VT4560_ F_060414 DIA-11000-05 ELAD Diagram Tall

In-Line Gas Analyzer

Cell Filter

QuickDisconnects

Non-InvasiveFlow Sensor

Pressure

Pressure

Air Detector

Dual Lumen CatheterUltrafiltrate Withdrawal

UF Pump30-60 mL/min

BloodPump120-200 mL/min

ELADCartridges

Ultrafiltrate Return

Blood Warmer

CentrifugalPump 2 L/min

Heater Exchanger

Oxygenator

Gas Blender DextrosePump

Reservoir

Bubble Trap / Screen Filter

Blood Return Line

Blood Withdrawal Line Pressure

UltrafiltrateGenerator

WaterHeater

ELAD is an allogeneic cellular therapy system based on our

human liver-derived cells com

bined with a reusable bedside unit.

During ELAD therapy, blood is drawn from

the patient via a central venous line and then passes through the bedside unit tubing w

here plasma ultrafiltrate is generated from

whole blood using

the ultrafiltrate generator. The patient’s plasma ultrafiltrate then

passes into the four ELAD cartridges where it contacts our C3A

cells after passing through fibers which allow

appropriate tw

o-way transfer of toxins, m

etabolites and nutrients, mim

icking liver function. The fibers, m

ade of a semi-perm

eable mem

brane, perm

it passage of macrom

olecules from our C3A cells to the

patient’s plasma ultrafiltrate. At the sam

e time, these fibers

permit the passage of toxins such as am

monia and bilirubin and

nutrients such as glucose and oxygen from the plasm

a ultrafiltrate to our C3A cells. Treated plasm

a ultrafiltrate is then filtered, reconstituted w

ith blood cells and returned to the patient via the central venous catheter. M

eanwhile, the bedside unit

monitors tem

perature, pH, and oxygen concentrations in the

plasma ultrafiltrate in order to m

aintain the cells’ viability.

TH

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Sample

Sample

INC

LU

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Subjects must m

eet ALL inclusion criteria to be eligible for the study per the VTI-208 Screening Form

s:

1. Age ≥

18 years;2.

Total Bilirubin ≥ 8 m

g/dL;3.

A clinical diagnosis of AILD, based on evidence or a clinical

judgement of a tem

poral (6 weeks or less) and causal

relationship betw

een alcohol use and symptom

s onset;4.

Classified as having either:

a. Severe acute alcoholic hepatitis (AAH), w

ith:

i.

Medical history of alcohol abuse; AN

D Maddrey Score

of ≥

32; AND

ii. AAH docum

ented by either:

1. Confirmatory liver biopsy, OR

2. Tw

o or more of the follow

ing: Hepatom

egaly, AST > ALT,

Ascites, Leukocytosis;

OR b. AILD of chronic disease that is not acute alcoholic hepatitis

(as defined above), with:

i. M

ELD score of 18-35, AND

ii. Underlying chronic liver disease documented by:

Liver biopsy, AN

D/OR Laboratory findings, AND/OR

M

edical history;5.

Not eligible for liver transplant during this hospitalization;

6. The Investigator believes the subject w

ill likely remain

hospitalized for at least 4 sequential days.

EX

CL

US

ION

CR

ITE

RIA

Subjects must NOT m

eet any of the exclusion criteria to be eligible for the study per the VTI-208 Screening Form

s:

1. Platelets <40,000/m

m3;

2. International N

ormalization Ratio (IN

R) > 3.5;3.

MELD Score > 35;

4. AST > 500 IU/L;

5. Evidence of infection unresponsive to antibiotics;

6. Evidence of reduction in total bilirubin of 20% or m

ore in the

previous 72 hours, if available. (Bilirubin measurem

ent

required at least 12 hours post procedure which m

ight alter

serum bilirubin);

7. Evidence of hem

odynamic instability;

8. Evidence of active bleeding or of m

ajor hemorrhage;

9. Clinical evidence of liver size reduction due to cirrhosis

(m

ay include US, CT, AND/OR investigator interpretation);

10. Occlusive portal vein thrombosis im

pairing hepatopetal flow,

or evidence of bile duct obstruction;

11. Evidence by physical exam, history, or laboratory evaluation,

of significant concom

itant disease with life expectancy of

less than 3 m

onths;12. Chronic end-stage renal disease requiring chronic

hemodialysis for m

ore than 8 weeks (not classified as

hepatorenal syndrom

e);13. Subject has liver disease related to hom

ozygous

hemachrom

otosis, Wilson’s Disease, has non-alcoholic fatty

liver disease, or Budd-Chiari Syndrom

e;14. Pregnancy or lactation;15. Participation in another investigational drug, biologic, or

device study within one m

onth of enrollment, except for

observational studies;

16. Previous liver transplant;17. Previous enrollm

ent in the treatment phase of another

ELAD trial;

18. Refusal to participate in the VTI-208E follow-up study;

19. Inability to provide an address for follow-up hom

e

health visits.

