1. ELAD® System:
Development of a Human Cell-Based, Bio-Artificial
Liver Support System for Acute Alcoholic Injury and
AHF
Lewis Teperman MD
Director of Transplantation
New York University Langone Medical Center

2. ELAD Clinical Development
Disclosure: Lewis Teperman, MD is a member of the
clinical advisory board and principal investigator
2

3. ELAD® C3A Cells
• Allogeneic cell therapy
•Human: No animal issues
•Immortal: Retain hepatocyte function
•Stable: Can be stored and grown
• C3A cells retain primary hepatocyte function
•Synthesize liver proteins, e.g., albumin, transferrin, factor V
•Make large quantities of alpha fetoprotein
•Active P-450 enzyme system
•Process toxins/metabolites:
•Consume large amounts of O2 and glucose
• With ELAD, rate of plasma flow is 50 mL/min = 3 L/hr = 72 L/day
•Higher than plasma exchange therapy (2-3 L/treatment)
3

4. • VTI C3A cells are grown between the fibers of the
ELAD cartridges
• Cells divide to fill available space
• 110g / cartridge – 440g in total
• Plasma flows through semipermeable hollow fibers
• 0.2µm pores
• Bidirectional diffusion between ultrafiltrate and
VTI C3A cell
ELAD® Cartridges
4

5. • Metabolically active - consume large amounts of O2 and glucose
• Inducible cytochrome P-450 enzyme system to metabolize toxins
• Manufacture urea
• Synthesize hepatocyte-specific proteins (transport
proteins, clotting factors, acute phase response proteins)
VTI C3A Cells
5
• Albumin
• α-Fetoprotein
• α-1-Antichymotrypsin
• α-1-Antitrypsin
• C3 Complement
• HGF
• Antithrombin III
• Factor V
• Fibrinogen
• Transferrin
• Factor VII
• TGF-α

6. Albumin Production by Single ELAD® Cartridge
In-Process Manufacture
6

7. AFP levels Treated Subjects VTI-208
(representative values)
0
0.5
1
1.5
2
2.5
3
3.5
Pre
ELAD
ELAD
D1
ELAD
D2
ELAD
D3
ELAD
D4
ELAD
D5
Post
ELAD
D1
Post
ELAD
D2
Ng/mL(105)
ELAD
Control
7
*Control levels: <0.005 throughout
*

8. Elimination of toxins
•Ultrafiltrate generator pore size (~130kDa) allows albumin (~66kDa) to deliver
toxins to VTI C3A cells
•VTI C3A cells metabolize toxins (e.g. using cytochrome P-450 system)
•Metabolized toxins diffuse back into ultrafiltrate and are returned to subject
•Subject eliminates toxins by the gastrointestinal tract or the genitourinary tract
VTI C3A Cells
Subject
eliminates
toxins
Toxins are
returned to
subject
ELAD Cells
metabolize
toxins
Albumin
delivers
toxins to
ELAD Cells
8

9. Lewis JA et al: Analysis of Secreted Proteins as an in vitro Model for Discovery of LiverToxicity Markers
Journal of Proteom Research 2010 (9): 5794
C3A Cells produce immune modulator proteins of the liver
9

10. Stages of Liver Disease—Quo Vadis?
10
Acute Chronic

11. 11
ELAD® System - Human Cell-Based, Bio-Artificial Liver Support System

12. Fulminant Hepatic Failure (FHF)
Phase 1 trial – PS-0698
• 26 subjects enrolled at 6 centers across the U.S. and UK
• Inclusion criteria (King’s College Criteria for Transplant in FHF subjects) defined to select for high
mortality
• 30-day overall survival endpoint
• Outcome confounded by high and rapid rate of transplant and unexpected post-transplant mortality
• Average time to transplant <3 days
• Positive subgroup data on bridge-to-transplant/recovery (BTT/R) endpoint
Phase 2 trial – CR-202
• 19 subjects enrolled at 8 centers in the U.S.
• Inclusion criteria relaxed to accept less sick patients; few deaths
• 30-day overall survival endpoint
• Overall outcome confounded by high rate of transplant and lack of mortality
• Vital Therapies Re-Analyzed Data Combining Two Studies
• Interesting Findings – Suggestive of Potential in FHF
12

