Lewis W. Teperman, MD The Mary Lea Johnson Richards Organ Transplantation Center at NYU and the ELAD Development Team

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1 Lewis W. Teperman, MD The Mary Lea Johnson Richards Organ Transplantation Center at NYU and the Development Team Bilirubin Improvement Correlates with 90-Day Survival with the Use of the System in a Randomized, led Study of Subjects with Acute Alcoholic Hepatitis (AAH) or Acute Decompensation of Cirrhosis (Non-AAH) Disclosure: VitalTherapies Medical Advisory Board Member MAY 19, 2013

2 Background Acute on Chronic Liver Failure has limited treatment options: Corticosteroids, cimetidine, hyperimmune gamma-globulin, exchange transfusions do not affect course of acute hepatitis 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 Due to the individual response by C3A Cells to hyper inflammation, my provide an individual immune-modulatory and antiapoptotic effect, more sophisticated than steroid therapy is designed to provide continuous support to possibly allow time for native liver to regenerate or provide a bridge to transplantation 2

3 Hypothesis Non alcohol induced AoCH is induced by other precipitating events (infections, bleeding) and occures in later stages of cirrhosis Alcohol induced Liver Failure (AAH) represents an acute toxic/inflammatory damage to the hepatocyte The current standard for AAH is antiinflammatory (Steroids) 3

4 : Bioartificial Liver Support System Live human liver cell line Hollow fiber of bioreactor Allogeneic cellular therapy 440g of immortalized human C3A liver cells Localized in 4 hollow fiber bioreactors Continuous treatment of plasma ultrafiltrate for up to 5 days Extra-corporeal support of liver function 4 Cartridges With Immortalized Human Liver Cells +/- HEPARIN INFUSION Metabolic Support Glucose & Oxygen UF Pump ULTRA FILTRATE GENERATOR Blood Pump CELL FILTER Cartridge Pump 4

5 : Bioartificial Liver Support System Selective Plasmafiltration into a Bioreactor containing appr. 440 g C3A human hepatoma cells Cells metabolize small molecules Cells provide active p450 Detoxification system Cells secret numerous proteins, such as albumin, acute phase response proteins 5

6 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 O 2 and glucose With, rate of plasma flow is 50 ml/min = 3 L/hr = 72 L/day Higher than plasma exchange therapy (2-3 L/treatment) 6

7 Albumin Production by Single Cartridge In-Process Manufacture 7

8 AFP levels Treated Subjects VTI-208 (representative values) Ng/mL (10 5 ) * Pre D1 D2 D3 D4 D5 Post D1 Post D2 * levels: <0.005 throughout 8

9 Secretory Proteomic Analysis Of C3A Cells when challenged with Toxins I Lewis JA et al: Analysis of Secreted Proteins as an in vitro Model for Discovery of Liver Toxicity Markers 9 Journal of Proteom Research 2010 (9): 5794

10 Trial Design Phase 2b trial in US/EU Open-label, randomized, controlled 1:1 randomization to therapy + standard medical therapy () - vs - standard medical therapy alone () 10

11 Key Entry Criteria Inclusion years old with acute decompensation of chronic liver disease over prior 28 days MELD score AOCH diagnosis: acute alcoholic hepatitis (AAH) or non-aah Exclusion Platelets <50,000/mm 3, INR >3.5 Chronic renal failure Septic shock, major hemorrhage, spontaneous bacterial peritonitis with uncontrolled systemic infection, hemodynamic instability Significant concomitant disease Previous liver transplant DNR 11

12 Efficacy Evaluation Overall survival (OS) at 30 and 90 days Pre-defined analysis populations All subjects, AAH, non-aah. AAH / non-aah populations were randomized independently. Results presented by subpopulation. Modified intent-to-treat (MITT) = subjects who received treatment (baseline failures excluded) with 90-day data Per-protocol (PP) = subjects who received 72 hrs treatment ( or control) OS assessed using Kaplan-Meier survival analysis with 2-tail alpha for log-rank test set at

