Slide 1: Celiac Disease R&D Webcast
Nepcast Rersistent Disease Act ical Ne 2
Slide 2: Cautionary Note Regarding Forward-Looking Statements
Cautionary Note Regarding Forward-Looking Statements This presentation contains “forward-looking statements” that involvesubstantial risks and uncertainties for purposesof the safe harbor within the meaning of Section 7A of the Securities Act of 1933, asamended, and Section 21£ of the Securities Exc
Slide 3: Agenda: Celiac Disease R&D Webcast
Agenda: Celiac Disease R&D Webcast Treatment of Celiac Disease: Current Pathways for Drug Development & Persistent Disease Activity Despite Gluten-Free Diet as the Unmet Medical Need : : Mechanism of Action and pea Preclinical Data for IMU-856 . . Expert Presentation: 12:05~ 12:25 S Michael Schumann
Slide 4: Welcome and Introductions
Slide 5: Featured Experts
aoe, Featured Experts Speakers: Celiac Disease R&D Webcast Immunic Speakers Joseph A. Murray, MD Professor of Medicine Celiac Disease Research John and Shirley Berry Professor of Gastrointestinal Sciences Division of Gastroenterology and Hepatology Department of Internal Medicine :, Rochester, MN Di
Slide 6: Advanced Clinical Pipeline
Advanced Clinical Pipeline Three Differentiated Programs in Various Phases of Clinical Development Program Target Preclinical Phase1 Phase 2 Phase 3 Key Milestones Vidofludimus Calcium (umu-838) DHODH ig Multiple Sclero: MS) — ENSURE Trials ive Multiple Sclerosis (PMS) ~ CALLIPER Trial IMU-935, IL-1
Slide 7: Disease Overview
Prevalence and Diagnosis Disease Overview
Slide 8: Disease Overview
Disease Overview
Slide 9: Celiac Disease is a Serious Life-Long Autoimmune Disease
Celiac Disease is a Serious Life-Long Autoimmune Disease = Celiac disease is a multifactorial, complex autoimmune disease caused by an immune reaction against a gut lumen degradation product of gluten and strongly associated with specific HLA class Il gene variants (HLA-DQ2/-DQ8)!1J gluten protein .
Slide 10: Celiac Disease Currently Has No Adequate Treatment Options
Celiac Disease Currently Has No Adequate Treatment Options How much is 10 mg of gluten? The Only Option Today is a Gluten-Free Diet!) Like a pin-point * The only established therapeutic option is a life-long strict adherence of flour to a gluten-free diet, which involves complete avoidance of protei
Slide 11: Ongoing Active Celiac Disease Despite Gluten-Free Diet as Unmet Medical Need
Ongoing Active Celiac Disease (OACD) Despite Gluten-Free Diet (GFD) as Unmet Medical Need Ongoing Active Unmet Celiac Disease (©) High Risk of Accidental, Medical Need </ Inadvertent Gluten Intake Most studies report between 24 % and 47 %l1-1 of patients with signs and symptoms of OACD despite Sourc
Slide 12: Persistent Villous Atrophy Despite Gluten-Free Diet is Common
Persistent Villous Atrophy Despite Gluten-Free Diet is Common Most Studies Report Rates of Persistent Villous Atrophy Between 24 % and 47 % Percentage of Persistent Villous Atrophy Despite2 12 Months Gluten-Free Diet (% of total celiac disease patients) 100% 80% 60% 40% * 20% 43.0% 44.0% 47.0% 23.8%
Slide 13: Celiac Disease is Not Restricted to the Small Intestine
Celiac Disease is Not Restricted to the Small Intestine and Results in Serious Consequences Clinical Findings ibicioates eee + Recurringheadaches and Consequences hypoplasia + Peripheral neuropathy + Dermatitisherpetiformis + short stature o fmmaictitios. [> tiiseeckcems + Delayed puberty mouth ulce
Slide 14: Signs and Symptoms in Ongoing Active Celiac Disease