13. Subject Disposition at 30-Day End of Study
p = 0.03 BTT/R Death w/o Transplant
ELAD 15 1
Control 6 4
Overall Survival Bridge-to-Transplant/ Recovery (BTT/R)
• Transplant censored
• Event = death without transplant
• Transplant not censored
• Event = death
FHF Meta Analysis Results
(26 subject subset of those listed for transplant)
13
p = 0.12
HR = 0.37
p = 0.06
HR = 0.17

14. Acute Flare Hepatitis B Trial in China
• Major health problem in China
• 140MM infected
• 400,000 deaths / year (1,000/day)
• VTI invited to China in October 2004 to run pivotal trial
• Initiated in March 2006 at 2 Beijing hospitals
• Randomized, controlled, open label trial design
• Continuous treatment for 3 days or until recovery
• Target enrollment of 120 patients randomized to the ELAD and control groups, respectively
• Trial halted early in June 2007 by Hospital Ethics Committee due to evidence of efficacy from analysis
of data on subset of 49/68 subjects enrolled prior to significant protocol amendment
• Unethical to continue to enroll controls
14

15. Data presented at AASLD 2007 Poster Session. Publication currently under review.
•49/68 patients assessed on
an intent to treat analysis
•Significant differences in
28- and 56-day survival
using the logrank test
(p=0.015 and 0.018
respectively)
•Significant difference in 84-
day survival using the
Wilcoxon test (p=0.049)
•No unexpected safety
issues
Acute Flare Hepatitis B Results
15
28 Days
p=0.015
56 Days
p=0.018
0 14 28 42 56 70 84 98
0.1
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ELAD®
Control
Days from Baseline
TransplantFreeSurvival(proportion)
Kaplan-Meier Plot of Transplant-Free Survival
p < 0.05, WIlcoxon
n = 49

16. China Data 3/5-Year Follow-Up
• Survival Advantage for ELAD Maintained over Extended Follow-Up
• Key Finding to Support Pharmacoeconomic Benefit
Data presented at AASLD 2010 Poster Session. Publication currently being assessed.
16
3 Year Transplant Free Survival
0 500 1000 1500 2000
20
30
40
50
60
70
80
90
100
Time (days)
Control
Treated
p<0.05
5 Year Transplant Free Survival
0 500 1000 1500 2000 2500
10
20
30
40
50
60
70
80
90
100
Time (days)
Survivalprobability(%)
Control
Treated
p<0.05

17. China Data 3/5-Year Follow-Up
• Survival Advantage for ELAD Maintained over Extended Follow-Up
• Key Finding to Support Pharmacoeconomic Benefit
Data presented at AASLD 2010 Poster Session. Publication currently being assessed.
17
3 Year Transplant Free Survival
0 500 1000 1500 2000
20
30
40
50
60
70
80
90
100
Time (days)
Control
Treated
p<0.05
5 Year Transplant Free Survival
0 500 1000 1500 2000 2500
10
20
30
40
50
60
70
80
90
100
Time (days)
Survivalprobability(%)
Control
Treated
p<0.05

18. Strategic Clinical Decision: What to Study Next ?
FHF
• Limited Patient Numbers
• Logistical Challenges Due to Critical
Nature / Rapid Progression of Illness
• High Transplant Rate may be
Confounding
• Evidence of Efficacy in Western
Population
Acute-on-Chronic Hepatitis
• Larger Patient Population
• China Experience Positive
• Fewer Logistical Challenges Due to
Slower Disease Progression
• Fewer Subjects Transplanted
• No Prior ELAD Studies in Western
Population
18

19. Two Pre-Pivotal Studies in AOCH: VTI-201 / VTI-206
VTI-201: Phase 2a Study in 18 Patients
Endpoint: 30 day survival
VTI-206: Phase 2b Study in 80 Patients
Endpoint: 90 day survival
Objectives:
• Refine the Inclusion/Exclusion Criteria
• Explore Liver Failure Induced by Alcohol as a Separate Group
• Explore Surrogate Endpoints (e.g. ΔMELD, bilirubin)
19

