SBIR-STTR Award

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 two 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 protection and repair of the intestinal epithelium. It is highly attractive if a treatment modality could indeed target the damaged gut mucosa, as this would complement approaches directed to the abnormal inflammatory response. Such a treatment paradigm would retain mucosal integrity and prevent or ameliorate a local breach, thereby reducing the impact infiltrating external (intra-luminal) factors may have on the pathophysiological process. Additionally, it could facilitate healing of breaches in the mucosa and restore integrity. Avexegen Therapeutics, Inc. in collaboration with Mark Frey’s group at Children’s Hospital, Los Angeles (CHLA), has identified Neuregulin-4 (NRG?4), a naturally occurring constituent of human breast milk, as a novel mucosal healing peptide. NRG-4 leverages physiological mechanisms to both directly protect the intestinal epithelium and to attenuate the inflammatory cascade. These actions have been shown to promote mucosal healing and the restoration of the damaged gut barrier in multiple experimental animal models of intestinal inflammation The NRG-4 product platform offers a wide range of product forms for the treatment of IBD. Based on the evidence gathered thus far, NRG-4 has a high potential for being a stand-alone treatment for these disorders or a complement to other treatment approaches. In this SBIR Phase I project, Avexegen aims to establish: (a) independent confirmation of pre-clinical findings from the Frey lab on the therapeutic potential of NRG-4 as a mucosal healing factor. This will be done by a 4 week in vitro potency determination study followed by an 8 week dose response study in a DSS mouse model. (b) Proof of concept of efficacy of oral administration in an IBD disease model. This will be done by first conducting a 4 week signaling study to demonstrate luminal ErbB4 receptor activation upon oral NRG-4 administration, and in vitro assessment of metabolic stability in a pancreatic digestive enzyme mix. Next, a 3 month analytical method and formulation development study will be conducted, and then followed with an 8 week dose-response study in a DSS mouse model using an oral NRG-4 formulation. These studies will add to the pre-clinical data package for filing the IND, and help transform IBD treatment and potentially other gastro- intestinal disorders where the repair and retention of intestinal mucosal integrity are key treatment objectives.

Public Health Relevance Statement:
NARRATIVE Inflammatory Bowel Disease (IBD) affect more than 1.4 million patients in the US, and manifest with a pathological inflammation of the bowel that causes breaks in mucosal integrity, frank ulceration and the risk of more severe complications. Current treatment approaches have shortcomings. Avexegen Therapeutics, Inc. has identified Neuregulin-4 (NRG?4) as a novel physiological mucosal healing peptide that directly promotes healing of inflamed and damaged intestinal tissue, and therefore restoration of mucosal integrity. Here, Avexegen is seeking to advance this compelling new peptide biology to an important new pharmacological application for the treatment of IBD.

Project Terms:
Affect; analytical method; Anti-inflammatory; Anti-Inflammatory Agents; Attenuated; base; Biological Preservation; Biology; Cells; Clinical; Clinical Data; Collaborations; Complement; Complex; Crohn's disease; Development; Disease; Disease model; Dose; Enzymes; Epithelial; ErbB4 gene; Etiology; Evaluation; Experimental Animal Model; Formulation; Funding; Future; Healed; healing; Human; Human Milk; immune function; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Inflammatory Response; Injection of therapeutic agent; Intestinal Diseases; intestinal epithelium; Intestines; Investments; Light; Los Angeles; manufacturing process; Metabolic; method development; Modality; Modeling; mouse model; Mucous Membrane; Mus; Names; neuregulin-4; novel; novel therapeutics; Oral; Oral Administration; Outcome; Pancreas; Patients; Pediatric Hospitals; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Physiological; pre-clinical; prevent; Prevention; Process; Program Development; receptor; Receptor Activation; Receptor Signaling; Recombinants; repaired; response; restoration; Risk; Route; Secondary to; Signal Transduction; Small Business Innovation Research Grant; Staging; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Ulcer; Ulcerative Colitis; Work

Inflammatory Bowel Disease (IBD) is a collective name for Crohn's Disease and Ulcerative Colitis (UC). Bothconditions manifest with a pathological inflammation of the bowel that causes breaks in mucosal integrity, frankulceration and the risk of more severe complications. While the etiology of IBD is complex and not fullyunderstood, the distinguishing hallmarks of IBD are dysregulation of normal immune function and impairedepithelial repair. None of the currently available treatment modalities have a specific targeted effect to retainmucosal integrity or to heal breaches in the gut mucosa. Moreover, most drugs in development are focused onmodifying 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 barrierprotection to restore mucosal integrity, and ameliorate the abnormal inflammatory response. AvexegenTherapeutics, Inc. is leveraging the biology of neuregulin-4 (NRG-4), a naturally occurring peptide found inhuman breast milk, as a novel mucosal healing therapy. NRG-4's physiological role is in the direct protection ofthe 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 systemicNRG-4 is efficacious in the mouse DSS-induced colitis model, and demonstrated that oral NRG-4, while beingmetabolized in the gut, dose-dependently reduces gut inflammation and showed a positive trend towards colonprotection. Based on our collective evidence, an orally-optimized NRG-4 can potentially be a superior treatmentfor IBD or a desired complement to other treatment approaches. For our Phase 2 program, Avexegen proposesthe following aims: conduct SAR studies to identify an intestinally stable peptidic NRG-4 analog with improvedreceptor potency and then demonstrate efficacy in the DSS mouse colitis model using intracecal administrationto bypass the stomach. Next, formulation development with a lead NRG-4 analog will be undertaken to generateenteric-coated NRG-4-microcystalline cellulose (NRG-4-MCC) beads that are stable in acidic pH conditions ofthe stomach and release NRG-4 under near-neutral pH conditions in the intestine. Finally, a dose-responsestudy with orally delivered NRG-4-MCC bead suspensions will be conducted to assess efficacy in the DSSmouse colitis model; receptor engagement, NRG-4 analog's presence in the colon, and little or no systemicexposure will be demonstrated. Successful completion of the studies will provide an oral NRG-4 drug productcandidate for IND-enabling activities and a rich dataset for the pre-clinical and CMC data package for an INDfiling. In addition to IBD, this NRG-4 drug will be highly valuable for treating other inflammatory GI conditionswhere the repair and retention of intestinal mucosal integrity are key treatment objectives.

Public Health Relevance Statement:
PROJECT NARRATIVE Inflammatory Bowel Disease (IBD) affects more than 3 million patients in the US, manifesting as a pathological inflammation of the bowel that causes breaks in mucosal gut integrity, ulceration and the risk of severe complications. Current treatment approaches have shortcomings. Neuregulin-4 (NRG-4) is a physiological factor that directly promotes healing of inflamed and damaged intestinal tissue, and therefore the restoration of mucosal integrity that is critical for disease remission. Avexegen seeks to develop an optimized NRG-4 analog as an oral mucosal healing drug to treat IBD.

Project Terms:
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