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Novel Therapeutic for Healing Gut Tissue Novel Therapeutic for Healing Gut Tissue D D E P r e s e n t a t i o n J u n e 2 8 , 2 0 1 8 D D E P r e s e n t a t i o n J u n e 2 8 , 2 0 1 8 Experienced Team, Focused on Executing Experienced


  1. Novel Therapeutic for Healing Gut Tissue Novel Therapeutic for Healing Gut Tissue D D E P r e s e n t a t i o n J u n e 2 8 , 2 0 1 8 D D E P r e s e n t a t i o n J u n e 2 8 , 2 0 1 8

  2. Experienced Team, Focused on Executing Experienced Team, Focused on Executing SCIENTIFIC ADVISORS SCIENTIFIC ADVISORS Mark Frey PhD Mark Fr ey PhD Artin Art in Asadourian Asadourian Co-Founder Co-Founder, Pr , President & CEO esident & CEO Inventor Former Amylin, Amgen, Bayer, Wyeth BS, BE, MBA BS, BE, MBA The Saban Research Institute Childrens Hospital Los Angeles Soumitra Soumitra S. Ghosh PhD S. Ghosh PhD Co-founder & CSO Co-founder & CSO Tachi achi Y Yamada, MD amada, MD Former Amylin, BMS, MitoKor, Baxter Former Executive Vice-President, Chief Medical and Scientific Officer of Takeda Pharmaceuticals Karl Sylvester Karl Sylvester, MD , MD CMO CMO Wil William iam Sand Sandborn born MD MD Pediatric Surgeon – Stanford Children’s Hospital Chief, Division of Gastroenterology Associate Dean Maternal Child Health- Research UC San Diego, Inflammatory Bowel Disease Professor of Surgery and Pediatrics Mark Underwood, MD Mark Underwood, MD Stanford University School of Medicine Chief of Neonatology David C. David C. Litzinger Litzinger PhD PhD CMC Lead & Scientific Advisor CMC Lead & Scient ific Advisor UC Davis Neonatology Former Amgen, Lilly, Ambrx, Amylin, Allergan Arthur Art hur D’Harl D’Harlingue ingue, MD , MD Attending Neonatologist, Children’s Hospital Oakland Larry Moss, MD Larry Moss, MD Harry Leonhar Harry Leonhardt Esq. Esq. Legal & IP Advisor Legal & IP Advisor Former Amylin Sr. VP , Deputy General Counsel Surgeon-in-Chief, Nationwide Children’s Hospital Pediatric Surgeon and Corp. Secretary Ohio State University 2

  3. Neuregulin-4 Asset Neuregulin-4 Asset § Naturally occurring physiological peptide § Present in maternal breast milk and the GI tract § Folded peptide (62 aa, 3 disulfides) with high chemical and metabolic stability § Selective ligand for ErbB4 receptor that is expressed in the GI tract and pro- inflammatory M1 macrophages § Exhibits novel protective and restorative effects on intestinal tissue. § No mitogenic effects § Oral delivery - ideally suited for targeted gut mucosal healing action. § Targeted GI disorders include Crohn’s disease, ulcerative colitis and necrotizing enterocolitis. § Licensed from Children’s Hospital Los Angeles 3

  4. The Progression The Progression of Compromised of Compromised Gut Tissue Gut Tissue PREEMIES ADULTS Immature Gut Gut Affected by INFLAMMATION INFLAMMA TION Crohn’s Disease or and Ulcerative Colitis Necrotizing INFECTION INFECTION Enterocolitis to IBD and Sepsis INTESTINAL INJURY INTESTINAL INJUR 1.4M 30% Affected Adults Incidence in the U.S. 4

  5. Novel Platform Biologic Applicable to Multiple Diseases Novel Platform Biologic Applicable to Multiple Diseases CRITICAL NEED UNMET NEED NEC / Sepsis IBD Driven by Common Disease Biology Driven by Common Disease Biology Frontline drugs do not No available therapies for target mucosal healing, treatment or prevention, Pass Thr Pass Through Common Pat ough Common Pathways hways have high non-response high mortality and of Inflammat of Inflammation and Cel ion and Cellular Injury lular Injury rates, and become life long complications refractory over time No Available Pr No A vailable Products That Pr oducts That Promote Cl omote Clinical inically ly Desir Desired Mucosal Heal ed Mucosal Healing ing NRG-4 Direct HEALING of Injured Gut Mucosa Preparing for IND Enabling and Clinical POC Studies 5

  6. A Novel Therapeutic for Unmet Needs in IBD A Novel Therapeutic for Unmet Needs in IBD Frontline Therapeutics NRG-4 Enable Enable INDIRECT INDIRECT Heal Healing by ing by Enable Enable DIRECT DIRECT Heal Healing via pr ing via protect otection of ion of Dampening Inflammation Dampening Inflammat ion Enter Enterocyte and Panet ocyte and Paneth Cel h Cells ls Specific M1 macrophage Limited to anti-inflammatory VS VS innate immunity target No direct mucosal integrity nor Direct mucosal integrity effects VS VS regenerative effects Significant co-morbidities, including Naturally occurring peptide with single VS VS increased risk of infections receptor and no mitotic effects Significant rate of non-responders 1 st in class, novel biologic with VS VS and progression of disease multi-faceted MOA Biologics are infusions or injectables Potential for oral therapy VS VS 6

