Immunic, Inc. · NASDAQ:IMUX
Immunic — Vital Therapies — Technical Presentation (August 2015)
67 slides from Immunic's technical presentation, Aug 31, 2015
Slide 1: Acute Alcoholic Hepatitis and Liver Support
Acute Alcoholic Hepatitis and Liver Support Julie Thompson, MD University of Minnesota A UNIVERSITY OF MINNESOTA
Slide 2: AAH: How common is it?
AAH: How common is it? Frequency is not well characterized 10-35% of heavy drinkers? 20% in series of 1600 alcoholics who were biopsied ¢ Alcoholism estimated in 8% of US population: — US population = 316 million — 8%= 25 million — Estimate = 5 million in US Lee eee McCullough. Am J Gastroenterol 19
Slide 3: A serious disease
A serious disease ¢ Mortality is high * 197 patients, meta analysis: — mortality at 28 days = 34% * 661 patients: — average follow up 160 d = 34% overall mortality — severe disease = 23% dead at 30 days Mathurin. Gut 2011 Yu. World J Gastroenterol 2010 UNIVERSITY OF MINNESOTA to Discover:
Slide 4: Where we are now...
Where we are now... ¢ Mortality hasn’t significantly changed in 20 years ¢ Despite the profound economic and health impacts of the disease, little progress has been made r..% UNIVERSITY OF MINNESOTA
Slide 5: Are there any treatments?
Are there any treatments? * STOPAH TRIAL: 4 groups, 1053 patients — Placebo, steroid+placebo, pentoxifylline+placebo, steroid+ pentoxifylline ¢ Inclusion criteria — Maddrey >32 < 3 months jaundice — Alcohol use within 4 weeks * Outcomes — Modest benefit in survival in steroid arms at 28 days (mortal
Slide 6: Acute Alcoholic Hepatitis: A Vicious Cascade
ACUTE ALCOHOLIC HEPATITIS: A VICIOUS CASCADE
Slide 7: The beginning of the vicious cascade
The beginning of the vicious cascade A NESOTA Driven to Discover’
Slide 8: Fever, anorexia, weight loss
Fever, anorexia, weight loss oo Attract Immune cell Activation of stellate cells neutrophils & activation = fibrosis macrophages ‘SITY OF MINNESOTA
Slide 9: FAS
FAS
Slide 10: Alcoholic hepatitis cascade
Alcoholic hepatitis cascade Results in multisystem organ failure Removal of albumin bound-toxins may improve liver function (bilirubin, ammonia, cyclic amino acids) If toxins are removed, this may facilitate a steady state, whereby a compensated state may be reestablished Aims are to modify hypermet
Slide 11: Fever, anorexia,
Fever, anorexia, mune cell activation MCP-1 Interleukin-8 — Attract Activation of stel 'S_ neutrophils & = fibrosis macrophages UNIVERSITY OF MIN! Driven to Discove
Slide 12: Extracorporeal Liver Assist (ELAD)
EXTRACORPOREAL LIVER ASSIST (ELAD)
Slide 13: ELAD Cartridges: C3A Cell Bioreactor
ELAD Cartridges: C3A Cell Bioreactor Proprietary C3A Cell Line * Human: No Animal or Safety Issues * Stable: Can Be Stored, Grown in Unlimited Quantities and Shipped Worldwide ¢ Immortal: Retain Hepatocyte Functions for Continuous Treatment - A Set of ELAD Cartridges Used 17 Days on One Subject (Typ
Slide 14: Modulation of Liver Inflammation
Modulation of Liver Inflammation ¢ Hepatocytes are a major source of acute-phase proteins (APPs), which dampen the harmful effects of inflammatory factors: — Hepatocytes respond to IL-1 and IL-6 by producing mediators of inflammatory resolution such as IL-1 receptor antagonist (IL-1Ra) and a1-antitr