13 Study Design D = study day; d = days 13

14 Study Population AAH Non-AAH Total Randomized Baseline failure Withdrew consent / Lost to follow up MITT <72 hrs therapy PP Reasons for Baseline Failures: Death Transplant Ineligible 0 2* 2** Total * DNR, portal vein thrombosis ** Hemodynamic instability, systemic fungal infection 14

15 Reasons for Hospitalization at Screening (in 2 or More Subjects in a Treatment Group) AAH Non-AAH n=16 n=21 n=13 n=11 AAH 100% (16/16) 100% (21/21) 0 0 Hepatic Encephalopathy 25.0% (4/16) 9.5% (2/21) 38.5% (5/13) 45.6% (5/11) GI Bleeding 18.8% (3/16) 14.3% (3/21) 23.1% (3/13) 9.1% (1/11) Jaundice 18.8% (3/16) 19.1% (4/21) 0 0 Ascites 6.3% (1/16) 14.3% (3/21) 7.7% (1/13) 0 Infection 6.3% (1/16) 4.8% (1/21) 15.4% (2/13) 0 Acute Renal Failure/ Hepatorenal Syndrome % (3/21) 15.4% (2/13) 27.3% (3/11) 15

16 Demographics - MITT n = 15 Males 10 (67%) Caucasian 9 (60%) Black 4 (13%) Age, Mean ± SD 46.4 ± 9.2 Baseline MELD, Mean ± SD 28.4 ± 5.4 AAH Non-AAH Total n = 16 8 (50%) 15 (94%) n = 9 5 (56%) 8 (89%) 0 1 (11%) 49.8 ± ± ± ± 5.8 n = 11 8 (73%) 10 (91%) n = (63%) 17 (71%) 0 5 (21%) 56.7 ± ± 4.8) 49.8 ± ± 5.5 n = (59%) 25 (93%) ± ± 4.9 Mean duration of treatment (N = 24): 93 hours (range ) 16

17 Baseline Conditions AAH Non-AAH n=16 n=21 n=13 n=11 MELD Score Mean (SD) 28.9 (5.13) 28.7 (8.7) 28.0 (5.34) 28.6 (5.09)* Min, Max 18, 40 2, 40 19, 36 18, 35 Maddrey Score Mean (SD) 69.3 (21.00) 79.9 (30.0) n.a. n.a. Min, Max 43, , 139 n.a. n.a. * n=10 Maddrey s Discriminant Function for Alcoholic Hepatitis Discriminant Function = 4.6 * (Pt's PT - PT) + Tbili

18 Efficacy: AAH Cohort, per-protocol (n=29) Median survival: : 65 days : >100 days No pt died after 12 days p = 0.27 HR =

19 Efficacy: Non-AAH Cohort, per-protocol (n=16) 6 Median survival: 10 : >100 days : 33 days p = 0.12 HR =

20 Percent change in creatinine vs % change creatinine Baseline Day 02 Day 03 Day 04 Day 05 Day Crea(nine (mg/dl) N Mean Mean±SD P- value N p- value Baseline ± ±1.53 * Percent change- from- baseline means Baseline Day ±10.22 * ± Day ± ± * * Day ± ± Day ± ± Day ± ±

21 Percent change in sodium vs % change sodium p= Baseline Day 02 Day 03 Day 04 Day 05 Day p-values vs baseline p= Sodium (mmol/l) N Mean Mean±SD p- value Mean Mean±SD N p- value Baseline ± ± * Percent change- from- baseline means Baseline * Day ± ± Day ± ±2.17 * * Day ± ± Day ± ± Day ± ±

22 Change in serum t-bilirubin (mg/dl) during treatment AAH Cohort, per-protocol (n=29) T-bili Change mg/dl Day post-baseline *p<0.05 vs. baseline * * * * 22

23 Change in serum t-bilirubin (mg/dl) during treatment Non-AAH Cohort, per-protocol (n=16) 4 *p<0.05 vs. baseline 3 T-bili Change mg/dl Day post-baseline * 23

24 Subject changes vs baseline in serum bilirubin during therapy: AAH Cohort, per-protocol (n=29) # subjects with > 10% improvement # subjects with < 10% change in either direction # subjects with > 10% worsening p-values are chi-square vs control 14 1 day 2 day 12 Number subjects p< Number subjects p< day 4 day 14 Number subjects p<0.01 Number subjects p<

