Development of NaV1.7 Inhibitors for the Treatment of Chronic Cough

PROJECT SUMMARYThe objective of our program is to develop a safe and effective therapeutic for chronic coughChronic coughor cough that persists for more than eight weeksis a condition that is often associated with diseases such as chronic obstructive pulmonary disorderCOPDasthmaidiopathic pulmonary fibrosisbronchiectasis or gastroesophageal reflux diseaseGERDIn other casesthe etiology is unknownChronic cough has significant physicalpsychologicalsocial and economic consequences that negatively impact quality of lifePrevalence in the United States is as high asand in a majority of cases the condition is refractoryCompelling evidence supports the hypothesis that chronic cough arises from alterations in sensory physiology that cause hypersensitivity to previously innocuous stimuliThe voltage gated sodium ion channel Navis highly expressed in unmyelinated vagal nerve afferents that trigger cough through a sensorimotor reflex circuitResults from a published pre clinical report show that reducing expression of Navnearly abolishes cough evoked by inhaled irritantsindicating that it is a promising target for reducing coughSiteOne Therapeutics has discovered potent and selective small molecule inhibitors of Navthat block vagal C fiber activity in a dose dependent mannerThe Aims of this Phase I project are to evaluate a series of Navinhibitors against physiologicalpharmacokineticand efficacy endpoints in order to demonstrate the feasibility of developing a therapeutic candidate for chronic cough and to select a candidate for nonclinical development PROJECT NARRATIVE Chronic cough is highly prevalent among adults in the United Statesand a large number of those who suffer from chronic cough do not respond to commonly prescribed antitussivesWe aim to develop a safe and effective local acting antitussive product that acts to reduce the sensory hypersensitivity that is associated with chronic cough