Slide 15: Modulation of Liver Inflammation
Modulation of Liver Inflammation ¢ AILD involves unregulated systemic inflammation’ and elevated plasma levels of inflammatory factors such as IL-1, IL-6, lipopolysaccharide (LPS), and TNF-a25 Se Louvet A, Mathurin P. 2015. Nat Rev Gastroenterol Hepatol Kawaratani H, et al. 2013. Mediators Inflamm,
Slide 16: Modulation of Liver Inflammation
Modulation of Liver Inflammation + VTL C3A cells secrete anti-inflammatory factors IL-1Ra and AAT — Constitutively — In response to co-incubation with IL-18 and IL-6 — In response to LPS - Response is dynamic — Temporal — Dose-dependent + May represent one of multiple mechanisms for therapeutic bene
Slide 17: C3A Cells: Upregulation of IL-1Ra and AAT in Response to Inflammatory Stimulation
C3A Cells: Upregulation of IL-1Ra and AAT in Response to Inflammatory Stimulation ‘i IL-1Ra oo IL-1Ra i. — 3 = S ill | 5 % oie. aa BD; sana Pry. a) we i aw we wig) 30'S) Ym am tah mt io amt aw , ah os 12 12 12 12/91 33/32 30/30/31 aT 30 AL 3D eon oa aaa Sih ia 1S 18 14 13 18 19 7499 127/72 4a 168 10
Slide 18: Support of Hepatocellular Metabolic Function
Support of Hepatocellular Metabolic Function e AAH/AILD are characterized by impaired liver function — Cell-based support of liver function could therefore be of therapeutic benefit if the cell therapy was demonstrated to provide metabolic functions required of normal hepatocytes, such as detoxifica
Slide 19: VTI-208: Randomized Open-Label Study of ELAD in AILD
VTI-208: A RANDOMIZED, OPEN- LABEL, MULTICENTER, CONTROLLED STUDY TO ASSESS SAFETY AND EFFICACY OF ELAD® IN SUBJECTS WITH ALCOHOL- INDUCED LIVER DISEASE (AILD)
Slide 20: The ELAD System
The ELAD System + Human cell-based liver support system (biologic/medical device) designed to improve survival in liver failure — Combination product regulated as a biologic by FDA (Center for Biologics Evaluation and Research); Advanced Therapy Medicinal Product by European Medicines Agency + Allog
Slide 21: VTI-208 Clinical Sites
VTI-208 Clinical Sites 40 Sites Enrolled Subjects UNITED STATES Tampa General Hospital = Albert Einstein Medical Center = University of Mississippi = Baylor University Medial = University ofAizona Conter = University of kansas nad = Beth israel Z Capital Health Medical Center *~ * = Cedars Sinai (LA
Slide 22: VTI-208 ELAD in AILD: Overview
VTI-208 ELAD in AILD: Overview ¢ Open Label, Multicenter, International, Phase III ¢ 1:1 randomization: ELAD plus standard of care (SOC) vs SOC alone (Control) ¢ Primary Endpoint: Overall Survival up to at least Day 91 ¢ Alcohol Induced Liver Decompensation (AILD) ¢ ELAD Treatment: 3-5 days — Stop E
Slide 23: VTI-208 ELAD in AILD: 208E
VTI-208 ELAD in AILD: 208E Follow-Up Year 1: Phone calls at 6, 9, and 12 months Years 2-5: 1 phone call each year ¢ Data: — Survival — Cancer (especially liver) — Liver transplant — EQ-5D-5L Quality of Life questionnaire Mandatory
Slide 24: Inclusion Criteria
Inclusion Criteria Age 2 18 years Total Bilirubin = 8mg/dL Clinical diagnosis of AILD, based on evidence (medical history, lab, family interview) or clinical judgment of temporal (< 6wks) and causal relationship between use of alcohol and this onset of symptoms Clinical Dx of AILD is classified as e
