8/10/2019 2008.Rozga

1/13

Bridge to recovery from liver failure with or withouttransplantation

Physiologic support after transplantation with marginal

livers

Physiologic support after liver surgery due to trauma or

cancer

There is a need to search for artificial means of liver assistancemaintain liver failure patients alive and neurologically intact until a

donor liver becomes available for transplantation or until their

livers recover from injury (regenerate)

Goals of Artificial Liver Support

8/10/2019 2008.Rozga

2/13

Artificial Liver Support

BLOOD PURIFICATIONSorbent - Based Therapy (MARS, Prometheus)

Ineffective in removing mediators of inflammation and other

protein-based mediators

Therapeutic Plasma Exchange

Complications Little effect on tissue levels of toxins

High cost

High Performance Hemofiltration Current membranes ineffective in removing mediators of

inflammation and other protein-based mediators

PROVISION OF WHOLE LIVER FUNCTIONSCell Therapy (BAL) to provide whole liver functions to

patients requiring maximum liver support High cost (up to $20K per treatment)

8/10/2019 2008.Rozga

3/13

Large Pore Haemofiltration for BloodPurification

Effective

Safe, even when used as high-volume

therapy

Low cost

Widely available (hemodialysis hardware)

8/10/2019 2008.Rozga

4/13

Selective Plasma Filtration Therapy (SEPET)

SEPETTM

is a single use hollow fiber filter designed to selectively reducethe level of circulating toxins of hepatic and renal failure plus mediators ofinflammation and inhibitors of hepatic regeneration

large-pore albumin leaking membrane

albumin replacement therapy

8/10/2019 2008.Rozga

5/13

Toxins & Mediators of Liver Failure & ItsComplications

AmmoniaAromatic amino acidsFalse neurotransmitters

Phenols

Bile acids

Bilirubin (marker of liver injury and not toxin)Mercaptans

Mediators of inflammation (IL-6, TNF-a,

IL-1b, Interferon g, C3a, chemokines,

lipid A)

Oxydative stress & its products (NO, oxyradicals)

TGF-b1(inhibitor of hepatic regeneration) Mediators of vascular responses

< 100 kDa

8/10/2019 2008.Rozga

6/13

Good Blood Components Retained in

Circulation

Blood clotting factors (9/13)

Immunoglobulins (IgG, IgM)

Complement system

Lipids

Hepatocyte Growth Factor

(stimulator of hepatic regeneration)

> 100 kDa

8/10/2019 2008.Rozga

7/13

STUDY DESIGNA single-arm study of patients with acute decompensationof cirrhosis and hepatic encephalopathy receiving Standard of Care + SEPETTM

PRIMARY ENDPOINTS (safety & tolerability)

Incidence and type of adverse events

Changes in laboratory parameters

Changes in vital signs

SECONDARY ENDPOINTS (efficacy)

Effect of SEPETTMon changes in:

Grade of hepatic encephalopathy (HE)

Disease severity scores (GCS, MELD, Child-Turcotte-Pugh)

Clinical, physiological and laboratory parameters

Phase I Study Protocol Accepted by FDA

8/10/2019 2008.Rozga

8/13

Conclusions

SEPET treatments were well tolerated and

reliably delivered.

Favorable Safety Profile Indications of potential clinical efficacy

Analysis of data supports moving forward with a

controlled, prospective, randomized trial.

8/10/2019 2008.Rozga

9/13

Multi-Center, Randomized, Controlled, Parallel Group Study of Standard

Medical Care + SEPET Compared to SMC Alone in Patients with Acute

Exacerbation of Chronic Liver Disease and Stage II-IV Hepatic Encephalopathy

Sequential Study Design with up to 3 Segments (116 -162 patients)*

Patients to be stratified for baseline HE grade, MELD score, listing for

transplant and need for renal replacement therapy

Up to 7 daily SEPET Treatments (veno-venous haemofiltration at 30 ml/kg/hr

requiring replacement of up to 75 g of albumin)

*If the primary and co-primary eff icacy endpoints both achieve a two-sided p-value

8/10/2019 2008.Rozga

10/13

SEPET Technology

Fiber Material Poylethersulfone, SYNCLEAR

0.5, Membrana, GmbH

Hollow-fiber membrane Asymmetric and hydrophil ic

Number of Fibers 12,000 +/- 100

Surface Area 1.7 sq. m

Fiber inner diameter 200 (nominal)

Wall thi ckness 35 (nominal)Effective Fiber Length 230 mm (nominal)

Yarn (acts as a spacer) Polye ster Performance Enhancing

Technology (P.E.T.)

Fiber/Yarn Ratio 10:2

Fiber Tensile Strength > 22 cN

Sieving cut off for plasma

constituents

150 kDa

Sieving coefficient for albumin 0.21

Sieving coefficient for IgG

8/10/2019 2008.Rozga

11/13

SELECTION CRITERIAHE grade II-IV

Lack of response to SMC lasting 20-26 hours

MELD score >24

No evidence of medical contraindication to transplantation

CO-PRIMARY ENDPOINTS

Improvement in HE by > 2 grades by the end of Day 7 is prognostic for

the Day 30 transplant-free survival

SEPET + SMC is safe and compared to SMC alone increases the

probability of recovery from HE by a minimum of 2 grades at the end

of Day 7 in patients with acute decompensation of cirrhosis and HE

Study Protocol Accepted by FDA

8/10/2019 2008.Rozga

12/13

8/10/2019 2008.Rozga

13/13

Questions?

THANK YOU