Signs and Symptoms in Ongoing Active Celiac Disease (OACD) Ongoing Exposure to Gluten Single Dose 3-7 Days 2-6 Weeks 6 Weeks — 1 Year Enterocyte/villous dainape, steatori hea Enterocyte/villous damage, Nausea, vomiting, diarrhea, Gastrointestinal dysmotility, weightloss, abdominal pain, bloating, sy
Slide 15: Prevalence and Diagnosis
Prevalence and Diagnosis
Slide 16: Celiac Disease is a Major Public Health Problem Worldwide
Celiac Disease is a Major Public Health Problem Worldwide A Systematic Review and Meta-Analysis of 96 Articles Published Between 1991 and 2016 Showed a Pooled Worldwide Prevalence of 1.4 % Based on Blood Tests!!! = Pooled seroprevalence of celiac disease in different continents ranged from 1.1% (95%
Slide 17: Celiac Disease Can Develop at Any Age With Often Delayed Diagnosis
Celiac Disease Can Develop at Any Age With Often Delayed Diagnosis The Median Age of Diagnosis is 40 Years With a Modest Female Predominance!” Diagnosis is Often Delayed Due to Non- Classical/Extra-Intestinal Symptoms Stud) Diagnostic Dela > 80 years M 3 M (4%) Swiss survey, N=1689!1 Average 7.3 yea
Slide 18: Overlap in Disease Symptoms Contributes to Diagnostic Delay
Overlap in Disease Symptoms Contributes to Diagnostic Delay in Celiac Disease Patients Celiac Disease Food Intolerance Microscopic Colitis Crohn’s Disease Irritable Bowel Syndrome Caio at a. BMC Madicine (2018) 17:162 18 | ©immunic,inc. | Feb/09/2023 ay Immunic
Slide 19: Diagnostic Approach in Suspected Celiac Disease
a. Celiac serology!#] Tissue Tissue Transglutaminase- |) ieee iro IgA (tTG- Iga IgA) (tTG-1ga) + + Deaminated Gliadin Total IgA level Peptide-IgG (DGP-IgG) Incase of IgA deficiency additional: Deamidated Gliadin Peptide-IgG (DGP-1g6) [a] Tye-Din, AIGPVOL.47,NO. 1-2, JAN-FEB 2018, b. Serology can be
Slide 20: Diagnosis of Celiac Disease: What Histology Tells Us
Diagnosis of Celiac Disease: What Histology Tells Us Well Controlled Celiac Disease B | Ongoing Active Celiac Disease (OACD) = Tip-predominant intraepithelial lymphocytosis = Villous height:Crypt depth ratio J alone (see arrow) = Intraepithelial Lymphocytes 1 b Figure andText Kamto| etal, Clinical a
Slide 21: Diagnosis of Celiac Disease: What Histology Tells Us
Diagnosis of Celiac Disease: What Histology Tells Us we. Schematic Depiction of Marsh- Histological Description a Ciesla colons 4 Oberhuber Grades I-III Crypts Marsh Villous TEL Oberhuber | height:Crypt | (cD3+/100 o 1 " Ma Mb Mic GEse seine SUES) Normal Normal MO 22,8 <25 (22.3) 22, (22.3) Enlarged
Slide 22: Regulatory Guidelines and Development Pathways
Regulatory Guidelines and Development Pathways Investigational Growing Interest Treatments in by Pharma Development Industry
Slide 23: Investigational Treatments in Development
Investigational Treatments in Development
Slide 24: No Approved Drugs Exist Today; Therapeutics Are in Development
No Approved Drugs Exist Today; Therapeutics Are in Development Across the Spectrum of Celiac Disease Drivers Celiac Disease Barrier e Insult +e Immune Response 2e Components Damage Reduce 5 : Increase : Therapeutic 7 Reduce barrier A Immune Immuno- Barrier Modify gluten immune Approaches permeabilit
Slide 25: Gluten Modification in the Lumen (Latiglutenase)
Gluten Modification in the Lumen (Latiglutenase) 2 Restricted to Patients With Ongoing Gluten Exposure Immunogen’ Study Phase 2b, CeliAction Study (NCT01917630)!22] Phase 2, CeliacShield™ Study (NCT03585478)) Gluten Challenge = None, OACD patients = 2 ggluten challenge daily for 6 weeks Primary Endp
Slide 26: Inhibition of Transglutaminase (ZED1227/TAK-1227)