Slide 25: Inclusion Criteria
Inclusion Criteria 5. Not eligible for liver transplant (OLT) during current hospitalization 6. Subject or LAR must provide Informed Consent 7. Subject must be eligible for SOC as defined by the Protocol r..% UNIVERSITY OF MINNESOTA
Slide 26: Exclusion Criteria
D OS e Exclusion Criteria Platelet < 40,000/mm3 INR > 3.5 MELD Score >35 AST >500 IU/L Infection unresponsive to antibiotics 2 20% Reduction of T Biliin previous 72 hr Bilirubin must be measured at least 12 hr after any procedure that could alter serum bilirubin (¢.g., PRBCs) Hemodynamic instability
Slide 27: Exclusion Criteria
Exclusion Criteria 8. Active bleeding — Requirement of 2 2 units PRBCs to maintain stable Hb within 48h of Screening 9. Clinical evidence of liver size reduction due to cirrhosis: — Liver size of the craniocaudal diameter (sagittal view) < 10 cm when measured on midclavicular line, (or liver volume
Slide 28: Exclusion Criteria
13. 14. 15. 16. Ad 18. 19. 20. Exclusion Criteria Liver disease related to homozygous Hemochromatosis, Wilson’s, Budd-Chiari Synd, NASH Pregnancy (HCG) or lactation Participation in another study within 1 month of enrollment (except observational studies provided safety/efficacy of ELAD® not affecte
Slide 29: Results from VTI-208
RESULTS FROM VTI 208
Slide 30: Summary of Analysis Populations
Summary of Analysis Populations Randomized (N=203) | Allocated to ELAD (n=96) Received ELAD (n=94) Received SOC (n=2) \ Allocated to Control (n=107) Received ELAD (n=1) Received SOC (n=106) Received >=72 hrs on ELAD (n=82), Discontinued before 72 hrs due to AE (n=6), by investigator (n=4), withdrew
Slide 31: Baseline Demographics: ITT Population
Baseline Demographics: ITT Population ELAD Treatment Control Total Characteristic (N=96) (N=107) (N=203) Randomization Stratum, n (%) Subject has AILD that is classified as severe Acute Alcoholic Hepatitis 92 (95.8) 101 (94.4) | 193 (95.1) Subject has AILD that is not classified as severe Acute Alco
Slide 32: Baseline Demographics: ITT Population
Baseline Demographics: ITT Population ELAD Treatment Control Total tharacteristic (N=96) (N=107) (N=203) lAge (years) Mean (SD) 46.5 (9.06) 44.8 (10.66) 45.6 (9.95) Median 48.0 45.0 46.0 Min, Max 25, 68 25,67 25, 68 lAge Category, n (%) 18-35 years 1202.5) 25 23.4) 3718.2) 36-50 years 48 (50.0) 49 (
Slide 33: Baseline Disease Characteristics: ITT population
Baseline Disease Characteristics: ITT population ELAD Treatment Control Total [aracterisic. (N96) 107) x=203) p-value 1] Basetine Mode for Endsiage Liver Disease (MELD) score ‘Mean (SD) 2768.99 271879) 273.80) oa ‘Medan 20 27.0 27.0 ‘Min, Ma 20,35 20.35 20,35 Category, OO: 0.100 MELD Seore 28 S158)
Slide 34: Study Disposition: ITT Population
Study Disposition: ITT Population /ELAD Treatment Control Total (N=96) (N=107) (N=203) ‘haracteristic n(%) n(%) n(%) [Completed Study to End of Study Day 91 Yes 50 (52.1) 57 (53.3) 107 (52.7) No 46 (47.9) 50 (46.7) 96 (47.3) Primary Reason for Early Discontinuation from the Study AE/SAE, 0 1.9) 1.0.