20. Background
• AAH patients are usually not eligible for transplant;
have marginal therapies, Corticosteroids and
Pentoxifylline, but limited cirrhosis may enable recovery
and regeneration of normal liver
• ELAD is designed to provide continuous support to possibly
allow time for native liver to regenerate or provide a bridge
to transplantation
20

21. VTI-206 – Inclusion/Exclusion Criteria
Inclusion Criteria
• Age ≥ 18 ≤ 67 years
• Acute decompensation in 28 days
• MELD score >18 <35
• Diagnosis of AOCH
• Alcohol-induced
• Non-Alcohol-induced
• Randomized separately
Key Exclusion Criteria
• Platelets <50,000/mm3
• INR >3.5
• Chronic renal failure
• Septic shock, major
hemorrhage, spontaneous bacterial
peritonitis with uncontrolled
systemic infection, significant
hypotension, hemodynamic
instability
• Significant concomitant disease
• Previous liver transplant
• DNR/DNI
21

22. VTI-206 Study Population
Alcohol-Induced
Non-Alcohol
Induced
Total
ELAD Control ELAD Control ELAD Control
Per–Protocol
Population
13 16 6 10 19 26
Mean Age 46.4 49.8 55.6 56.7 49.8 52.6
Baseline disease
severity (Mean MELD)
28.4 29.3 27.1 27.5 27.9 28.5
Mean Duration of ELAD Treatment: 93 Hours (Range 24 – 144)
22

23. Alcohol-
Induced
Non-Alcohol
Induced
Total
ELAD Control ELAD Control ELAD Control
Randomized 16 21 13 12 29 33
Baseline failure 0 2 4 0 4 2
Withdrew consent /
Lost to follow up
1 3 0 1 1 4
MITT 15 16 9 11 24 27
<72 hrs therapy 2 0 3 1 5 1
PP 13 16 6 10 19 26
Reasons for Baseline Failures:
Death 0 0 1 0 1 0
Transplant 0 0 1 0 1 0
Ineligible 0 2* 2** 0 2 2
Total 0 2 4 0 4 2
* DNR, portal vein thrombosis
** Hemodynamic instability, systemic fungal infection
VTI-206 Study Population
23

24. AILD PP
Subjects
N=29
13
16
14
8
A 6
D 8
A 5
D 3
Control
ELAD
PCTx
Outcome
Outcome
5
2
A 4
D 1
No PCTx
No PCTx
PCTx
A 1
D 1
VTI-206 AILD Study Population:
Outcomes vs. Use of Pharmacotherapy
24
Outcome Per-Protocol
Outcome
ELAD
n = 13
Control
n = 16
Overall
Survival
9/13 7/16
69.2% 43.8%
Median
survival,
days
>100 65

25. Efficacy: Alcohol-Induced Cohort, Per-Protocol (n=29)
Data presented at Plenary Session of 18th Congress of the International Liver Transplant Society (2012),
by Lewis Teperman, MD, Chief of Transplant Surgery at New York University.
25

26. Favorable Trends for Key Biomarkers Supports Proposed
Mechanism of Action
-6
-5
-4
-3
-2
-1
0
1
0 1 2 3 4
Day post-baseline
*p<0.05 vs. baseline
T-biliChangemg/dL
CONTROL
ELAD
*
*
*
*
16 16
16 15
16 15
13 13
13
13 10
9-2.00
-1.50
-1.00
-0.50
0.00
0.50
1.00
1.50
Baseline Day 02 Day 03 Day 04 Day 05 Day 06
ELAD
Control
p=0.0425
p=0.0231
%changesodium
Data presented at American Transplant Congress (2013), by Lewis Teperman, MD, Chief of Transplant
Surgery at New York University.
%changecreatinine
13
14 15
14
14
1416
11
11
10
8
6-25.00
-20.00
-15.00
-10.00
-5.00
0.00
5.00
10.00
Baseline Day 02 Day 03 Day 04 Day 05 Day 06
Control
ELAD
Change in Bilirubin Percent Change in Sodium Percent Change in Creatinine
*
26