Inhibition of Transglutaminase 2 (ZED1227/TAK-1227) Protects Against Gluten-Induced Epithelial Damage zeQra Study Phase 2b Study (EudraCT number 2020-004612-97) Phase 2a Study (EudraCT number 2017-002241-30)!4) Gluten Challenge = None, OACD patients * 3 ggluten challenge daily for 6 weeks Primary En
Slide 27: IMU-856 Addresses Two Key Pathological Aspects of Celiac Disease
IMU-856 Addresses Two Key Pathological Aspects of Celiac Disease — Applicable for Other Inflammatory Bowel Indications IMU-856 Mode of Action Orally available and systemically acting small molecule modulator that targets a protein which serves as a transcriptional regulator of intestinal barrier fun
Slide 28: Intestinal Barrier Function is a Therapeutic Target Beyond Celiac Disease
Intestinal Barrier Function is a Therapeutic Target Beyond Celiac Disease Compromised intestinal barrier function has been associated not only with celiac disease but with a number of disease states, both intestinal and systemic Crohn’s disease: low bowel permeability has better probability to maint
Slide 29: Growing Interest by Pharma Industry
Growing Interest by Pharma Industry
Slide 30: Pharma Industry Has Become Active in the Celiac Disease Space
Pharma Industry Has Become Active in the Celiac Disease Space Company ey roventionbio ANOKION! @Pfizer see zeQra AMGEN Program KAN-101 ZED1227 PRV-015 (intravenous) (oral) (IL-145 monoclonal antibody) Stage at Time Phase 1b/2 Phase 2b Phase 2b of Deal ready ongoing ready Year 2022 2022 2018 30 | ©Im
Slide 31: Highly Underserved Therapeutic Area
Highly Underserved Therapeutic Area No drug treatments A Permanent A available Persistent symptoms Gapienaas villous High presence ames | atrophy prevalence > Prbnics ai é Significant presence Serious complications clseeke burden 2 Gluten-Free Diet not Clear sufficient > development pathway Unmet Me
Slide 32: Regulatory Guidelines and Development Pathways
Regulatory Guidelines and Development Pathways
Slide 33: Regulatory Guidelines and Development Pathways
Regulatory Guidelines and Development Pathways Two Recent Important FDA Guidances for Drug Development =) FDA Workshop on Celiac Disease FDA Draft Guidance Sia) July 22, 202110 April 2022/21 Gastroenterology Regulatory Endpoints Celiac Disease: Developing Drugs for Adjunctive Treat- and the Advancem
Slide 34: FDA Draft Guidance April 2022
FDA Draft Guidance April 2022 Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet Recommended Trial Population Recommended Trial Design Recommended Efficacy Assessments Adults with OACD despite GFD Randomized, double blind, placebo-controlled design Goals of treatment in
Slide 35: Gluten Challenge as Important Tool in Early Clinical Development
Gluten Challenge as Important Tool in Early Clinical Development FDA Workshop on Celiac Disease, July 22, 2021 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics VI (GREAT VI): Study subjects: Screening Run-out/ fac di Safety followup Well-controlled celiac disease Duodenal
Slide 36: Interleukin-2 Response Following Gluten Ingestion
Slide 37: Interleukin-2: An Emerging Biomarker to Gluten Exposure
Interleukin-2: An Emerging Biomarker to Gluten Exposure Gluten 3g P= 018 500 — IL-2 (pg/mL) 2° a 5 2 1 0s 02 LLoa i Runin Day1 Dayt Day (Pre- (4h Post- FigureRef [2] Dose) Dose) [1] Tye-Din etal, Aliment Pharmacol Ther. 2015,50-501-510[2] Leonard etal, Gastroenterclogy 202;160.720-7334 IL: intertauk
Slide 38: Interleukin-2 Correlates With Onset and Severity of Symptoms
Interleukin-2 Correlates With Onset and Severity of Symptoms Serum Interleukin-2 elevations correlate —@- Severe symptoms (N = 4) —- Moderate symptoms (N = 7) > oi onset and peur open ers after —t Mild symptoms (N= 8) —- Very Mild symptoms (N = 6) aeecuarae Sooo eee We ce ee —@- Healthy (N = 25) 100