25 Correlation between percent change from baseline total bilirubin and days of survival. Visit Correlation P-value POST POST POST * * * * 25

26 Mean MADDREY Score Post-baseline: AHH Subjects (MITT) 120 Mean MADDREY Score * * Day Post-baseline * * 26

27 Efficacy: AAH Cohort n = 15 OS through Day 90 9 (60%) MITT n = 16 7 (43.8%) n = 13 9 (69.2%) PP n = 16 7 (43.8%) Median survival, days > > Differences in survival were not statistically significant (p>0.05) but mathematically favored 1/13 (8%) -treated and 0/16 patients had transplant at 90 days 27

28 Efficacy: Non-AAH Cohort n = 9 OS through Day 90 2 (22.2%) MITT n = 11 6 (54.5%) n = 6 1 (17%) PP n = 10 6 (60%) Differences in survival were not statistically significant (p>0.05) 1/6 (17%) -treated and 4/10 (40%) patients had transplant by 90 days 28

29 Serious Adverse Events Considered Related to Treatment Hematemesis (1 Non-AAH, subject) Renal failure and vaginal hemorrhage (1 Non- AAH, subject) GI hemorrhage and sepsis (1 AAH, subject) Intravascular hemolysis (1 Non-AAH, subject) 29

30 Conclusions No unexpected safety issues Possible benefit of for AAH subjects may provide bridge to recovery and/or transplantation An early sustained decrease in bilirubin indicates a response to therapy. No benefit observed in AOCH subjects with acute liver failure due to non-aah disease. A Pivotal trial is currently underway for AAH. A FHF trial will initiate in

31 Study Participants Lewis W. Teperman 1, Todd Frederick 2, David Kaufman 3, Steven A. Conrad 4, David C. Wolf 5, Julia Wendon 6, Robert S. Brown 7, Rasheed A. Balogun 8, Paul Y. Kwo 9, Nick Murphy 10, Fin Stolze Larsen 11, Abdullah Mubarak 12, F. Fred Poordad 13, Santiago J. Munoz 14, Helen S. Te 15, Alistair Lee 16, James F. Trotter 17, Andrew Austin 18, James O'Beirne 19, Robert Ashley NYU School of Medicine, NYU Langone Medical Center, New York, NY, United States. 2. Department of Transplantation, California Pacific Medical Center, San Francisco, CA, United States. 3. Strong Memorial Hospital, Rochester, NY, United States. 4. Emergency Medicine LSUHSC, Louisiana State University Health Sciences Center, Shreveport, LA, United States. 5. Division of Gastroenterology and Hepatobiliary Disease, Westchester Medical Center, Valhalla, NY, United States. 6. Institute of Liver Studies, Kings College London, London, United Kingdom. 7. Center for Liver Disease and Transplantation, Columbia University Hospital, New York, NY, United States. 8. Department of Medicine, Nephrology Division, University of Virginia Health System, Charolettesville, VA, United States. 9. Indiana University, Indianapolis, IN, United States. 10. Critical Care & Anaesthetics, Queen Elizabeth Hospital, Birmingham, United Kingdom. 11. Hepatology Department, Rigshospitalet Denmark, Copenhagen, Denmark. 12. The Liver Institute at Methodist in Dallas and Plano, Dallas, TX, United States. 13. Cedars Sinai Medical Center, Los Angeles, CA, United States. 14. Temple University Hospital, Philadelphia, PA, United States. 15. University of Chicago Medical Center, Chicago, IL, United States. 16. Department of Anesthetics, Royal Infirmary Edinburgh, Edinburgh, United Kingdom. 17. Baylor University Medical Center, Dallas, TX, United States. 18. Derby Digestive Diseases Center, Royal Derby Hospital, Derby, United Kingdom. 19. The Sheila Sherlock Liver Center, Royal Free Hospital London, London, United Kingdom. 20. Vital Therapies, Inc., San Diego, CA, United States. 31