Pulmokine, Inc. — Department of Health and Human Services SBIR Phase I: NHLBI

Description

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 Th lymphocytes with production of allergen specific IgE and activation of mast cells and eosinophils In severe asthma a more complex phenotype involving Th Th and Th 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 IC values for inhibition of c kit PDGFR alpha and PDGFRbeta in the nanomolar range In Aim we will develop pre clinical formulations of the candidate APIs for inhalation Three drug candidates PK and will be synthesized and formulated as a spray dry powder The lead candidates are highly soluble in ethanol down to 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 Aim 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 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