27. Subject changes vs baseline in serum bilirubin
AILD cohort, per-protocol (n=29)
0
2
4
6
8
10
12
14
ELAD Control
Numbersubjects
0
2
4
6
8
10
12
ELAD Control
Numbersubjects
0
2
4
6
8
10
12
ELAD Control
Numbersubjects
0
2
4
6
8
10
12
14
ELAD Control
Numbersubjects
1 day 2 day
3 day 4 day
# subjects with > 10% improvement
# subjects with < 10% change in either direction
# subjects with > 10% worsening
p-values are chi-square vs control
p<0.0001 p<0.01
p<0.01 p<0.01
27

28. Transplant Free Survival – Non-Alcohol Induced Cohort
28

29. VTI-206 Safety
29
ELAD Control
# SAEs 28 39
# Subjects 18 17
ELAD
# SAEs 6
# Subjects 4
Overall SAE SAE Attributed to ELAD
• Hematemesis
• Vaginal Bleeding
• Renal Failure
• GI Hemorrhage
• Sepsis
• Intravascular hemolysis

30. Efficacy Evaluation / Outcomes
Study Terminated Early after Enrollment of 62 Subjects by
Data and Safety Monitoring Board (DSMB)
•No Unexpected Safety Issues
•Clear Difference in Outcomes Between Populations
• No Alcohol Involved – ELAD Did Not Improve Survival
• Alcohol Involved – ELAD Did Improve Survival
30

31. Conclusions From VTI-206
No Unexpected Safety Issues
Statistically Significant Difference in Outcome Between Cohorts
Potential Benefit of ELAD for AILD Subjects
• ~70% survival vs ~45% survival; 25% increase in survival
• ELAD May Provide Bridge to Recovery
• Worthy of Further Exploration in Pivotal Study
No Benefit Observed in Non-AILD Subjects
31

32. Study Participants: VTI-206
32
1) Lewis W. Teperman | NYU Langone Medical Center
2) Todd Frederick | California Pacific Medical Center
3) David Kaufman | Strong Memorial Hospital, Rochester
4) Steven A. Conrad | Louisiana State University Health
Sciences Center
5) David C. Wolf | Westchester Medical Center
6) Julia Wendon | Kings College London
7) Robert S. Brown | Columbia University Hospital,
8) Rasheed A. Balogun | University of Virginia Health System
9) Paul Y. Kwo | Indiana University
10) Nick Murphy | Queen Elizabeth Hospital, Birmingham
11) Fin Stolze Larsen | Rigshospitalet Denmark
12) Abdullah Mubarak | The Liver Institute at Methodist in
Dallas and Plano
13) F. Fred Poordad | Cedars Sinai Medical Center
14) Santiago J. Munoz | Temple University Hospital
15) Helen S. Te | University of Chicago Medical Center
16) Alistair Lee | Royal Infirmary Edinburgh
17) James F. Trotter | Baylor University Medical
Center, Dallas
18) Andrew Austin | Royal Derby Hospital
19) James O'Beirne | Royal Free Hospital London

33. ELAD: Overall Safety Summary
33
Overall Incidence of Adverse Events
(>10% in ELAD Group)
Preferred Term
N=96 N=62
ELAD (%) Control (%)
Thrombocytopenia 32.3 9.7
Anemia 27.1 8.1
Hypotension 25.0 22.6
Coagulopathy 22.9 6.5
Pyrexia 21.9 12.9
Hypokalemia 17.7 16.1
Hyperglycemia 15.6 1.6
Ecchymosis 12.5 4.8
Peripheral Edema 11.5 3.2
Acidosis 10.4 4.8
Hypomagnesemia 10.4 6.5
Hypothermia 10.4 4.8

34. ELAD: Overall Safety Summary
34
Adverse Events Attributed to ELAD
(>5%)
Preferred Term
ELAD
N=96
N %
Thrombocytopenia 26 27.1%
Anemia 19 19.8%
Coagulopathy 16 16.7%
Hypothermia 8 8.3%
Hypofibrinogenemia 7 7.3%
Hypotension 7 7.3%

