Development of an Oral Acidic Mammalian Chitinase Inhibitor to Treat Asthma

Approximatelymillion Americans suffer from asthmawhich leads to aboutdeaths per yearand is responsible for estimated annual total direct and indirect costs of $billionDespite the existing treatments for asthmapredominantly combinations of inhaledagonists and corticosteroidsCSsthere remains a significant unmet medical need for new therapies which address two key issuesapproximatelyof patients are insensitive to current medicinesanda significant number of patientsup tohave adherence challenges with the inhaled drugsdue to inhaler misuselack of use and or side effectsThere is compelling evidence implicating T helperThcells in asthma viaithe induction and maintenance of inflammation and iithe progression to the morphological changes associated with chronic diseaseAlsothere is growing published support that acidic mammalian chitinaseAMCasea member of the chitinase family of hydrolasescontributes to the Thdriven inflammatory responsestissue injury and remodeling associated with diseases such as asthmaHypothesisWe thus hypothesize that an oral AMCase inhibitor will alter the pattern of inflammation in CS insensitive asthmaticsmay augment the response to CSs in severe asthmatics and will also be effective in Thmediated asthmaas well as avoiding the adherence issues with inhaled medicinesInnovationOur companyOncoArendi Therapeuticsinitiated a Drug Discovery Program focused on developing potent and selectiveorally active AMCase inhibitors for asthma and other Thassociated diseasesAfter synthesizing and testing more thancompoundswe have selected a clinical candidate to progress into development for asthmaOur lead candidate OATis very selectivehas high potencyexcellent oral bioavailability in rodentswith long terminal half lifelow clearance and high volume of distributionand activity in two standard models of asthmaIn additionOAThas moderate plasma protein binding across speciesno significant inhibition of CYP enzymes or hERGand is negative in the Ames genotoxicity testOAThas first in class potentialwith no known competition from other BioPharmaceutical companiesWe 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 patientsThe major goals of this Fast track proposal arePhase ISpecific AimEvaluate the effects of the clinical candidateOATin a murine chronic model of asthma involving exposure to Aspergillus fumigatuswhich is not sensitive to inhaled CSsPhase IISpecific AimTranslational medicine studies in human lungSpecific AimFile an IND for OATafter completing the standard IND enabling studiesOATis the first of a new class of oral compoundsAMCase inhibitorswhich have the potential to manage patients with moderate to severe asthma who are not adequately controlled by current medicineswhile significantly improving treatment adherence compared to standard inhaled therapy Asthma is a very common and serious lung disease that affects more thanmillion people in the USwith more thandeaths per yearThere are established treatments for asthmahoweverapproximatelyof patients do not respond to these medicinesIn additiona large number of patientsestimated to be as high asdo not take their inhaler medicines every day as requiredwhich can make their disease worsePeople prefer to take oral medicines rather than drugs given via an inhalerThere remains a significant unmet medical need in asthma for new therapies which address these two key issuesWe are developing a new type of oral drug to treat this population of asthmatics who do not get better with current medicinesand also to help patients adhere better to taking their daily treatments for asthma