Novel ROCK inhibitors for COPD

DESCRIPTION provided by applicant Our overall objective is to develop an inhaled safe and efficacious Rho kinase ROCK inhibitor as novel maintenance therapy for patients with chronic obstructive pulmonary disease COPD with the unique potential to slow disease progression COPD is one of the leading causes of morbidity and mortality worldwide due to high disease prevalence and ineffective therapies COPD is the rd leading cause of death in the United States and is responsible for billions of dollars in annual healthcare costs Current treatments are largely palliative and have minimal impact on the key inflammatory processes in COPD that inexorably lead to disease progression and associated decline in lung function Therefore there is an urgent need to develop drugs that target components of COPD not affected by present medicines There is increasing evidence that the ROCK isoforms ROCK and ROCK play an important role in the maintenance of airways tone and in lung inflammation and remodeling suggesting that ROCK inhibitors may represent a novel approach for COPD Theratrophix TRX has identified potent inhibitors of the human ROCK and ROCK isoenzymes including the lead TRX that are more potent than the prototype ROCK inhibitors fasudil and Y The results of the previous Phase SBIR R HL demonstrated that TRX had bronchoprotective anti inflammatory and anti fibrotic effects in rodent systems in vitro and in vivo In this proposal we outline a series of decision making preclinical studies to evaluate and progress an inhaled ROCK inhibitor TRX or analog to the preclinical development phase as a potential novel therapeutic for COPD the profiling is underpinned by investigation in several disease relevant systems The specific aims of this Phase proposal are Aim Developability profile of TRX and analogs including pharmacokinetic PK characteristics to determine which compound has the desired characteristics for a long acting inhaled compound including sustained lung retention and pharmacodynamic activity and the physicochemical characteristics for inhaled delivery Aim Assessment of bronchodilator and anti inflammatory effects of selected TRX compound in human lung systems A series of key translational medicine studies will be conducted using human precision cut lung slices and human airway smooth muscle cells and human lung fibroblasts Aim Evaluation of inhaled TRX compound in mouse models of cigarette smoke induced COPD to determine the in vivo effects in a disease relevant animal model that is resistant to corticosteroids By achieving the specific aims outlined it is anticipated that Theratrophix will have identified a quality inhaled ROCK inhibitor which will be ready to enter IND enabling studies as a critical step towards initiation of clinical trials in COPD Based upon the ability to produce potent bronchodilation anti inflammatory activity and an impact on tissue remodeling in a single molecular entity an inhaled ROCK inhibitor has the potential to have a unique profile which could offer unprecedented therapeutic benefits in COPD in particular slowing disease progression PUBLIC HEALTH RELEVANCE Chronic obstructive pulmonary disease COPD is a very serious common lung disease which is a global problem and does not have good medicines to treat it COPD is the rd leading cause of death in the United States and is responsible for billions of dollars in annual healthcare costs Current treatment for COPD improves some symptoms but does not impact the progressive damage to the airways and decline in lung function This research proposal seeks to investigate whether a potential new type of COPD drug we have identified called a Rho kinase or ROCK inhibitor will likely have benefit and be safe to test in humans The overall goal is to progress an inhaled ROCK inhibitor to clinic trials with the hope that it will become a breakthrough medicine for COPD with a unique profile by both improving symptoms and slowing the progression of the disease