35. ELAD: Overall Safety Summary
35
Serious Adverse Events
(>1 in ELAD Group)
Preferred Term
ELAD
N = 96
Control
N=62
n % n %
Hypotension 8 8.3% 3 4.8%
Thrombocytopenia 6 6.3% 0 0.0%
Multi-organ failure 5 5.2% 4 6.5%
Hepatic failure 4 4.2% 0 0.0%
Anemia 3 3.1% 2 3.2%
Sepsis 3 3.1% 2 3.2%
Acidosis 2 2.1% 2 3.2%
Application site bleeding 2 2.1% 0 0.0%
Hepatic encephalopathy 2 2.1% 1 1.6%
Lung Edema 2 2.1% 0 0.0%
Note: 48/96 (50.0%) ELAD subjects compared to 28/62 (45.2%) control subjects had at least one SAE

36. Consistent Outcomes: Recoverable / Regenerable Livers
36

37. Lessons Learned from ELAD Clinical Development Program
• ELAD may:
• Allow FHF subjects to survive long enough to receive a liver transplant and/or recover;
• Improve the overall 84-day transplant-free survival of subjects with acute liver failure arising
due to acute flare of viral hepatitis, and;
• Improve the overall 90-day survival of subjects with AILD
•It is not possible to bridge subjects with End-Stage Liver Disease to
recovery with the ELAD System
• Transplant seriously confounds outcomes
• Bilirubin is a good surrogate marker for outcomes in ELAD-treated subjects
• At least 3 days of ELAD therapy seems to be necessary for optimal outcomes
37

38. Trial Start Date Design Indication(s) Location N
VTI – 208
(Phase 3)
Commenced
March 2013
Randomized,
controlled
Alcohol Induced
Liver
Decompensation
U.S.,
Europe,
Australia
200
VTI – 210
(Phase 3)
Commenced
H1: 2014
Randomized,
controlled
Severe AAH
Steroid non-
responsive
U.S.,
Europe,
Australia
120
VTI – 212
(Phase 3)
Commenced
H1: 2014
Randomized,
controlled
FHF U.S. 126
ELAD: New Clinical Studies
38

39. 39
Alcoholic Hepatitis
A systemic inflammatory disease induced by acute
Alcohol Intoxication
Producing a range of Immune Modulators and
Growth Factors
ELAD – A Biochemical Factory

40. The Spirit of 208 Criteria
•Liver more inflamed/necrotic than fibrotic/cirrhotic
•High expected mortality within 90 days but related to the
gradual degeneration of an initial recoverable Liver
•Good Survival, if only the Liver would recover
•Stable enough to make it through the Therapy
In short:
•Jaundiced Patients after recent ETOH intoxication with
swollen livers, mostly „First Timers― in their 30s and
40s, who don`t bleed and are not sliding into Sepsis.

41. Inclusion Criteria
1. Age ≥ 18 years
2. Total Bilirubin ≥ 8mg/dL
3. Clinical Dx of AILD, based upon evidence (medical history, lab) of
causal relationship between use of alcohol and onset of symptoms
(≤6wks)
VTI-208 ELAD in AILD
41

42. VTI-208 ELAD in AILD
Inclusion Criteria
4. Clinical Dx of AILD is classified as either:
• Severe AAH
• Medical h/o alcohol abuse AND Maddrey score ≥32
• Documented by liver Bx, OR 2 or more of the following:
hepatomegaly, ascites, AST>ALT, leukocytosis
• Alcohol-induced decompensation of chronic liver disease that
is not AAH (as defined above), with
• MELD 18-35; AND
• Underlying chronic liver disease documented by Liver Bx
and/or MH and/or Lab
42

43. 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
VTI-208 ELAD in AILD
43

44. Exclusion Criteria
1. Platelet < 40,000/mm3
2. INR >3.5
3. MELD Score >35
4. AST >500 IU/L
5. Infection unresponsive to ABx
6. ≥ 20% Reduction of T Bilirubin in previous 72 hr
• Bilirubin must be measured at least 12 hr after any
procedure that could alter serum Bilirubin (e.g.,
PRBCs)
VTI-208 ELAD in AILD
44