Slide 39: Expert Presentation: Joseph A. Murray, MD
Slide 40: Joseph A. Murray, MD
Joseph A. Murray, MD Professor of Medicine Director, Focus of today’s Presentation Celiac Disease Research John = Role of the innate and adaptive immune system in and Shirley Berry Professor celiac disease E& Gatircintestinal Stiences + Relevance of the pro-inflammatory cytokine IL-2 as objective bi
Slide 41: Tightness of the Barrier and Regeneration
Tightness of the Regeneration of Barrier the Barrier
Slide 42: IMU-856's Target is Expressed in Colon and Small Intestine
IMU-856’s Target is Expressed in Colon and Small Intestine Target is Predominantly Expressed in Intestinal Epithelial Cells in Intestinal Crypts Colon murine Small intestine — murine Colon—IBD patient— earata villus "Lumen inflamed tissue Target Epithelial cell marker EpCAM Nucleus Right: magekindly
Slide 43: IMU-856 Exhibits High Selectivity Over Other Protein Family Members
IMU-856 Exhibits High Selectivity Over Other Protein Family Members IMU-856 potently inhibits the target’s enzyme 120 activity with an ICso of 15 nM ina biochemical 100 assay = 80 @ SubT1 i} A SubT2 = 60 As typical for epigenetic targets, the inhibition of 2 40 ©, sub =z the enzyme activity by IMU-8
Slide 44: IMU-856 Improves Intestinal Barrier Function
IMU-856 Improves Intestinal Barrier Function Intestinal permeability was measured as TEER after TNFa barrier-disrupting stimulation in Caco-2 cells 160 3. + 2 10 ~ E120 ai Transwell 8 e = we lab ry & 80 Cel Seana = 75 = atl ti | Ul il | Permeable Basolateral 0: T T T T T membrane chamber DMso 01 03
Slide 45: Initial Hypothesis: IMU-856 Impacts Tight Junction Protein Expression
Initial Hypothesis: IMU-856 Impacts Tight Junction Protein Expression fo Downregulation! Upregulation!2) | Relocation of ZO-1 Leaky gut away from the TJ Disruption of the architecture of the TJs [a]Poritz etal 2008 2} Luetig etal. 2015, w ‘ight junctions, 20-1: Zonula occudene-;L interleukin 45. | ©
Slide 46: IMU-856 Treatment Results in More Normal Crypts in DSS Colitis Model
IMU-856 Treatment Results in More Normal Crypts in DSS Colitis Model IMU-856 treatment during onset of colitisin a DSS model preserves more normal crypts and improves regeneration Morphology Normal Atrophic Hypertrophic crypts crypts crypts Homeostasis injury Repair So Mucosal healing Wangetal, 2018
Slide 47: Renewal of Intestinal Crypt Cells Enables Regeneration of Gut Architecture
Renewal of Intestinal Crypt Cells Enables Regeneration of Gut Architecture after Damage Treatment with IMU-856 slightly induced the renewal Repair of the gut architecture after damage is driven of intestinal epithelial cells in a murine DSS model by renewal of epithelial intestinal crypt cells and s
Slide 48: Expert Presentation: Michael Schumann, MD
Slide 49: Michael Schumann, MD
Michael Schumann, MD Attending Physician in Internal Medicine Focus of Tfoday’s Presentation and Gastroenterology + Role of the intestinal barrier function in the Department of Gastroenterology, pathophysiology of celiac disease Infectious Deeasesand Rheumatology + Research results from preclinical
Slide 50: Clinical Overview for IMU-856
Slide 51: Summary Phase 1 and Ongoing Phase 1 Part C
Summary Phase 1 Ongoing Phase 1 SAD/MAD Data in Part C Trial in Healthy Subjects Celiac Disease
Slide 52: Summary Phase 1 SAD/MAD Data in Healthy Subjects
Summary Phase 1 SAD/MAD Data in Healthy Subjects
Slide 53: Phase 1 Clinical Trial: Trial Design and Current Status
