A novel inhaled c-kit/PDGFR inhibitor for the treatment of asthma

一种用于治疗哮喘的新型吸入性 c-kit/PDGFR 抑制剂

• 批准号: 9139718
• 负责人: LAWRENCE S. ZISMAN
• 金额: $ 33.73万
• 依托单位: PULMOKINE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-07 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139718
• 关键词: Acute; Address; Adverse effects; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Brain; Breathing; Bronchodilator Agents; Cells; Cessation of life; Characteristics; Chronic; Clinical Trials; Complex; Country; Deposition; Differential Scanning Calorimetry; Disease; Dose; Drug Kinetics; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Ethanol; Excipients; Extracellular Matrix; Feasibility Studies; Fibrosis; Formulation; Glass; Goblet Cells; Grant; Health Care Costs; Heart; High Pressure Liquid Chromatography; Histologic; Human; Hyperplasia; Hypertrophy; IgE; Inflammatory; Injury; Interleukin-13; Interleukin-4; Interleukin-6; KDR gene; Kidney; Lead; Leucine; Liver; Lymphocyte; Measures; Modeling; Morbidity - disease rate; Morphology; Mucous body substance; Organ; PDGFRB gene; PI3K/AKT; Particle Size; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Powder Diffraction; Powder dose form; Prevalence; Production; Proto-Oncogene Protein c-kit; Public Health; Rattus; Roentgen Rays; Series; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Societies; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; Transition Temperature; Tyrosine; Tyrosine Kinase Inhibitor; United States; Water; airway hyperresponsiveness; angiogenesis; clinical efficacy; drug candidate; eosinophil; improved; inflammatory marker; inhibitor/antagonist; interest; kinase inhibitor; liquid chromatography mass spectrometry; methacholine; method development; nanocrystal; nanomolar; neutrophil; novel; particle; phase II trial; pre-clinical; preclinical study; public health relevance; respiratory smooth muscle; response

 DESCRIPTION (provided by applicant): The purpose of this project is to develop an inhaled combined c-kit/PDGFR inhibitor as a treatment for asthma. Asthma is a chronic inflammatory disease characterized by airway hyper-responsiveness, and remodeling. A key underlying mechanism of asthma involves activation of T-helper type 2 (Th2) lymphocytes with production of allergen specific IgE, and activation of mast cells and eosinophils. In severe asthma a more complex phenotype involving Th2, Th1, and Th17 cells develops with increased neutrophils and tissue injury. Goblet cell hyperplasia and increased mucus production is another factor involved in chronic and acute asthma exacerbation. Hypertrophy and hyperplasia of airway smooth muscle cells (ASM), angiogenesis, and increased deposition of extracellular matrix (ECM), lead to chronic remodeling of the conduit airway. Despite currently available treatments, asthma remains a disease of significant morbidity. While most patients can be effectively managed with anti-inflammatory drugs and bronchodilators, a significant subset continue to be symptomatic with resultant high health care costs and, rarely, death. There is a growing interest in the potential use of tyrosine kinase inhibitors to treat asthma. Kinase pathways implicated in the pathogenesis and progression of asthma include EGFR, c-kit, PDGFR, and VEGFR. Pulmokine has invented a series of combined tyrosine inhibitors with high potency against c-kit and PDGFR. By delivering the API by inhalation we hope to increase efficacy and decrease systemic side-effects. The lead candidates to be developed all show IC50 values for inhibition of c-kit, PDGFR alpha, and PDGFRbeta in the nanomolar range. In Aim1 we will develop pre-clinical formulations of the candidate APIs for inhalation. Three drug candidates (PK1019, 1035, and 1036) will be synthesized and formulated as a spray dry powder. The lead candidates are highly soluble in 100% ethanol down to 50% ethanol. Therefore, DSPC or leucine may be used as excipients. Spray dry parameters will be optimized according to key thermodynamic parameters. Analytic method development will consist of HPLC or LC/MS/MS. The SDDs will be characterized, for particle size distribution (NGI cascade impaction), water content (TGA), glass transition temperature (modulated differential scanning calorimetry, mDSC), X ray powder diffraction (XRPD), and SEM for morphology. In Aim2 we will perform pharmacokinetic and pre-clinical efficacy studies in a rat model of asthma. Two drug candidates formulated as spray dry powders will be studied to determine pharmacokinetics and determine effect of formulated drug candidate. In the repeat exposure OVA model, methacholine response will be tested. Airway smooth muscle cell (ASM) area, goblet cell hyperplasia, and peribronchial fibrosis will be assessed by histomorphometry. Epithelial changes and an inflammatory profile will also be measured. Non-GLP toxicity will be assessed by histologic examination of other organs including heart, liver, kidney, and brain. After demonstrating feasibility in phase I we will then o on to a phase II SBIR study that will undertake the preclinical studies required prior to testing i a first in human clinical trial. The results of this study could lead to a new treatment for asthma and thereby benefit patients and society in the United States and other countries.

