A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

Frederik Nevens; Thierry Gustot; Pierre-François Laterre; Luc L Lasser; Lyudmil E Haralampiev; Victor Vargas; Desislava Lyubomirova; Agustin Albillos; Mustapha Najimi; Sébastien Michel; Ivaylo Stoykov; Noelia Gordillo; Yelena Vainilovich; Virginie Barthel; Nathalie Clerget-Chossat; Etienne M Sokal

doi:10.1016/j.jhepr.2021.100291

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

JHEP Rep. 2021 Apr 18;3(4):100291. doi: 10.1016/j.jhepr.2021.100291. eCollection 2021 Aug.

Authors

Frederik Nevens¹, Thierry Gustot², Pierre-François Laterre³, Luc L Lasser^{4

5}, Lyudmil E Haralampiev⁶, Victor Vargas⁷, Desislava Lyubomirova⁸, Agustin Albillos⁹, Mustapha Najimi¹⁰, Sébastien Michel¹¹, Ivaylo Stoykov¹¹, Noelia Gordillo¹¹, Yelena Vainilovich¹¹, Virginie Barthel¹¹, Nathalie Clerget-Chossat¹¹, Etienne M Sokal^{10

11

12}

Affiliations

¹ Department of Gastroenterology and Hepatology, University Hospitals, KU Leuven, Belgium.
² Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
³ Intensive Care Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
⁴ Gastroenterology Clinic, CHU Brugmann, Brussels, Belgium.
⁵ Department of Hepatogastroenterology, CHU Brugmann, Brussels, Belgium.
⁶ Department of Internal Diseases, Multiprofile Hospital for Active Treatment (MEDICA), Ruse, Bulgaria.
⁷ Liver Unit, Hospital Vall d'Hebron, Universitat Autònoma Barcelona, CIBERehd, Barcelona, Spain.
⁸ Department of Clinical Gastroenterology with Hepatology, Gastroenterology Clinic, University Multiprofile Hospital for Active Treatment "Georgi Stranski", Pleven, Bulgaria.
⁹ Gastroenterology and Hepatology, University Hospital Ramón y Cajal, Madrid, Spain.
¹⁰ UCLouvain, Institute of Experimental and Clinical Research (IREC), Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Brussels, Belgium.
¹¹ Promethera Biosciences, Mont-Saint-Guibert, Belgium.
¹² Cliniques Universitaires Saint-Luc, UCLouvain, Pediatric Hepatology & Gastroenterology Unit, Brussels, Belgium.

Abstract

Background & aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD).

Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3.

Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×10⁶ cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×10⁶ cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF.

Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×10⁶ HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy.

Clinical trials registration: EudraCT 2016-001177-32.

Lay summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy.

Keywords: ACLF, acute-on-chronic liver failure; AD, acute decompensation of liver cirrhosis; AE, adverse event; AESI, AE of special interest; ATMP, advanced therapy medicinal product; Alcoholic liver disease; BW, body weight; CRP, C-reactive protein; EASL-CLIF, European Association for the Study of Chronic Liver Failure; HALPC, human allogeneic liver-derived progenitor cells; INR, international normalised ratio; Liver regenerative medicine; MELD, model for end-stage liver disease; MSC, mesenchymal stem cells; SAE, serious AE; SAS, safety analysis set; SUSAR, suspected unexpected serious adverse reaction; Stem cell; TEG, thromboelastography; TGT, thrombin generation test; i.v., intravenous.