ABSTRACT Inflammatory Bowel Disease (IBD) is a collective name for Crohn’s Disease and Ulcerative Colitis (UC). Both conditions manifest with a pathological inflammation of the bowel that causes breaks in mucosal integrity, frank ulceration and the risk of more severe complications. While the etiology of IBD is complex and not fully understood, the distinguishing hallmarks of IBD are dysregulation of normal immune function and impaired epithelial repair. None of the currently available treatment modalities have a specific targeted effect to retain mucosal integrity or to heal breaches in the gut mucosa. Moreover, most drugs in development are focused on modifying the local inflammatory response and not on direct protection and repair of the intestinal epithelium. Therefore, there is a high unmet medical need for a treatment modality that could both directly target gut barrier protection to restore mucosal integrity, and ameliorate the abnormal inflammatory response. Avexegen Therapeutics, Inc. is leveraging the biology of neuregulin-4 (NRG-4), a naturally occurring peptide found in human breast milk, as a novel mucosal healing therapy. NRG-4’s physiological role is in the direct protection of the intestinal epithelium, attenuation of inflammation and the preservation of Paneth cells that are critical for anti- microbial defense and trophic support of intestinal stem cells. Our SBIR Phase 1 studies showed that systemic NRG-4 is efficacious in the mouse DSS-induced colitis model, and demonstrated that oral NRG-4, while being metabolized in the gut, dose-dependently reduces gut inflammation and showed a positive trend towards colon protection. Based on our collective evidence, an orally-optimized NRG-4 can potentially be a superior treatment for IBD or a desired complement to other treatment approaches. For our Phase 2 program, Avexegen proposes the following aims: conduct SAR studies to identify an intestinally stable peptidic NRG-4 analog with improved receptor potency and then demonstrate efficacy in the DSS mouse colitis model using intracecal administration to bypass the stomach. Next, formulation development with a lead NRG-4 analog will be undertaken to generate enteric-coated NRG-4-microcystalline cellulose (NRG-4-MCC) beads that are stable in acidic pH conditions of the stomach and release NRG-4 under near-neutral pH conditions in the intestine. Finally, a dose-response study with orally delivered NRG-4-MCC bead suspensions will be conducted to assess efficacy in the DSS mouse colitis model; receptor engagement, NRG-4 analog’s presence in the colon, and little or no systemic exposure will be demonstrated. Successful completion of the studies will provide an oral NRG-4 drug product candidate for IND-enabling activities and a rich dataset for the pre-clinical and CMC data package for an IND filing. In addition to IBD, this NRG-4 drug will be highly valuable for treating other inflammatory GI conditions where the repair and retention of intest...