Phase 1 Clinical Trial: Trial Design and Current Status PARTA | PART B PART C Evaluation of single ascending doses (SAD) Healthy human subjects randomized to receive single dose of IMU-856 or placebo = Planned dose escalation completed: 10, 20, 40, 80, 120 and 160 mg of IMU-856 = 45 subjects enrolle
Slide 54: Dose-Linear Pharmacokinetics in Multiple Dosing
Dose-Linear Pharmacokinetics in Multiple Dosing Part B, Multiple Ascending Doses, Day1 and 14 * Terminal plasma half-life at steady state (Day 14 values) Mean plasma concentrations over time by treatment Part B (linear) 17 to 21 hours comparable to single dose * Linear pharmacokinetics also after mu
Slide 55: Pharmacokinetic Results: Trough Levels After Multiple Dosing
Pharmacokinetic Results: Trough Levels After Multiple Dosing Part B, Multiple Ascending Doses A Favorable Pharmacokinetic Properties Day 1-Day 14: Mean plasma concentrations over time by treatment Part B (linear) for IMU-856 Day 15—Day 17: Drop in plasma concentrations over time post treatment « Fas
Slide 56: Overall Summary of TEAE, SAE and AE Severity
Overall Summary of TEAE, SAE and AE Severity Part B, Multiple Ascending Doses Category Treatment Cohort7N | Cohort8N | Cohort9N Placebo 40 mg 80 mg 160 mg (N=5) (N=5) (N=6) (N=6) ‘Subjects with mild TEAES, n (%) 3 (60%) 3 (50%) 2 (33%) 8 (47%) 4 (67%) ‘Subjects with moderate TEAES, n (%) 1 (20%) 1 (
Slide 57: Most Common Treatment-Emergent Adverse Events
Most Common Treatment-Emergent Adverse Events Part B, Multiple Ascending Doses MedDRA. Number (%) of subjects with TEAEs occurring in more than 2 subjects Preferred erm [Number of TEAEs reported] Cohort 7N Cohort 8N Cohort 9N Active Placebo 40mg 80mg 160mg (N=17) (N=6) (N=5) (N=6) (N=6) Headache a 3
Slide 58: Laboratory Parameters: No Hy's Law Cases Observed
Laboratory Parameters: No Hy’s Law Cases Observed Part B, Multiple Ascending Doses Bilirubin vs. AST Showed No Evidence of DILI Potential Bilirubin vs. ALT Showed No Evidence of DILI Potential Hys Law Plot: BIL vs ALT across all postdose visits Hys Law Plot: BIL vs AST across all post-dose visits 3W
Slide 59: Multiple Doses of IMU-856 in Healthy Human Subjects
Multiple Doses of IMU-856 in Healthy Human Subjects Found to Have a Favorable Safety and Tolerability Profile No IMP-related serious adverse events No dose-dependency in adverse events — No maximum tolerated dose reached v- Ss = No trends for post-dose changes in any laboratory parameter No medicall
Slide 60: Ongoing Phase 1 Part C Trial in Celiac Disease
Ongoing Phase 1 Part C Trial in Celiac Disease
Slide 61: Phase 1 Clinical Trial of IMU-856: Part C Design
Phase 1 Clinical Trial of IMU-856 Part Cin Patients with Celiac Disease During Periods of GFD and Gluten Challenge Flow Chart of Part Cin Celiac Disease Proof-of-Concept Study = Part C includes a well-controlled celiac disease as patient population, designed to assess safety and Gluten challenge wit
Slide 62: Phase 1 Clinical Trial of IMU-856: Eligibility and Objectives
Phase 1 Clinical Trial of IMU-856 Part Cin Patients with Celiac Disease During Periods of GFD and Gluten Challenge Fea. Eligibility Criteria 60 Key Objectives/Endpoints = Age 18 to 65 years (inclusive) * Primary: = Biopsy proven diagnosis of celiac disease * Safety and tolerability for at least 12 m
Slide 63: Q&A Session with the Two Experts
Slide 64: IMU-856 Could Present a New and Innovative Approach
—— — 64 | ©Immunic, Inc. | Feb/03/2023 IMU-856 Could Present a New and Innovative Approach for the Treatment of Gastrointestinal Diseases = IMU-856 showed a favorable safety, tolerability and pharmacokinetic profile in the single and multiple ascending dose portions of the phase 1 clinical trial in
Slide 65: Thank You!
