Approximately 15 million Americans suffer from asthma, which leads to about 4000 deaths per year, and is responsible for estimated annual total direct and indirect costs of $56 billion. Despite the existing treatments for asthma, predominantly combinations of inhaled ?2-agonists and corticosteroids (CSs), there remains a significant unmet medical need for new therapies which address two key issues: 1) approximately 10% of patients are insensitive to current medicines; and 2) a significant number of patients (up to 50%) have adherence challenges with the inhaled drugs, due to inhaler misuse, lack of use and/or side-effects. There is compelling evidence implicating T-helper 2 (Th2) cells in asthma via: i) the induction and maintenance of inflammation and ii) the progression to the morphological changes associated with chronic disease. Also, there is growing published support that acidic mammalian chitinase (AMCase), a member of the chitinase family of hydrolases, contributes to the Th2-driven inflammatory responses, tissue injury and remodeling associated with diseases such as asthma. Hypothesis: We thus hypothesize that an oral AMCase inhibitor will alter the pattern of inflammation in CS-insensitive asthmatics, may augment the response to CSs in severe asthmatics and will also be effective in Th2-mediated asthma, as well as avoiding the adherence issues with inhaled medicines. Innovation: Our company (OncoArendi Therapeutics) initiated a Drug Discovery Program focused on developing potent and selective, orally active AMCase inhibitors for asthma and other Th2-associated diseases. After synthesizing and testing more than 500 compounds, we have selected a clinical candidate to progress into development for asthma. Our lead candidate OAT-889 is very selective, has high potency, excellent oral bioavailability in rodents, with long terminal half-life, low clearance and high volume of distribution, and activity in two standard models of asthma. In addition, OAT-889 has moderate plasma protein binding across species, no significant inhibition of CYP enzymes or hERG, and is negative in the Ames genotoxicity test. OAT-889 has first-in-class potential, with no known competition from other BioPharmaceutical companies. We propose to file an IND for this novel oral small molecule AMCase inhibitor as a critical step towards the clinical development of this innovative asset to treat moderate-to-severe asthma patients. The major goals of this Fast-track proposal are: Phase I.
Specific Aim 1 : Evaluate the effects of the clinical candidate, OAT-889, in a murine chronic model of asthma involving exposure to Aspergillus fumigatus, which is not sensitive to inhaled CSs. Phase II.
Specific Aim 1 : Translational medicine studies in human lung.
Specific Aim 2 : File an IND for OAT-889 after completing the standard IND-enabling studies. OAT-889 is the first of a new class of oral compounds, AMCase inhibitors, which have the potential to manage patients with moderate-to-severe asthma who are not adequately controlled by current medicines, while significantly improving treatment adherence compared to standard inhaled therapy.
Asthma is a very common and serious lung disease that affects more than 15 million people in the US, with more than 3,000 deaths per year. There are established treatments for asthma, however, approximately 10% of patients do not respond to these medicines. In addition, a large number of patients (estimated to be as high as 50%) do not take their inhaler medicines every day as required, which can make their disease worse. People prefer to take oral medicines rather than drugs given via an inhaler. There remains a significant unmet medical need in asthma for new therapies which address these two key issues. We are developing a new type of oral drug to treat this population of asthmatics who do not get better with current medicines, and also to help patients adhere better to taking their daily treatments for asthma.