Slide 35: Primary Endpoint
Primary Endpoint Overall Survival, ITT population, including VTI-208E through 7/30/15 Veal Trempee age bee WVTL-00822, VTL.208 Figue 14210 Summary of Kn ter Analyse of Oneal Suri TT Feplatisn wo. ELA Team 96 » = Cone io) COOELADTeemeatSsjecseamtel #8 Fao emt Sayer aren 6 ». pde[i0 00 » § o 3 _—— ; e
Slide 36: Primary Endpoint
Primary Endpoint Overall Survival, PP population, including VTI-208E Vital Therapies Page of | VIL-D0822. VIL-208 Figure 14216 ‘Summary of Kaplan-Meier Analy of Overall Survival BP Population LAD Trane +82 a ot 10 Frm ayer SSG Ewaargnte cures a perenne) g ores 2 6 eevee. Sg 2570-08 pcam op mo ---ocm
Slide 37: Predefined Subgroup Analysis: MELD <28
PREDEFINED SUBGROUP ANALYSIS: MELD <28
Slide 38: Demographics (1) MELD <28
Demographics (1) MELD < 28 ELAD Treatment Control Total Characteristic (N=51) (N=69) (N=120) Randomization Stratum, n (2%) Subject has AILD that is classified as severe Acute Alcoholic Hepatitis 47 (92.2) 64 (92.8) 111 (92.5) Subject has AILD that is not classified as severe Acute Alcoholic Hepatiti
Slide 39: Demographics (2) MELD <28
Demographics (2) MELD <28 ELAD Treatment Control Total Characteristic (N=51) (N=69) (N=120) Height (em) [1] n 45 64 109 Mean (SD) 170.1 (11.84) 173.4(10.54) 172.0 (11.16) Median 170.0 173.0 172.0 Min, Max 144, 200 150, 193 144, 200 Weight (kg) [1] n 45 62 107 Mean (SD) 76.32 (21.518) 85.96 (20.740)
Slide 40: Liver disease characteristics (1) MELD <28
ELAD Treatment Control Total Characteristic (E51) (N=69) (N=120) p-value [1] Medical treatments at Baseline, n (°%): Steroids 24 (47.1) 39 (56.5) 63 (52.5) 0.305 Pentoxifylline 17333) 2130.4) 3831.7) 0.736 N-acetyl-cysteine 239) 343) 5(4.2) 0.908 Baseline Model for Endstage Liver Disease (MELD) scor
Slide 41: Liver disease characteristics (2) MELD <28
Liver disease characteristics (2) MELD < 28 ELAD Treatment Control Total Characteristic (N=51) (-69) (N=120) p-value [1] Subject had dialysis at least twice in the past week, n (%) Yes 0 0 0 No 51100) 69 (100) 120 (100) Baseline Maddrey Discriminant Function (MDF) score Mean (SD) 59.5(13.97) 61.8 (1
Slide 42: Liver disease characteristics (3) MELD <28
ELAD Treatment Control Total Characteristic ass) (N=69) (N=120) p-value [1] On renal replacement therapy (hemodialysis, CVVHD, CVVH, peritoneal, etc) at randomization, n (%) * Yes 0 o o No 51 (100) 69 (100) 120 (100) On vasopressors at Baseline, n (%) 0.404 Yes 35.9) 7(10.1) 10 (83) No 43 04.1) 62 (
Slide 43: Subgroup Analyses: Overall Survival incl. VTI-208E: ITT
Subgroup Analyses: Overall Survival incl. VTI-208E: ITT ‘Sunival Probability 04 02 Subjects with MELD < 28 Product-Limit Survival Estimates With Number of Subjects at Risk + Censored 27 ® a a 2 200 400 600 Analysis Value Planned Treatment for Period 01 41: Control 2. ELAD Treatment Driven to Discove
Slide 44: Predefined Subgroup Analysis: Age < Median (46.9 yrs)
PREDEFINED SUBGROUP ANALYSIS: AGE < MEDIAN (46.9 YRS)
Slide 45: Subgroup Analyses: Overall Survival incl. VTI-208E: ITT
Subgroup Analyses: Overall Survival incl. VTI-208E: ITT By Age @ < Median Years ‘Age > Median Years ELAD ELAD ‘Treatment Control ‘Treatment Control Survival Estimates. (N=43), (N=58) (N=53) (N=49) umber (°) of Subjects who Died 1432.6) 26 (44.8) 32(60.4) 25 (51.0) jumber (%) of Subjects Censored 29
