Novel Therapeutic for Healing Gut Tissue Novel Therapeutic for - - PowerPoint PPT Presentation

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

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Experienced Team, Focused on Executing Experienced Team, Focused on Executing

Art Artin in Asadourian Asadourian BS, BE, MBA BS, BE, MBA

Co-Founder Co-Founder, Pr , President & CEO esident & CEO

Former Amylin, Amgen, Bayer, Wyeth

Soumitra Soumitra S. Ghosh PhD

• S. Ghosh PhD

Co-founder & CSO Co-founder & CSO

Former Amylin, BMS, MitoKor, Baxter

Karl Sylvester Karl Sylvester, MD , MD

CMO CMO

Pediatric Surgeon – Stanford Children’s Hospital Associate Dean Maternal Child Health- Research Professor of Surgery and Pediatrics Stanford University School of Medicine

David C. David C. Litzinger Litzinger PhD PhD

CMC Lead & Scient CMC Lead & Scientific Advisor ific Advisor

Former Amgen, Lilly, Ambrx, Amylin, Allergan

Harry Harry Leonhar Leonhardt Esq. Esq.

Legal & IP Advisor Legal & IP Advisor

Former Amylin Sr. VP , Deputy General Counsel and Corp. Secretary

Mark Fr Mark Frey PhD ey PhD

Inventor The Saban Research Institute Childrens Hospital Los Angeles

Tachi achi Y Yamada, MD amada, MD

Former Executive Vice-President, Chief Medical and Scientific Officer of Takeda Pharmaceuticals

Wil William iam Sand Sandborn born MD MD

Chief, Division of Gastroenterology UC San Diego, Inflammatory Bowel Disease

Mark Underwood, MD Mark Underwood, MD

Chief of Neonatology UC Davis Neonatology

Art Arthur hur D’Harl D’Harlingue ingue, MD , MD

Attending Neonatologist, Children’s Hospital Oakland

Larry Moss, MD Larry Moss, MD

Surgeon-in-Chief, Nationwide Children’s Hospital Pediatric Surgeon Ohio State University

SCIENTIFIC ADVISORS SCIENTIFIC ADVISORS

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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

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PREEMIES Immature Gut ADULTS Gut Affected by Crohn’s Disease or Ulcerative Colitis INFLAMMA INFLAMMATION TION and INFECTION INFECTION to INTESTINAL INJUR INTESTINAL INJURY

Necrotizing Enterocolitis and Sepsis

30%

Incidence

IBD 1.4M

Affected Adults in the U.S.

The Progression The Progression

• f Compromised
• f Compromised

Gut Tissue Gut Tissue

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Novel Platform Biologic Applicable to Multiple Diseases Novel Platform Biologic Applicable to Multiple Diseases

No available therapies for treatment or prevention, high mortality and life long complications

Driven by Common Disease Biology Driven by Common Disease Biology

Frontline drugs do not target mucosal healing, have high non-response rates, and become refractory over time

Pass Thr Pass Through Common Pat

• ugh Common Pathways

hways

• f Inflammat
• f Inflammation and Cel

ion and Cellular Injury lular Injury No A No Available Pr vailable Products That Pr

• ducts That Promote Cl
• mote Clinical

inically ly Desir Desired Mucosal Heal ed Mucosal Healing ing

NEC / Sepsis

CRITICAL NEED

IBD

UNMET NEED

NRG-4

Direct HEALING of Injured Gut Mucosa

Preparing for IND Enabling and Clinical POC Studies

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A Novel Therapeutic for Unmet Needs in IBD A Novel Therapeutic for Unmet Needs in IBD

Enable Enable INDIRECT INDIRECT Heal Healing by ing by Dampening Inflammat Dampening Inflammation ion Enable Enable DIRECT DIRECT Heal Healing via pr ing via protect

• tection of

ion of Enter Enterocyte and Panet

• cyte and Paneth Cel

h Cells ls Limited to anti-inflammatory

VS VS

Specific M1 macrophage innate immunity target No direct mucosal integrity nor regenerative effects

VS VS

Direct mucosal integrity effects Significant co-morbidities, including increased risk of infections

VS VS

Naturally occurring peptide with single receptor and no mitotic effects Significant rate of non-responders and progression of disease

VS VS

1st in class, novel biologic with multi-faceted MOA Biologics are infusions or injectables

VS VS

Potential for oral therapy

NRG-4 Frontline Therapeutics

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IBD: A Prevalent Disease with Unmet Needs IBD: A Prevalent Disease with Unmet Needs 1.4M