Thank You! Immunic, Inc. 1200 Avenue of the Americas Teer nse 21 New York City, NY 10036 etait; - ie fork City, 82166 Grafelfing (Munich) Germany Head of IR & Communications : +49-89-2080477-09 Immunic Australia Pty. Ltd. Melbourne “Australia 65 | ©immunic,inc. | Feb/09/2023 © Immunic
Slide 66: Back-Up
Slide 67: How Fast Do Signs and Symptoms Resolve Under Gluten-Free Diet?
How Fast Do Signs and Symptoms Resolve Under Gluten-Free Diet? Symptoms | « Symptoms resolve in 1-3 monthsl1] Serology = Serology levels fall substantially in six months and often negative after one year of GFD = Persistent positive one year serology usually indicates gluten exposurel2] Histology |
Slide 68: How Often is Persistent Villous Atrophy Despite Gluten-Free Diet?
How Often is Persistent Villous Atrophy Despite Gluten-Free Diet? Most Studies Report Rates of Persistent Villous Atrophy Between 24 % and 47 % Study Name Percentage of Persistent Villous Atrophy Study Details Selby et al., 19997 = 32% with partial VA + 9 %with subtotal VA + 2 %with total VA § N=89
Slide 69: What Are the Consequences of Gluten Exposure in Celiac Disease?
What Are the Consequences of Gluten Exposure in Celiac Disease? Gluten Exposure Single Dose 3-7 Days 2-6 Weeks 1 Year+ Decades Onset/Duration Immediate / short lived Delayed / variable Slow / prolonged Variable / chronic Slow or abrupt / catastrophic Impact a7 +/+ +H +H oe Mechanism CD4+T cells a cy
Slide 70: Conditions or Associated Disorders That Should Make You Think About Celiac Disease
Conditions or Associated Disorders That Should Make You Think About Celiac Disease = Dermatitis herpetiformis (see picture) = Diabetes mellitus, type | = Selective IgA deficiency Autoimmune thyroid disease Microscopic colitis Autoimmune hepatitis Psoriasis Lupus ‘Oxentenko etTepi Maye Clin Proc. Dec
Slide 71: Experimental Non-Dietary Therapies for Celiac Disease
a (hIL-22) - Phase 1 ~__ Immunic: IMU-856 - Phase 1 J) Zedira/Falk Pharma/Takeda: ZED1227 — Phase 2b <_ GSk/sitari: GSK-3915398 (TG2 inhib) - Phase 1 UCB Pharma: Preclinical tTG in 732 toniors JI) chugai: Donas2~ Phase 1b SYA) Nextera: Preclinical ToR-like mAb @ Giutenpepise HE Clinical |@ Dead guto
Slide 72: How to Monitor Adherence to Gluten-Free Diet?
How to Monitor Adherence to Gluten-Free Diet? Symptom Assessment Physician and dietician Symptom Celiac Disease Specific Serology _| Transglutaminase-igA (tTG-IgA) + Deaminated Gliadin Peptide-IgG (DGP-IgG) Urine/ Fecal GIPs fa] Fecal GIPs (ELISA, LFIA) Urine GIPs (LFIA) Sensitivity/specifity 100/97
Slide 73: Dose Escalation Algorithm in Healthy Human Subjects
Dose Escalation Algorithm in Healthy Human Subjects Part A: Single Ascending Doses Part B: Multiple Ascending Doses (14 days) Cohorts Cohorton 160 mg IMU-856 or placebo 160 mg IMU-856 or placebo ( (ratio 6:2) ( (ratio 6:2) Cohorts Cohort8N 120 mg IMU-856 or placebo ‘80 mg IMU-856 or placebo if (rati