Slide 46: Subgroup Analyses: Overall Survival incl. VTI-208E: ITT
Subgroup Analyses: Overall Survival incl. VTI-208E: ITT Subjects < median age (46.9 yrs) Product-Limit Survival Estimates With Number of Subjects at Risk 10 + Censored 08 ny 2 rrr 2 08 | « 2 os 3 02 | oo 1| 0 2 2 9 = 7 2 wo wom ne 8 4 3 8 {-2eestaeaeek Fee: 8 0 200 400 600 00 Analysis Value 4:Contro
Slide 47: Liver Disease Characteristics < Median Age
Liver Disease Characteristics < Median Age ELAD Treatment ‘contol Characteristic ga43 gies8) pevalue(a] ‘Medical treatments at Baseline, n (4) sercide 200465) 27466) 47455) ooet Pentcfyine G26 27466) 41406) o1s7 Naacayloyteine 30.0) 362, 669) 0708 Baseline Model for Endstage Liver Disease (MELD) sco
Slide 48: Liver Disease Characteristics < Median Age
Liver Disease Characteristics < Median Age ELAD Treatment Contra Total Characteristic 13) 58) x10) prvalue[t} Subject had dialysis at least twice in the past week, n 0) Yes o o ° No 43 (100) 58 (100) 101 (100) Baseline Maclrey Discriminant Function (MDF) score 8 e 38 101 Mean (SD) 7130308) 773.@218)
Slide 49: Liver Disease Characteristics < Median Age
Liver Disease Characteristics < Median Age ELAD Treatment Control Total Characteristic (s=43) vss8) o=101) pwvalue (1) (on renal replacement therapy (hemodialysis, CVVHD, CVVH, pesitonedl, et) at randomization, n (99) S Yes ° o ° No 48.00) 58,100) 101 (100) ‘on vasopressrs at Basdine, n (9) oats Yer
Slide 50: Demographics < median age
Demographics < median age ELAD Treatent centro Tetal Chanawistc a ors) os=101 Randomizaten Saturn, (4) Subjecthae AILD thats clatied se severe Acute Aleohelic Hepatitis 2077) 5548) 910960) Subjecthas AILD thats net classified as severe Acute Alechehe Hepatitis 1@3) 362) 440 Age Gear) 2 43 38 01 ‘Mea
Slide 51: Adverse Events Summary
ELAD Treatment Characteristic (N=13) Number (°6) of Subjects Reporting Any TEAE, 43 (100) 57 (98.3) 100 (99.0) Number of TEAES 837 830 1667 Number (°6) of Subjects Reporting Any TESAE 2967.4) 37 (63.8) 66 (65.3) Number of TESAES 65 83 4s Subjects with TEAEs by Highest Severity [1], n 6) Mild 13) 610
Slide 52: Key Conclusions Data Summary
Key Conclusions Data Summary Key Sub Groups + MELD <28 (mean MELD 24.5 {59% 90-d survival}, mean age 45.7) ITT Total N=120 ELAD: N=51 Control: N=69 - HR: 0.575 (1.74) — Proportion survivors (91d): PP Total N=116 ELAD: N=48 Cntrol “eee — HR: 0.538 (1.86) p=0.059 — Proportion survivors (91d): ELAD: 81
Slide 53: Predefined Subgroup Analysis: MELD <28 and Age < Median
PREDEFINED SUBGROUP ANALYSIS: MELD <28 AND AGE < 47 YRS
Slide 54: Primary Endpoint
Primary Endpoint Overall Survival, ITT population, including VTI-208E through 7/30/15 Age < median years (46.9 yrs) and Baseline MELD <28 ELAD Treatment Control Survival Estimates (N=26) {N=33) Number (%) of Subjects who Died 4154) 1133.3) Number (°) of Subjects Censored 22 (84.6) 22 (66.7) Censored
Slide 55: Primary Endpoint
Primary Endpoint Overall Survival, ITT population, including VTI-208E through 7/30/15 Age < median years (46.9yrs) and Baseline MELD <28 Nits Therapiee Page 1 of VIL bo822_ T1208 Figure 1421 a ‘Summary of Kaplan Meier Analysis of Overall ural for Subjects wth Age Median years and Baveline MELD <28 T