  7. (team to research patient pop. in Japan and verify non-response rates) IBD: A Prevalent Disease with Unmet Needs IBD: A Prevalent Disease with Unmet Needs IBD Pat IBD Patient Populat ient Population ion 30% primary primary non-response rate 2.2M for TNF biologics EUROPEANS 210K 50% 1.4M CANADIANS acquire resistance for AMERICANS leading TNF biologics Perpetual Mucosal Injury and Inflammation Inflammation Etiological Factors NOX, iNOS, MPO NF- κΒ , others Genetic Factors Development and Predisposition of IBD Oxidative Stress 7

  8. Critical Unmet Need Critical Unmet Need NEC is a LEADING NEC is a LEADING Cause of Cause of Mortality and Morbidity Mortality and Morbidity in Premature Infants in Premature Infants • From 2000-2011 deaths of extremely premature infants from other causes declined, but NEC related deaths increased • No effective preventive therapies, current treatment is supportive • Breast milk is efficacious but availability and quality is inconsistent • Probiotics have some use (OUS) – with inconsistent evidence of benefit Patel RM et al. N Engl J Med 2015;372:331-340 8

  9. ANTI-INFLAMMATORY Novel, Multi-Factor Novel, Multi-Factor 1 Induces apoptosis of M1 macrophages, MOA Promotes MOA Promotes protects against pathogen induced Direct Healing Direct Healing inflammatory injury NRG-4 Naturally Occurring Peptide That Works with the Body to Restore Intestinal Homeostasis 2 3 PROTECTIVE RESTORATIVE Prevents intestinal cell death Promotes survival of Paneth triggered by inflammatory cells, maintaining the stem cytokine, chemical, or cells niche to regenerate the pathogen insults epithelium 9

  10. ErbB4 Expression Is Increased in Disease States ErbB4 Expression Is Increased in Disease States NEC Control B. B. A. A. • Tissues from patients with and without epithelial cells NEC stain for ErbB4 receptor NEC NEC goblet cell • Abundant brown stain along epithelium villus and crypts indicate presence of ErbB4 receptor in newborn intestine crypt Crohn’s Normal • Representative crypts show nuclear staining IBD IBD in the epithelium of the Crohn’s tissue 10 10

  11. NRG-4 Levels are Decreased in IBD Human IBD Samples Human IBD Samples Mouse Model of Colit Mouse Model of Col itis is Normal Normal Crohn’ Cr ohn’s UC UC Normal Normal Crohn’ Cr ohn’s UC UC A & B. qPCR Analysis for NRG4 (A) and HRG-1 β (B) gene expression was performed on TissueScan Crohn’s/colitis A & B. qPCR arrays. Relative mRNA levels were calculated using actin as reference. No change in expression was noted for the shared ErbB3/ErbB4 ligand HRG-1 β . C. C. Colonic homogenates from wild type controls (WT) or IL-10 -/- mice were subjected to Western blot analysis for ErbB4, phospho-ErbB4 (P-ErbB4), and NRG4. UC: ulcerative colitis Bernard, J.K. et al. (2012) Neuregulin-4 is a survival factor for colon epithelial cells both in culture and in vivo. J. Biol. Chem. 287 (47), 39850-39858. 11 11

  12. Rebalancing the Levels of NRG-4 and ErbB4 Rebalancing the Levels of NRG-4 and ErbB4 to Prevent / Treat Disease to Prevent / Treat Disease Pr Pre-Cl e-Clinical Stud inical Studies Have Establ ies Have Established That NRG-4 and ErbB4 ished That NRG-4 and ErbB4 Ar Are Al e Alter tered in GI Mucosa in Heal ed in GI Mucosa in Health and Disease h and Disease ErbB4 ErbB4 ErbB4 ErbB4 NRG-4 NRG-4 ErbB4 ErbB4 NRG-4 NRG-4 NRG-4 NRG-4 NO DISEASE DISEASED REBALANCED Receptor and ligand Receptor levels dramatically increase NRG-4 is administered levels are balanced in epithelial cells, NRG-4 levels are pharmacologically to lower in disease state prevent /treat disease ErbB4 Receptor NRG-4 Ligand • Plays a natural protective role in the gut • Naturally found in the gut • Binds exclusively to ErbB4 • Plays an important role in gut homeostasis • Signals through the AKT pathway • Induced by inflammation in pathologic • state Human breast milk contains 159± 34ng/mL* of NRG-4 • NRG-4 expression is decreased during * Mean ± SD active inflammation 12 12

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