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.
Public Health Relevance Statement: Public Health Relevance: Asthma is a disease of increasing prevalence associated with significant morbidity and health care costs. This project will develop a new treatment for asthma, thereby benefiting patients, the public health, and society in the United States and around the world
NIH Spending Category: Asthma; Lung
Project Terms: Acute; Address; Adverse effects; airway hyperresponsiveness; Allergens; angiogenesis; Anti-inflammatory; Anti-Inflammatory Agents; Area; Asthma; Brain; Breathing; Bronchodilator Agents; Cells; Cessation of life; Characteristics; Chronic; clinical efficacy; Clinical Trials; Complex; Country; Deposition; Differential Scanning Calorimetry; Disease; Dose; drug candidate; Drug Kinetics; eosinophil; 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; improved; Inflammatory; inflammatory marker; inhibitor/antagonist; Injury; interest; Interleukin-13; Interleukin-4; Interleukin-6; KDR gene; Kidney; kinase inhibitor; Lead; Leucine; liquid chromatography mass spectrometry; Liver; Lymphocyte; Measures; methacholine; method development; Modeling; Morbidity - disease rate; Morphology; Mucous body substance; nanocrystal; nanomolar; neutrophil; novel; Organ; particle; Particle Size; Pathogenesis; Pathway interactions; Patients; PDGFRB gene; Pharmaceutical Preparations; Phase; phase II trial; Phenotype; Phosphotransferases; PI3K/AKT; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Powder Diffraction; Powder dose form; pre-clinical; preclinical study; Prevalence; Production; Proto-Oncogene Protein c-kit; Public Health; public health relevance; Rattus; respiratory smooth muscle; response; 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