 描述(由申请人提供)：该项目的目的是开发一种吸入型c-kit/PDGFR联合抑制剂作为哮喘的治疗方法。哮喘是一种以呼吸道高反应性和重塑为特征的慢性炎症性疾病。哮喘的一个关键潜在机制涉及T辅助2型(Th2)淋巴细胞的激活，产生过敏原特异性IgE，以及肥大细胞和嗜酸性粒细胞的激活。在重度哮喘中，随着中性粒细胞的增加和组织损伤，出现更复杂的表型，包括Th2、Th1和Th17细胞。杯状细胞增生和粘液产生增加是慢性和急性哮喘加重的另一个因素。气道平滑肌细胞(ASM)肥大和增殖、血管生成和细胞外基质(ECM)沉积增加，导致慢性管状气道重塑。尽管目前有可用的治疗方法，哮喘仍然是一种发病率很高的疾病。虽然大多数患者可以通过抗炎药物和支气管扩张剂得到有效控制，但仍有相当一部分患者继续出现症状，从而导致高昂的医疗费用，很少会导致死亡。人们对酪氨酸激酶抑制剂治疗哮喘的潜在用途越来越感兴趣。参与哮喘发生和发展的激酶通路包括EGFR、c-kit、PDGFR和VEGFR。Pulmokine发明了一系列高效的联合酪氨酸抑制剂来对抗c-kit和PDGFR。通过吸入给药，我们希望提高疗效并减少全身副作用。待开发的候选先导药物对c-kit、PDGFRα和PDGFRβ的抑制IC50值均在纳摩尔范围内。在Aim1中，我们将开发用于吸入的候选原料药的临床前配方。三种候选药物(PK1019、1035和1036)将被合成并制成喷雾干粉。候选铅在100%乙醇至50%乙醇中高度可溶。因此，DMPC或亮氨酸可以作为辅料使用。喷雾干燥参数将根据关键的热力学参数进行优化。分析方法的发展将包括高效液相或LC/MS/MS，SDDS将进行表征，包括粒度分布(NGI级联撞击)、水分含量(TGA)、玻璃化转变温度(调制差示扫描量热法，MDSC)、X射线粉末衍射(XRPD)和扫描电子显微镜(SEM)的形貌。在AIM2中，我们将在哮喘大鼠模型上进行药代动力学和临床前疗效研究。将对两种作为喷雾干燥粉剂的候选药物进行研究，以确定其药代动力学并确定其疗效。在重复暴露OVA模型中，将测试乙酰甲胆碱反应。将通过组织形态计量学评估气道平滑肌细胞(ASM)面积、杯状细胞增生和支气管周围纤维化。还将测量上皮变化和炎症情况。非GLP的毒性将通过对其他器官的组织学检查进行评估，包括心脏、肝脏、肾脏和大脑。在论证了第一阶段的可行性后，我们将继续进行第二阶段的SBIR研究，该研究将在测试第一个人类临床试验之前进行所需的临床前研究。这项研究的结果可能会导致一种治疗哮喘的新方法，从而使美国和其他国家的患者和社会受益。