Slide 56: Primary Endpoint
Primary Endpoint Overall Survival, ITT population, up to Study Day 91 Age < median years (46.9 yrs) and Baseline MELD <28 ELAD Treatment Control Survival Estimates (N=26) (N=33) Number (%) of Subjects who Died 0 8 (24.2) Number (%) of Subjects Censored 26 (100) 25 (75.8) Censored reason: Still Alive
Slide 57: Primary Endpoint
Primary Endpoint Overall Survival, ITT population, up to Study Day 91 Age < median years (46.9 yrs) and Baseline MELD <28 Vite Therepies Page| of ‘vr ios22vi208 Figuei42213 Summary of Kaplan Meier Andy's of Overall Survival up to Study Day 91 fr Subjects with Age <Medin yeas and Badline MELD <28 TTT
Slide 58: Key Conclusions Data Summary
Key Conclusions Data Summary Key Sub Groups * MELD <28 and Age <median (46.9 years) ITT Total N=59 ELAD: N=26 Control: N=33 - HR: 0.375 (1.18) p=0.085 — Proportion survivors (91d): ELAD: 100% Control: 72.7% p=0.006
Slide 59: Summary
Summary ¢ Acute alcoholic liver disease has high mortality and no effective treatment yet ¢ The inflammatory cascade involved in AAH is a target for future treatments * C3A cells express factors that may have modulatory effects on the inflammatory cascade F MINNESOTA
Slide 60: Summary
Summary ¢ While the VTI ELAD study did not meet primary endpoint for overall survival, a subset of patients showed a 90-day survival benefit (100% vs 73%, p=0.006) — Less than 47 years old — MELD less than 28 r..% UNIVERSITY OF MINNESOTA
Slide 61: Appendix
Appendix UNIVERSITY OF MINN Driven to Discover’
Slide 62: Analysis of Baseline MELD vs Mortality
Analysis of Baseline MELD vs Mortality Control ELAD Proportion of Subjects in MELD group ameng Subjects who Died at Day 91 Correlation (CMH) p=0.003
Slide 63: Regression Analysis of Baseline MELD vs Mortality
Regression Analysis of Baseline MELD vs Mortality Control ELAD p=0.52 p=0.006 y 4 UNIVERSITY OF MINNESOTA
Slide 64: Distribution of Baseline Age
Distribution of Baseline Age Histogram of Age Control ELAD
Slide 65: Odds Ratio: MELD group comparison, Age
Odds Ratio: MELD group comparison, Age Control ELAD fe be -_———_+_____, or a — — rr ‘Odds Ratio Estimates ‘Odds Ratio Estimates Point] 95% Wald Point] 95% Wald. [Effect Estimate] Confidence Limits Estimate| Confidence Limits [AGE 1o37[ 0.997] __1.078| [AGE Tai6[ LoisT 1.191 [MELDCAT 1:<=23 vs4:30% |
Slide 66: MELD Groups vs Age
MELD Groups vs Age Control ELAD ‘Analysis of Maximum Likelihood Estimates: ‘Analysis of Maximum Likelihood Estimates [Standard] Wald Standard] ‘Wald Estimate] __Error| Chi-Square|Pr > ChiSq DF] Estimate] Error] Chi-Square| Pr > ChiSq| 2.1204] _ 0.9325] 5.2145) 0.0224 15.6802] 1.6335 12,0921 0,005 0.
Slide 67: Support of Hepatocellular Metabolic Function
Support of Hepatocellular Metabolic Function e C3A cells exhibit a diverse expression of various critical cytochrome P450 isozymes including those most involved in drug metabolism such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 — The mRNA expression of these CYPs increases when the C3A ce
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