PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF), the most common of the interstitial lung diseases, occurs in about 128,000
people, with 48,000 new cases diagnosed annually in the US. The typical clinical course is a progressive
fibrotic disease characterized by scarring and `honeycombingandapos; of the lungs causing an irreversible loss of the
tissueandapos;s ability to transport oxygen. Co-morbid pulmonary hypertension is commonly seen in patients with IPF
and contributes to a worsening clinical prognosis. IPF ultimately robs a patient of the ability to breathe leading
to a mortality rate of 66% at five years following diagnosis. This high death rate corresponds to an
unappreciated large number of fatalities per year (n=40,000), about the same yearly rate as deaths due to
breast cancer. Current treatments have mainly focused on blocking proliferation of lung fibroblasts. A novel
target—Protease-Activated Receptor-2 (PAR2)—has recently been identified as an important mediator in the
pathogenesis of IPF. PAR2 is a cell surface receptor that is upregulated in reactive lung epithelium, fibroblasts,
and inflammatory cells during progression of IPF, and IPF patients with high expression of PAR2 in the lung
have worse survival and clinical indices. Increased pro-coagulant protease (factors VIIa/Xa/TF) activity in the
lung, and local inflammatory proteases such as mast cell tryptase trigger aberrant PAR2 signaling and
activation of the fibrotic response. The goal of this Oasis fast-track STTR proposal is based on our discovery of
a PAR2 inhibitor, OA-235c, as a potent suppressor of aberrant lung fibrotic processes. The cell-penetrating,
lipidated inhibitor OA-235c, was developed using our proprietary Pepducin™ technology. Pepducin™
technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled
receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug
exposure to the target tissue, namely lung. In pre-clinical studies, we show that OA-235c significantly
suppresses fibrosis and inflammation in IPF and other fibrotic-organ models. In preliminary toxicology studies,
OA-235c was safe and tolerated in dogs, rats, and mice with no evidence of pancreas, liver, heart, kidney,
lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic
dose. Oasis Pharmaceuticals successfully preformulated and produced OA-235c at 98% purity and high
chemical and proteolytic stability. Phase 1 (Aim 1) will identify and validate a formulation at 50-100 mg/mL
solubility for OA-235c and demonstrate significant suppression of lung fibrosis and determine any drug-drug
interactions with the two standard-of-care IPF agents. The goal of Phase 2 (Aim 2) will be to complete the IND
Data Package under GLP conditions with GMP OA-235c with submission of the IND to the FDA as the final
milestone. Rapid 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.