或其他器官毒性或高倍数的任何实验室异常 剂量。 Oasis Pharmaceuticals以98％的纯度成功地预建了OA-235C，高 化学和蛋白水解稳定性。第1阶段（AIM 1）将以50-100 mg/ml的形式识别和验证公式 OA-235C的溶解度，表现出对肺纤维化的显着抑制，并确定任何药物药物 与两个护理标准IPF代理的相互作用。第2阶段的目标（AIM 2）将是完成IND GMP OA-235C在GLP条件下的数据包，将IND提交给FDA作为最终 里程碑。提出的临床前和辅助研究的快速完成将产生一种新的药物 具有抗纤维化作用方式的候选者，用于患者IPF的潜在治疗。