PI3K delta inhibition confer efficacy in experimental models of allergic airway inflammation

Uncontrolled severe asthma is characterized by the generation of allergen-responsive Th2/Th17 memory T cells in lymph nodes, their excessive cytokine production in lung tissue and consequent infiltration of eosinophils and neutrophils from the peripheral circulation. Understanding how and where a potent and selective PI3Kd inhibitor will be maximally efficacious is key to developing effective therapies for severe asthma. To elucidate the pharmacodynamic effects of our highly selective PI3Kd inhibitors on multiple targets of allergic airway inflammation, we compare topical and systemic drug exposures in chronic OVA/alum rats. In addition, we investigated the effect of PI3Kd inhibition on CD4 memory T cells in BAL fluid from the OVA specific, MHC class II restricted αβ T-cell receptor (TCR) OT.2 transgenic mice, by measuring the PI3Kd pathway signaling phosphorylation of S6 ribosomal protein (pS6RPSer235/236)). Therapeutic intervention in the rat OVA/alum model was achieved by dosing on day 20 within the lung challenge phase. Efficacy readouts on day 23 showed elevated Th2 cytokine and granulocyte chemokine levels in BAL, which were reduced dose dependently by PI3Kd inhibition by either route of administration. Consequent influx of eosinophils was also reduced to a comparable degree by either i.t. or i.v. drug. Our results in the OT.2 mice demonstrate the utility of pS6RPSer235/236 in CD4+ T cells as a target engagement marker reflecting PI3Kd activity. We also demonstrate the importance of exposure in systemic circulation, regardless of route of administration, to inhibit Th2 signaling and optimally drive efficacy in experimental asthma-related pathophysiology.