VT

I-2

08

PR

OT

OC

OL

Title A Randomized, Open-Label, M

ulticenter, Controlled Study to Assess Safety and Efficacy of ELAD® in Subjects w

ith Alcohol-Induced Liver Decom

pensation (AILD).

Objective The primary objective of this study is to evaluate the

safety and efficacy of ELAD with respect to overall survival in

subjects with AILD up to Study Day 91.

Study Design This is a randomized, m

ulticenter, open-label, concurrent control study of subjects w

ith AILD. Approximately

200 evaluable subjects meeting the eligibility requirem

ents of the study w

ill be randomly assigned in a 1:1 ratio to receive

either standard of care treatment for AILD (as defined in the

protocol) plus treatment w

ith the ELAD system (ELAD group)

or standard of care treatment for AILD alone (Control group).

Therapy ELAD therapy involves continuous treatment, w

ith duration up to five days (120 hours). The ELAD system

is a closed loop system

with no fluid rem

oval. The treatment duration w

ill be the discrete responsi-bility of the prim

ary investigator and sub-investigators. Vital Therapies, Inc. provides continuous ELAD system

monitoring and m

aintenance by an ELAD Specialist. Subjects w

ill remain under continuous observation during the

treatment period. The study involves m

ultiple clinic-based and at-hom

e visits, and post-study phone follow-ups.

A b s t r A c tImprovements in clinical outcomes led to the hypothesis that ELAD treatment stimulates recovery and regeneration of hepatocytes in subjects with Acute Liver Failure. To gain an understanding of what facets of C3A cell function contribute to this phenomenon, subjects’ blood and the plasma ultrafiltrate into (“UF IN”) and out (“UF OUT”) of the ELAD cell circuit at distinct time points were assayed for proteins and metabolites during ELAD treatment.

M e t h o d sThe ELAD System recirculates ultrafiltrated plasma from subjects’ blood through the cell cartridges, which is then combined with the whole blood returning to the subject. The System is operated continuously for up to five days and the C3A cells monitored for oxygen and glucose consumption at prespecified time points during the treatment period. Samples are taken from the subjects’ blood and ultrafiltrate prior to and after cell exposure during ELAD treatment. Data from one example Alcohol-Induced Liver Decompensation (AILD) subject for whom there are matching samples of blood and ultrafiltrate are shown in the Results.

r e s u lt s d i s c u s s i o nProtein production by ELAD cell cartridges is shown by increased levels of trackable proteins in the returning ultrafiltrate (“UF OUT”) as compared to ultrafiltrate entering the ELAD cell circuit (“UF IN”). This may contribute to increased blood protein concentrations in subjects during ELAD treatment. Due to the high flow rate through the ELAD cell circuit (“UF Pump” in the ELAD System Schematic, 30-60 mL/min), it is only possible to detect UF differences in proteins manufactured in high abundance by the C3A cells (e.g. α-fetoprotein [AFP], Gelsolin, C3 Complement), which match increases in blood levels of these proteins during ELAD treatment. Cumulative production of low abundance proteins (e.g. Factor V) can be observed in increased blood levels but not in UF differences. Gelsolin, C3 complement, Factor V and AFP blood levels are observed to fall 24 hours post ELAD treatment in this example subject. Oxygen and glucose consumption rates of the ELAD cell cartridges for this example subject are also shown. Coupled with the histology and electron microscopy findings, these observations suggest that the C3A cells in the ELAD System maintain viability through the ELAD treatment and may contribute significantly to circulating proteins levels in treated subjects .

The ELAD System has not been demonstrated to be safe or effective for any indication and is not available for sale in the United States or any other country. CAUTION: Investigational New Drug. Limited by Federal (or United States) law to investigational uses.

l teperman, Md1, J brotherton, Phd2, M eggert, Phd3, A dominik, Ms3 & J stange, Md2 � nYu langone Medical center, new York, nY, usA � Vital therapies, inc, san diego, cA, usA � university of rostock, Germany

disclosure: l teperman – consultant/Advisor: other, disclosure: M eggert & A dominik – consultants: other, disclosure: J brotherton & J stange – employees: other

Elad® Cell Cartridge

Histological Cross-Section

Elad® SystemElad® System Schematic

Gelsolin

elAd subject

Factor V

C3 Complement

Rough endoplasmic reticulum

Ribosomes

Mitochondrion

α-FetoproteinElad Cartridges

Oxygen & Glucose Consumption

A556Protein content AssessMent durinG treAtMent with the elAd® bioArtificiAl liVer suPPort sYsteM

Transmission Election Micrograph