Multiorgan Support Therapies (MOST): Are We Ready? Liver Support Rajiv Jalan UCL Hepatology Royal Free Hospital

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1 CRRT/AKI, workshop, Honore/Jalan/ Noiri/Ricci/Ronco Multiorgan Support Therapies (MOST): Are We Ready? Liver Support Rajiv Jalan UCL Hepatology Royal Free Hospital

2 Disclosures: Inventor: Ornithine phenyl acetate for the treatment of hepatic encephalopathy (licensed to Mallinckrodt Therapeutics) Research Collaboration: Yaqrit Ltd. Founder: UCL spin-out company, Yaqrit Ltd Yaq-001 DIALIVE TLR4 antagonist

3 Outline ACLF: Characteristics and reversibility Liver Support devices Artificial Biological

4 What is the correct duration of Rx? Moreau, Jalan, et al. Gastroenterology

5 Hypothesis why LAD should work is pretty simplistic.. 100% Acute Insult Different results/goals depending upon timing of Intervention Threshold for organ failure 0 alan et al. Gut (2004)?Too late! Months

6 This is the reality INITIAL GRADE FINAL GRADE No ACLF (n=165) ACLF-1 (n=70) ACLF-2 (n=59) ACLF-3 (n=94) ACLF -1 The Prevalence potential (n=202) 110 (54.5%) for reversibility 49 (24.3%) 18 (8.9%) is greatest 25 (12.4%) 28-day tx-free 7/104 (6.7%) 10/47 (21.3%) 8/15 (53.3%) 21/24 (87.5%) mortality (n=190) ACLF -2 Prevalence (n=136) 47 (34.6%) 19 (14.0%) 35 (25.7%) 35 (25.7%) 28-day tx-free mortality (n=118) ACLF -3 1/42(2.4%) 2/17(11.8%) 8/27 (29.6%) 29/32 (90.63%) Prevalence (n=50) 8 (16.0%) 2 (4.0%) 6 (12%) 34 (68%) 28-day tx-free mortality (n=45) in patients with ACLF 1 and 2 1/8 (12.5%) 0/2 (0.0%) 4/6 (66.7%) 28/29 (96.6%)

7 A working model to define the use of the scoring system for patient selection in clinical trials Estimated probability of death Low Mortality Inclusion of these patients will require very large numbers w/out BB's Suitable for clinical trials allowing power calculations CLIF-C ACLF Score Very high mortality: Graveyard for drug development w/out BB's Mookerjee et al. JHEP 2015

8 Liver support devices Artificial Current Available for use MARS Prometheus Plasma Exchange In clinical trials DIALIVE Biological Historical Hepatasisst Current In clinical trials ELAD AMC BAL SRBAL

9 Liver support devices Artificial Current Available for use MARS Prometheus Plasma Exchange In clinical trials DIALIVE Biological Historical Hepatasisst Current In clinical trials ELAD AMC BAL SRBAL

10 Plasmapheresis with plasma exchange Advantages: HVP removes all molecules, even if large Substitutes plasma products Coagulation factors, albumin, immunoglobulins Improves hemodynamics Increases splanchnic blood flow increases CPP and CBF No adverse effect upon ICP Improves HE, CMRgl and O2 Disadvantages: Limited transport of water-soluble substances Unselective removal substances Requires donor plasma Larsen et al. Eur J Gastroenterol Hepatol 1996;8: Clemmesen et al. Am J Gastroenterol Apr;96(4): Larsen et al. Eur J Gastroenterol Hepatol 1995;7: Clemmesen et al. Hepatology 1999;29:347-55

11 Improvement of transplant free survival in Acute Liver Failure This study took nearly 10 years to complete?relevance to current day clinical practice

12 The MARS circuit MARS membrane Port 1 Dialysis membrane Albumin dialysate Haemofiltrat circuit Port 3 Port 4 Anion Exchange Resin Activated Charcoal Port 2

