PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosisIPFthe most common of the interstitial lung diseasesoccurs in aboutpeoplewithnew cases diagnosed annually in the USThe typical clinical course is a progressive
fibrotic disease characterized by scarring and `honeycombingandaposof the lungs causing an irreversible loss of the
tissueandapos s ability to transport oxygenCo morbid pulmonary hypertension is commonly seen in patients with IPF
and contributes to a worsening clinical prognosisIPF ultimately robs a patient of the ability to breathe leading
to a mortality rate ofat five years following diagnosisThis high death rate corresponds to an
unappreciated large number of fatalities per yearnabout the same yearly rate as deaths due to
breast cancerCurrent treatments have mainly focused on blocking proliferation of lung fibroblastsA novel
target Protease Activated ReceptorPARhas recently been identified as an important mediator in the
pathogenesis of IPFPARis a cell surface receptor that is upregulated in reactive lung epitheliumfibroblastsand inflammatory cells during progression of IPFand IPF patients with high expression of PARin the lung
have worse survival and clinical indicesIncreased pro coagulant proteasefactors VIIa Xa TFactivity in the
lungand local inflammatory proteases such as mast cell tryptase trigger aberrant PARsignaling and
activation of the fibrotic responseThe goal of this Oasis fast track STTR proposal is based on our discovery of
a PARinhibitorOAcas a potent suppressor of aberrant lung fibrotic processesThe cell penetratinglipidated inhibitor OAcwas developed using our proprietary PepducinTM technologyPepducinTM
technology offers a unique opportunity to target the intracellular surface of recalcitrant G protein coupled
receptorsGPCRssuch as PARwith exquisite specificitypotency and long half liveswith prolonged drug
exposure to the target tissuenamely lungIn pre clinical studieswe show that OAc significantly
suppresses fibrosis and inflammation in IPF and other fibrotic organ modelsIn preliminary toxicology studiesOAc was safe and tolerated in dogsratsand mice with no evidence of pancreasliverheartkidneylungbone marrowor other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic
doseOasis Pharmaceuticals successfully preformulated and produced OAc atpurity and high
chemical and proteolytic stabilityPhaseAimwill identify and validate a formulation atmg mL
solubility for OAc and demonstrate significant suppression of lung fibrosis and determine any drug drug
interactions with the two standard of care IPF agentsThe goal of PhaseAimwill be to complete the IND
Data Package under GLP conditions with GMP OAc with submission of the IND to the FDA as the final
milestoneRapid completion of the proposed preclinical and IND enabling studies would generate a novel drug
candidate with an anti fibrotic mode of action for the potential treatment of IPF in patients Idiopathic pulmonary fibrosisIPFthe most common of the chronic lung diseasesoccurs in aboutpeoplewithnew cases diagnosed annually in the USThe typical clinical course is a progressive fibrotic disease of the lungs causing an
irreversible loss of the tissueandapos s ability to transport oxygenA novel targetProteaseActivated ReceptorPARis an important mediator in the pathogenesis of IPF and is
an emerging new targetIn this grant we provide a path to rapid drug development plan
that could lead to new therapeutic treatment for IPF in a very near future