AMERICANS

2.2M

EUROPEANS

30% primary primary non-response rate

for TNF biologics

50% acquire resistance for

leading TNF biologics

IBD Pat IBD Patient Populat ient Population ion

210K

CANADIANS Etiological Factors Genetic Factors and Predisposition

Perpetual Mucosal Injury and Inflammation

Development

• f IBD

Inflammation Oxidative Stress

NOX, iNOS, MPO NF-κΒ, others

(team to research patient pop. in Japan and verify non-response rates)

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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

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Novel, Multi-Factor Novel, Multi-Factor MOA Promotes MOA Promotes Direct Healing Direct Healing NRG-4

Naturally Occurring Peptide That Works with the Body to Restore Intestinal Homeostasis

ANTI-INFLAMMATORY

Induces apoptosis

• f M1 macrophages,

protects against pathogen induced inflammatory injury

1 2

PROTECTIVE

Prevents intestinal cell death triggered by inflammatory cytokine, chemical, or pathogen insults

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RESTORATIVE

Promotes survival of Paneth cells, maintaining the stem cells niche to regenerate the epithelium

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ErbB4 Expression Is Increased in Disease States ErbB4 Expression Is Increased in Disease States

NEC NEC

NEC Control

• Tissues from patients with and without

NEC stain for ErbB4 receptor

• Abundant brown stain along epithelium

and crypts indicate presence of ErbB4 receptor in newborn intestine

B. B. A. A.

goblet cell villus epithelial cells crypt

IBD IBD

Crohn’s Normal

• Representative crypts show nuclear staining

in the epithelium of the Crohn’s tissue

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NRG-4 Levels are Decreased in IBD

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.

A & B. A & B. qPCR Analysis for NRG4 (A) and HRG-1β (B) gene expression was performed on TissueScan Crohn’s/colitis qPCR arrays. Relative mRNA levels were calculated using actin as reference. No change in expression was noted for the shared ErbB3/ErbB4 ligand HRG-1β. 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

Normal Normal Cr Crohn’

• hn’s

UC UC Normal Normal Cr Crohn’

• hn’s

UC UC

Human IBD Samples Human IBD Samples Mouse Model of Col Mouse Model of Colit itis is

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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

NO DISEASE ErbB4 ErbB4 NRG-4 NRG-4

Receptor and ligand levels are balanced

DISEASED ErbB4 ErbB4 NRG-4 NRG-4

Receptor levels dramatically increase in epithelial cells, NRG-4 levels are lower in disease state

REBALANCED ErbB4 ErbB4 NRG-4 NRG-4

NRG-4 is administered pharmacologically to prevent /treat disease

• Plays a natural protective role in the gut
• Binds exclusively to ErbB4
• Signals through the AKT pathway
• Human breast milk contains 159±

34ng/mL* of NRG-4

• NRG-4 expression is decreased during

active inflammation

NRG-4 Ligand ErbB4 Receptor

• Naturally found in the gut
• Plays an important role in gut homeostasis
• Induced by inflammation in pathologic

state

* Mean ± SD

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NRG-4 Plays a Natural Protective Role in the Gut NRG-4 Plays a Natural Protective Role in the Gut

EXPERIMENTAL CONDITION GI DISEASE RELEVANCE NRG-4 PROTECTION Inflammatory Injury Inflammatory Injury (TNF/ (TNF/IFNy IFNy chal challenge) lenge)

• Intestinal inflammation
• Colonic cell apoptosis
• Chemical Injury

Chemical Injury (DSS col (DSS colit itis model) is model)

• Damaged mucosal barrier
• Intestinal inflammation
• Hypoxia Chal

Hypoxia Challenge lenge (Formula Feed (Formula Feeding/Hypoxia NEC ing/Hypoxia NEC* model) model)

• Immature gut development
• Hypoxic injury
• Damaged mucosal barrier
• Bacterial Injury

Bacterial Injury (Dit Dithiazone hiazone/Klebsiel Klebsiella la Pneumonia Pneumonia NEC* NEC* model) model)

• Immature gut development
• Compromised gut anti-microbial defenses
• Bacterial colonization
• Damaged mucosal barrier
• NRG-4 is effective against a broad range of insults including

chemical, inflammatory and bacterial challenges

*NEC: necrotizing enterocolitis

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NRG-4 Blocks Cytokine-induced Apoptosis NRG-4 Blocks Cytokine-induced Apoptosis In Vivo In Vivo and Improves and Improves Experimental Colitis. Experimental Colitis.

