Phase I/II Trial of Liver Derived Mesenchymal Stem Cells in Pediatric Liver Based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-Derived Progenitor Cells (HepaStem®) in Urea Cycle Disorders and Crigler-Najjar Syndrome patients

BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. AIM: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem®) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months post-transplantation. The secondary objective included the assessment of safety up to 12 months post-infusion, and of preliminary efficacy. METHODS: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with three doses of HepaStem®. Clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events (SAEs) to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem® was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the SAEs, of which 38% occurred within one month post-infusion. There was a trend of higher events in UCD as compared to CN patients. Segmental left portal vein thrombosis occurred in one patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age and underlying diseases. CONCLUSIONS: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses. * Françoise Smets and Dries Dobbelaere contributed equally. Disclosure: Françoise Smets, Dries Dobbelaere, Carlo Dionisi-Vici, Danièle Pariente and Pierre Broué have provided consulting services to Promethera Biosciences SA. Beatrice De Vos was consultant for Promethera Biosciences SA. Joëlle Thonnard was employee of Promethera Biosciences SA. Maria Mercedes Binda and Nathalie Belmonte are employees of Promethera Biosciences SA. Mustapha Najimi provides consulting services to Promethera Biosciences SA. He owns patents and owns stocks in the company. Etienne Sokal is founder and Chief Scientific & Innovation Officer for Promethera Biosciences SA. He is a member of the board, owns patents and owns stocks in the company. Registration of the Clinical Trial: The clinical trial was registered at the EU Clinical Trials Register at EudraCT. EudraCT identification number: 2011-004074-28. Patrick McKiernan, Emmanuel Jacquemin, Ana Isabel Lopes, Isabel Gonçalves, Hana Mandel, Joanna Pawloska, Eyal Shteyer, Guiliano Torre, Riki Shapiro, François Eyskens, Philippe Clapuyt, Paul Gissen, Stephanie Grunewald and Mark Yudkoff declare that they have no conflict of interest. List of funding: This study was sponsored by Promethera Biosciences S.A. It has been partly supported by the Wallonia region: grants 6604, 7236 and 7623. Corresponding author: Françoise Smets, MD, PhD, Department of Paediatrics, Paediatric Gastroenterology and Hepatology unit, Cliniques Universitaires St Luc, Université Catholique de Louvain Avenue Hippocrate, 10/1301, 1200 Brussels, Belgium. Email: francoise.smets@uclouvain.be Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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