Project 3. Mechanisms of benefit of biologic agents for patients with aspirin-exacerbated respiratory disease (AERD)

PROJECT SUMMARY/ABSTRACT Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory syndrome that affects 14% of adults with severe asthma, and 30% of adults with asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Patients with AERD develop recurrent nasal polyps that cause nasal blockage, sinus pain, and complete loss of sense of smell. Neither the initial cause nor the driver of ongoing inflammation and polyp regrowth are known, and there are few effective therapies. Newly developed biologic anti-type 2 cytokine therapies are a significant treatment advance, but the roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with asthma, CRSwNP, and AERD are not known. Our preliminary data show that AERD pathophysiology involves persistently abnormal functions of both mast cells and epithelial cells within the nasal polyp tissue, which contributes to disease persistence, recurrence and severity. The dysregulation of these cells is tightly linked and potentially regulated by IL-4Rα and IL-33 signaling. This Project will determine the cell-specific roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with AERD and nasal polyposis. Using a double-blind, placebo-controlled parallel-design trial of dupilumab, a potent IL-4Rα antagonist, and REGN3500, a potent IL-33 inhibitor, we will test the central hypotheses that (1) the rapid onset of clinical improvement provided by IL-4Rα inhibition with dupilumab in AERD is due largely to the drug’s direct effects on both MCs and EpCs; and (2) REGN3500 will rapidly and directly suppress MC activation, but will not effect EpCs until it inhibits IL-13 production, and therefore will have a more delayed onset for full clinical effectiveness. Aim 1 will determin the efficacy of dupilumab and REGN3500 as treatments for AERD. Aim 2 will determine the relevance of IL-4Rα and IL-33/ST2 signaling on on mast cell activation, epithelial cell dysfunction, and the respiratory inflammation in AERD. To address our hypotheses, we propose the following Aims: Aim 1. Compare the clinical efficacy of anti-IL-4α (dupilumab) and anti-IL-33 (REGN3500) as treatments for nasal polyps in AERD in a double-blind, placebo-controlled clinical trial. Aim 2. Define the mechanism(s) of anti-IL-4Rα and anti-IL-33-induced therapeutic benefit in AERD by linking early and later changes in mediator and effector cell readouts to clinical efficacy.