NRG-4 NRG-4 blocked blocked apoptosis apoptosis in in the the colons colons of

• f

mice mice induced induced by by TNF TNFα and and IFN IFNγ . . Co- Co- injection injection of

• f NRG-4

NRG-4 i.p i.p. . with with TNF TNF and and IFN IFNγ reduced educed cleaved cleaved caspase-3 caspase-3 on

• n isolated

isolated epithelial epithelial cells cells fr from

• m colons

colons harvested harvested 24 24 hours hours after after the the injection.

• injection. Inhibition

Inhibition of

• f

a p o p t o s i s b y N R G - 4 w a s a l s o

• demonstrated

demonstrated to to be be statistically statistically significant significant in in situ situ by by reduced educed ISOL ISOL staining staining of

• f fixed,

fixed, paraf paraffin-embedded colons. fin-embedded colons.

Ber Bernar nard, J.K. et al. (2012) Neur d, J.K. et al. (2012) Neuregulin-4 is a survival factor for colon epithelial cells both in cultur egulin-4 is a survival factor for colon epithelial cells both in culture e and in vivo. J. Biol. Chem. 287 (47), 39850-39858. and in vivo. J. Biol. Chem. 287 (47), 39850-39858.

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NRG-4 Improves Outcome in IBD Rodent Model NRG-4 Improves Outcome in IBD Rodent Model

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.

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NRG-4 Ameliorates Inflammation in IBD Rodent Model NRG-4 Ameliorates Inflammation in IBD Rodent Model

Outcome in DSS tr Outcome in DSS treatment model: eatment model: IP inject IP injection of NRG-4 r ion of NRG-4 reversed weight-loss, amel eversed weight-loss, ameliorated colon shortening iorated colon shortening and d and diarrhea, r iarrhea, reduced macr educed macrophage numbers, and r

• phage numbers, and reduced levels of t

educed levels of the he macr macrophage-expr

• phage-expressed pr

essed pro-inflammatory cytokines TNF

• -inflammatory cytokines TNFα, IL6, and

, IL6, and IFN IFNγ.

Schumacher et al (2017) ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. Feb 23;8(2):e2622.

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NRG-4 Activation of ErbB4 Induces Apoptosis of Pro-Inflammatory NRG-4 Activation of ErbB4 Induces Apoptosis of Pro-Inflammatory M1 Macrophages in Culture M1 Macrophages in Culture

Schumacher et al (2017) ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. Feb 23;8(2):e2622.

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NRG-4 Blocks NRG-4 Blocks Paneth Paneth Cell Loss and Pathogen-Induced GI Damage Cell Loss and Pathogen-Induced GI Damage

Dithizone Dithizone/Klebsiella Klebsiella Pneumoniae Pneumoniae NEC Model NEC Model

D/K: Dithizone/ Klebsiella pneumoniae

McElroy, S.J. et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J. Pathology 184(10): 2768-2778.

• A. Ileums from 14-day-old mice subjected to D/K NEC, with or without NRG4, underwent

staining by Alcian blue/periodic acideSchiff (AB/PAS) and immunohistochemical analysis for lysozyme to identify Paneth cells (arrowheads).

• B. B: Paneth cells per crypt from five mice per condition (>50 crypts per mouse) were counted.

*P < 0.05, **P < 0.01.

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NRG-4 Prevents Apoptosis in Immature Gut NRG-4 Prevents Apoptosis in Immature Gut

Formula Feeding/Hypoxia NEC Model Formula Feeding/Hypoxia NEC Model

Oral dosing of NRG-4 impr Oral dosing of NRG-4 improved t

• ved the histology and r

he histology and reduced apoptosis in t educed apoptosis in the FFH NEC model in rat pups. he FFH NEC model in rat pups. Immunostaining for ErbB4 showed an incr Immunostaining for ErbB4 showed an increase in r ease in receptor expr eceptor expression in FFH versus dam-fed (DF) pups. ession in FFH versus dam-fed (DF) pups.

McElroy, S.J. et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing

• enterocolitis. Am J. Pathology 184(10): 2768-2778.