13 Why MARS did not work? Blood Plasma Albumin with toxins bound Albumin toxin Binding sites on MARS membrane Albumin Dialysate

14 EXTRACORPOREAL LIVER SUPPORT WITH THE MOLECULAR ADSORBENT RECIRCULATING SYSTEM (MARS) IN PATIENTS WITH ACUTE-ON-CHRONIC LIVER FAILURE (AOCLF). THE RELIEF TRIAL R. Bañares 1, F. Nevens 2, F.S. Larsen 3, R. Jalan 4, A. Albillos 1, M. Dollinger 5, Relief Study Group 1 Liver Unit, Hospital General Universitario Gregorio Marañon, CIBEREHD, Madrid, Spain, 2 Department and Lab of Hepatology, University Hospitals, Leuven, Belgium, 3 Dept. Hepatology A-2121, Rigshospitalet, Copenhagen, Denmark, 4 Institute of Hepatology, University College London, London, UK, 5 Servicio de Gastroenterología, Hospital Ramón y Cajal. University of Alcalá. CIBEREHD, Madrid, Spain, 6 First Department of Medicine, Martin- Luther-University, Halle, Germany. *rbanares@telefonica.net ACLF: n=189 patients Randomized MARS (n=95) Standard therapy (ST) (n=94). Survival (PP population n=156). The study took 8 years to complete MARS 59.2% ST 60.0% Post Hoc analysis MARS group had a higher improvement in HE 56 % vs. 39 % p=0.06 Hepatology 2013

15 What about targeting a specific complication: MARS is an effective Rx for HE Effectively reduces bilirubin, bile acids and many protein bound toxins Reduces ammonia Modifies oxidative stress and inflammation Hassanein et al. Hepatology 2007

16 ALIVER Project overview Development of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF)

17 The development of DIALIVE Lee et al. J Hepatol 2016

18 Pivotal Animal Study for Evaluation of Safety and Efficacy Pigs with Acute Liver Failure The model has 100% mortality within 14 hours from time of ALF Randomised to DIALIVE or SOC at ALF Treatment start at the point of ALF Lee et al. Liver International 2013

19 Endotoxin APAP APAP DIALIVE Control CD J Hepatol Sep;63(3):634-42

20 Does it improve survival? J Hepatol Sep;63(3):634-42

21 Liver support devices Artificial Current Available for use MARS Prometheus Plasma Exchange In clinical trials DIALIVE Biological Historical Hepatasisst Current In clinical trials ELAD AMC BAL SRBAL

22 Demetriou s BAL, Porcine Hepatocytes Treatment circuit includes Charcoal hemoperfusion n=171, ALF:147; PNF: 24 Primary End-point: 30-day survival All patients BAL-71%, controls-62% Subgroups» All ALF: BAL-73%, controls-59% (p=0.1)» ALF due to Paracetamol: BAL-70%, controls-37% (p<0.05) Demetriou, Ann Surg 2004

23 ELAD in Alcoholrelated ACLF Liver Transplantation 2018

24 New study design of ELAD based upon risk stratification Subgroup. Age <50; MELD<28; Cr: <1.5 A new trial is nearly finished recruitment

25 Mayo Spheroid Reservoir Bioartificial Liver (SRBAL) T T Spheroid Hepatocytes (>300 grams) Albumin Dialysis Spheroid Formation by Rocker Method T = 6hr 12hr 24hr Hepatocyte Reservoir

26 RALF Study: Improved Liver Regeneration with SRBAL therapy Ammonia Detoxification with SRBAL Therapy Blood Ammonia (μg/dl) Benefit of SRBAL Therapy Improved Survival with SRBAL Therapy in a Drug Overdose Pig model of Acute Liver Failure (ALF) ALF pig ambulatory at 90 hrs after 24hr SRBAL treatment

27 Summary The lack of understanding of disease has led to failed trials of LADs New definitions, prognostic criteria and futility of ACLF The importance of the duration and intensity of Rx End points need to be targeted New devices address deficiencies of both previous artificial and bio-artificial devices