ELAD study vti 208 - Maimonides Team Brooklyn Dinner - March 4 2014

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

ELAD Clinical Development

Disclosure: Lewis Teperman, MD is a member of the

clinical advisory board and principal investigator

2

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

• 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

• 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

Albumin Production by Single ELAD® Cartridge

In-Process Manufacture

6

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

(10

5)

ELAD

Control

7

*Control levels: <0.005 throughout

*

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

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

Stages of Liver Disease—Quo Vadis?

10

Acute Chronic

11

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

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

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

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

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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 Daysp=0.015

56 Daysp=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

Tra

nsp

lan

t Fr

ee S

urv

iva

l (p

rop

ort

ion

)

Kaplan-Meier Plot of Transplant-Free Survival

p < 0.05, WIlcoxonn = 49

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)

Surv

ival pro

bability (

%)

ControlTreated

p<0.05


0 500 1000 1500 2000 2500

10

20

30

40

50

60

70

80

90

100

Time (days)

Surv

ival pro

bability (

%)

ControlTreated

p<0.05

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


0 500 1000 1500 2000

20

30

40

50

60

70

80

90

100

Time (days)

Surv

ival pro

bability (

%)

ControlTreated

p<0.05


0 500 1000 1500 2000 2500

10

20

30

40

50

60

70

80

90

100

Time (days)

Surv

ival pro

bability (

%)

ControlTreated

p<0.05

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

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)

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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

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

VTI-206 Study Population

Alcohol-InducedNon-Alcohol

InducedTotal

ELAD Control ELAD Control ELAD Control

Per–Protocol

Population13 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)

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Alcohol-

Induced

Non-Alcohol

InducedTotal

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

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

OutcomeELAD

n = 13

Control

n = 16

Overall

Survival

9/13 7/16

69.2% 43.8%

Median

survival,

days

>100 65

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

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. baselineT-b

ili C

ha

ng

e m

g/d

L

CONTROL

ELAD*

**

*

1616

16 1516 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

% c

hange s

odiu

m

Data presented at American Transplant Congress (2013), by Lewis Teperman, MD, Chief of Transplant

Surgery at New York University.

% c

hange c

reatin

ine

13

14 15

14

141416

11

11

10

86

-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

Subject changes vs baseline in serum bilirubin

AILD cohort, per-protocol (n=29)

0

2

4

6

8

10

12

14

ELAD Control

Nu

mb

er

su

bje

cts

0

2

4

6

8

10

12

ELAD Control

Nu

mb

er

su

bje

cts

0

2

4

6

8

10

12

ELAD Control

Nu

mb

er

su

bje

cts

0

2

4

6

8

10

12

14

ELAD Control

Nu

mb

er

su

bje

cts

1 day 2 day

3 day 4 day

# subjects with > 10% improvement

# subjects with < 10% change in either direction

# subjects with > 10% worseningp-values are chi-square vs control

p<0.0001 p<0.01

p<0.01 p<0.01

27

Transplant Free Survival – Non-Alcohol Induced Cohort

28

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

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

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

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

ELAD: Overall Safety Summary

33

Overall Incidence of Adverse Events

(>10% in ELAD Group)

Preferred TermN=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

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

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

Consistent Outcomes: Recoverable / Regenerable Livers

36

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

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

Alcoholic Hepatitis

A systemic inflammatory disease induced by acute

Alcohol Intoxication

Producing a range of Immune Modulators and

Growth Factors

ELAD – A Biochemical Factory

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.

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


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

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


43

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)


44

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


45


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


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


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


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

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

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

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

Dinner, Drinks, and Questions

53


Early Liver Transplantation for Severe Alcoholic Hepatitis

New England Journal of Medicine, 365;19 Nov 10, 2011

Food for Thought

55Confidential: VTI Investigator's Meeting


57

Cut1, Right Lobe Graft without MHV, Graft and Remnant



60



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

Health & Medicine

ELAD study vti 208 - Maimonides Team Brooklyn Dinner - March 4 2014