45. Exclusion Criteria
7. Hemodynamic instability, with evidence of diminished perfusion
• SBP < 90 unresponsive to fluid and/or low-dose pressors
• MAP < 60 unresponsive to fluid and/or low-dose pressors
• Increasing requirements of vasopressors prior to Screening
• Maximum vasopressor dose at Screening
8. Active bleeding
• Requirement of ≥ 2 units PRBCs to maintain stable Hb within
48h of Screening
VTI-208 ELAD in AILD
45

46. VTI-208 ELAD in AILD
Exclusion Criteria
9. Clinical evidence of liver size reduction due to cirrhosis:
• Liver size < 10 cm when measured laterally on the
mid clavicular line by US, or liver volume <750cc by
CT, unless PI interpretation indicates otherwise
10. Occlusive PV thrombosis impairing hepatopetal flow or evidence of bile
duct obstruction
46

47. VTI-208 ELAD in AILD
Exclusion Criteria
11. Significant concomitant disease with life expectancy
< 3 months:
• Severe CV, CNS, or pulmonary disease
• Cancer that has metastasized or has not yet been treated
12. End-stage renal disease requiring HD >8 wks
13. Liver disease related to homozygous Hemochromatosis, Wilson’s, Budd-Chiari
Synd, NASH
47

48. VTI-208 ELAD in AILD
Exclusion Criteria
14. Pregnancy (HCG) or lactation
15. Participation in another study within 1 month of enrollment (except
observational studies)
16. Previous liver transplant
17. Previous participation in a clinical trial involving ELAD
48

49. VTI-208 ELAD in AILD
Exclusion Criteria
18. DNR/DNI, or any advanced directive limiting SOC
19. Refusal to participate in the VTI-208E follow-up
study
20. No address for follow-up home health visits
49

50. VTI-208: Subject Enrollment:
50
0
20
40
60
80
100
120
140
160
180
200
Actual Subjects
Planned Subjects
74
200
Current Enrollment - 74

51. 51
NYU LANGONE MEDICAL CENTER
TRANSPLANT RESEARCH/STUDY TEAM
•Lewis Teperman, MD: Principal Investigator
•Aaron Winnick, MD: Sub-Investigator
•Bruce Gelb, MD: Sub-Investigator
•Glyn Morgan, MD: Sub-Investigator
•Raj Mittal, MD: Sub-Investigator
•James Park, MD: Sub-Investigator
•Robin Layman, RN: Sub-Investigator
•Ariana Rabinovicz, NP: Sub-Investigator
•Christelle Sommervil: Study Coordinator
•Cecilia Deterville: Study Coordinator
•Nadine Meyers-Jack: Study Coordinator

52. Presentation Title Goes Here 52
CONTACTS
• Dr. Lewis Teperman, Cell: (917) 453-2578
• Dr. Raj Mittal, Cell: (310) 483-5411
• Dr. Aaron Winnick, Cell: (201) 303-8878
• Dr. James Park, Cell: (201) 618-4805
• Christelle Sommervil, Cell: (212) 263-8391
• Robin Layman, Cell: (540) 798-2569

53. Dinner, Drinks, and Questions
53

54. Presentation Title Goes Here 54
Early Liver Transplantation for Severe Alcoholic Hepatitis
New England Journal of Medicine, 365;19 Nov 10, 2011
Food for Thought

55. 55Confidential: VTI Investigator's Meeting

56. Presentation Title Goes Here 56

57. 57
Cut1, Right Lobe Graft without MHV, Graft and Remnant

58. Presentation Title Goes Here 58

59. Presentation Title Goes Here 59

60. 60

61. Presentation Title Goes Here 61

62. Presentation Title Goes Here 62

63. Next Step: Consult with the Regulators
FDA Proposed Special Protocol Assessment (SPA)
• Two Submissions – 6 Months
• Challenge Due to Open Label Nature of Study
• Provided Comprehensive Guidance
• Main Concern: Potential for Bias
• Define Standard of Care
SAWP (European Scientific Advice)
• Two Submissions – 12 Months
• Require Single Study in Treating Steroid Failures
• Also Provided Comprehensive Guidance
• Would Accept US Study as ―Supportive‖
• Also Concerned About Bias
63