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NRG-4 Safety Profile NRG-4 Safety Profile

DOES NOT DOES NOT have tumor- promoting effects in an animal model of chronic gastrointestinal inflammation

Based on These Data, Oral NRG-4 Administration, That Is Expected to Have Minimal Systemic Exposure, Should Not Have Undesirable Mitogenic Effects

DOES NOT DOES NOT stimulate cell proliferation in several human colon cancer cell lines Unlike EGF , DOES NOT DOES NOT stimulate cell proliferation in rodent intestinal cell lines

NRG-4

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IBD IBD

A Novel Topical

• pical / Oral

Oral Treatment That Directly Protects and Repairs the Mucosal Lining

NRG-4

First in Human Proof of Concept UC Enema Patients Phase 2 IND study Commercial Formulation Oral (tablet/capsule)

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Clinical Development Strategy - Clinical Development Strategy - Co-Induction and Maintenance through Mucosal Healing Co-Induction and Maintenance through Mucosal Healing

Alternative to Immune Modulators Combination Induction Rx, Maintenance Rx to Control Flares

Target Target Population(s) Population(s)

Additional IBD Clinical Applications

• 1. Co-induction or Maintenance with ASA, displacing steroids (unwanted

side effects)

• 2. Maintenance or flare Rx in place of immune-modulators (6-MP,

Azathioprine)

• 3. Bridge or prior to existing IV Biologics (i.e. TNF, Integrins, JAK)

*Primary non-responders (30%); 50% acquire resistance to anti-TNF*

*BMJ 2017;357:j2505

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First in Human Proof of Concept First in Human Proof of Concept

Safety Distal UC Adults n=75 (to detect endoscopic response) Topical Enema Administration Efficacy: Endoscopic Response Rate

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SHORTER timeline to value SHORTER timeline to 1st in human safety and efficacy data HISTOLOGIC EVIDENCE of healing PROOF OF CONCEPT of direct gut mucosal activity, non-systemic FASTER PROGRESS to a potential liquidity event at completion of initial human POC

Multiple Benefits of Our Development Strategy Multiple Benefits of Our Development Strategy

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UC- NRG4 - Oral Therapy UC- NRG4 - Oral Therapy IBD-UC IBD-UC

Phase 1 ORAL Phase 2 Efficacy Design(s)

• Adult, healthy volunteers n = 25
• Safety
• Oral administration
• 4 weeks
• Moderate-Severe disease, escalating Rx
• Steroid Sparing
• Dose escalation à 2 doses of NRG4
• Safety determinants
• Efficacy
• 12 weeks dosing

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NRG-4 Development Timeline NRG-4 Development Timeline

Complete Complete YEAR 1 YEAR 1 YEAR 2 YEAR 2 YEAR 3 YEAR 3 YEAR 4 YEAR 4

Preclinical Pharmacology Dev

UC POC Tox

GLP Tox

MCB Eng. Run GMP DS & DP Process Dev. & Demo Run

UC UC IND IND Pre-IND

Enema & Oral Formulation Dev.

Phase 1 Phase 2

CRO Clinical Study Management

Seed

Bioanalytical Method Development

Human POC: $13M Through Clinical Phase 2: UC UC POC POC AUS AUS IRB IRB

Human POC UC Enema

Backup Slides Backup Slides

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Distal UC- Topical Therapy (Enema) Distal UC- Topical Therapy (Enema)

• 1. Miner PB, Jr. In: Kirsner JB, ed. Inflammatory Bowel Disease. 5th ed. 2000.
• 2. Farmer RG, et al. Dig Dis Sci. 1993;38:1137-1146
• 3. Crohn’s & Colitis Foundation, http://www.crohnscolitisfoundation.org
• 4. CDC - Epidemiology of the IBD - Inflammatory Bowel Disease 2017
• 60-80% of UC pat

60-80% of UC patients pr ients present as d esent as distal UC istal UC

• Rx of d

Rx of distal UC, tar istal UC, target geting of drug to t ing of drug to the d he distal istal colon is a priority colon is a priority

• Maintenance Rx

Maintenance Rx – long-term toxicity and long-term toxicity and compl compliance wit iance with med h medicat ications ar ions are key e key determinants determinants

• 40%

40% Pr Proct

• ctit

itis is- Pr

• Proctosigmoid
• ctosigmoidit

itis wit is with mild- h mild- moderate d moderate disease isease à Not in Remission Not in Remission

ADRESSABLE MARKET ADRESSABLE MARKET

• Appr

Approximately 700,000 pat

• ximately 700,000 patients in US suf

ients in US suffer fer wit with UC h UC

• 30% ar

30% are d e diagnosed wit iagnosed with left-sided UC h left-sided UC