Development of Nav1.7 Selective Inhibitors for the Treatment of Chronic Cough

点击翻译按钮获取中文摘要

PROJECT SUMMARY Chronic cough, or cough that persists for more than eight weeks, is a condition that is often associated with diseases such as chronic obstructive pulmonary disorder (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis or gastroesophageal reflux disease (GERD). In other cases, the etiology is unknown, although it has been noted that the cough often first arises following a severe viral respiratory infection. Chronic cough has significant physical, psychological, social and economic consequences that negatively impact quality of life. Prevalence in the United States is as high as 11%, and in a majority of cases the condition is refractory. Compelling evidence supports the hypothesis that chronic cough arises from alterations in sensory physiology that cause hypersensitivity to previously innocuous stimuli. The voltage-gated sodium ion channel NaV1.7 is highly expressed in unmyelinated vagal nerve afferents that trigger cough through a sensorimotor reflex circuit. Results from a published pre-clinical report show that reducing expression of NaV1.7 nearly abolishes cough evoked by inhaled irritants, indicating that it is a promising target for reducing cough. SiteOne Therapeutics has discovered potent and selective small molecule inhibitors of NaV1.7 that block vagal C fiber activity in a dose-dependent manner. During a Phase 1 program, our team demonstrated that systemic administration of an isoform-selective NaV1.7 inhibitor abolishes the cough response to inhaled irritants in conscious guinea pigs. The objective of our Phase 2 program is evaluate safety, pharmacokinetic and efficacy endpoints, and to advance an inhaled NaV1.7 inhibitor into IND-enabling development as a therapeutic for chronic cough.