Safety and preliminary efficacy of human adult liver progenitor cells (HepaStem TM) in patients with acute-on-chronic liver failure (ACLF) or acute decompensation (AD) at risk of developing ACLF

F. NEVENS (1), T. GUSTOT (2), P. LATERRE (3), L. LASSER (4), L. HARALAMPIEV (5), V. VARGAS (6), D. LYUBOMIROVA (7), A. ALBILLOS (8), V. BARTHEL (9), N. CLERGET-CHOSSAT (9), E. SOKAL (9) / [1] KU Leuven, , Belgium, Hepatology and Liver Transplantation , [2] Erasme Hospital, Brussels, Belgium, Gastroenterology/HepatoPancreatology/Digestive Oncology, [3] Saint-Luc University Hospital, Brussel, Belgium, Intensive Care, [4] CHU Brugmann, Brussels, Belgium, Gastroenterology, [5] Hospital Medica Ruse, Ruse, Bulgaria, Internal Diseases, [6] Hospital Vall d’Hebron, Barcelona, Spain, Hepatology, [7] University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski", Pleven, Bulgaria, Clinical Gastroenterology with Hepatology, [8] Hospital Universitario Ramón y Cajal Catedrático de Medicina, Universidad de Alcalá, Madrid, Spain, Gastroenterology and Hepatology, [9] Promethera Biosciences, Mont-Saint-Guibert, Belgium, Product Development Introduction Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis associated with failure of one or more organs. HepaStem™ is a suspension of Human Allogenic Liver Progenitor Cells derived and expanded from the parenchymal fraction of collagenase-digested adult human liver. The immunomodulatory properties of HepaStem™ are expected to restore immune balance and liver function in patients with ACLF or AD. Aim The primary objective is the safety of 1 or 2 infusions of various doses of cells up to Day (D)28 post treatment. Secondary objectives include preliminary efficacy up to month (M)3. Methods Twenty-four patients were enrolled. The first patient (ACLF) received no cells due to technical issue. The second patient (ACLF) received 2 infusions of 4.2 x 10⁶ cells/kg, the third patient (ACLF) received 1 infusion of 5.3 x 10⁶ cells/kg, 6 patients (2 ACLF and 4 AD) 1 infusion of 0.6-0.8 x 10⁶ cells/kg, 3 patients (2 ACLF and 1 AD) 2 infusions of 0.6 x 10⁶cells/kg, and 12 patients (9 ACLF and 3 AD) 1 or 2 infusion of 1.2 x 10⁶ cells/kg. Results The second patient had severe epistaxis and the third one bled at the puncture site of the transjugular biopsy. They recovered; one had liver transplantation and the other one was well at 1 year. After dose adjustment in the subsequent dose-cohorts, no serious events causally related to HepaStem™ were reported. No other bleedings occurred, or any drop of platelets, fibrinogen, or coagulation factors. Adverse events were in line with those expected regarding the underlying diseases and comorbidities. In patients without liver transplantation (N=18), bilirubin and MELD score decreased, and albumin slightly increased as compared to pre-infusion values. Also, elevated baseline levels of C-Reactive Protein and neutrophil counts returned to normal in most patients. Conclusions At high cell doses (250 x 10⁶ cells), 2 patients with initial severe coagulation disturbances experienced bleeding possibly related to HepaStem™. This could be linked to tissue factor expressed by HepaStem™, which activate the coagulation cascade and lead to consumption of coagulation factors, as shown in preclinical studies. No bleedings related to HepaStem occurred at 0.6 to 1.2 x 10⁶ cells/kg doses, or changes in coagulation parameters; these dosages were safe in this AD/ACLF patient population. Preliminary data showed improvement of liver function and systemic inflammation post infusion. The clinically significant MELD and bilirubin improvement is considered as an encouraging sign of efficacy