Preclinical evaluation of a novel small molecule STAT inhibitor

Project Summary Problem statementAsthma is one of the most common and burdensome of all chronic inflammatory diseasescausing almost lifelong respiratory symptoms to various degrees through a patient s life due to severe airway inflammationairway obstructionand triggered hyper responsivenessAlmostof these individuals experience very severecomplexand heterogeneous disease symptoms that remain intractable and treatment resistantCurrent therapy is often ineffective in severe asthma conditionsImportantlylong term use of corticosteroids and long actingagonistsLABAsis associated with disabling side effectsleading to worsening of the disease and excess asthma related mortalityThere is thus a clear unmet need for novel therapies that can significantly improve outcomes over current standard of careInnovationNew therapies to treat asthma include monoclonal antibodies targeting cytokines and receptors of the ILILJAK STATpathwayThe pathway has been validated in clinical trials of dupilimaban antibody that targets ILRreceptorand lebrikizumaban anti ILantibodyamong othersHowevermost biologics also have a significant risk of developing neutralizing immune reactionsanti drug antibodiesAtrapos TherapeuticsLLC was founded into develop and commercialize a first in class small molecule therapeutic technology developed by a team of academic scientists at the MD Anderson Cancer Center and Baylor College of MedicineThis technology uniquely targets a crucial intracellular pathway that drives the immune response in a host of chronic diseasesincluding asthmaThe team successfully demonstrated the ability of the lead moleculePMIto significantly reduce the severity of established asthma in mice modelsThey also demonstrated the effectiveness of the molecule to prevent asthma in mice with no prior diseaseAn important differentiating factor from established immunosuppressant therapies in severe asthmasteroidsis the precision of the immunomodulationwhereby the antiviral immunity is unaffectedreducing the risk of secondary infectionsa common problem with prolonged steroid therapyTechnology Development StatusWe successfully met and expanded the Specific Aims of our Phase I proposalPMI was shown to have activity primarily limited to the lung when delivered intranasallyand a greatly expanded toxicity assessment program unequivocally established the safety of the molecule at significantly high dosesProposalThe long term plan of this project is to develop PMI for clinical use in treatment of moderate to severe asthmaThe goal of the work outlined in this grant proposal is to characterizesynthesize and test the drug product for this indicationOverallthe Specific Aims outlined in this proposal will help to complete the preclinical and product development work for PMIWhile Atrapos has had some success in raising angel capital coupled with NIH fundingthe successful awarding of this proposal would complete the remaining preclinical and product development of PMI required for regulatoryFDA and IRBapprovals for clinical translation Project Narrative Severe asthma is a commondebilitating chronic disease that is challenging to treat with current medications like high dose steroidsWe have developed a new class of small molecule therapeutic that can specifically target a critical cellular processreducing the severity of the diseasewhile having an outstanding safety profileIn this proposalwe request funding for further preclinical and regulatory development of the lead moleculegearing towards first in man clinical trials