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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

Smets, Françoise MD, PhD1; Dobbelaere, Dries MD2; McKiernan, Patrick MD3; Dionisi-Vici, Carlo MD, PhD4; Broué, Pierre MD5; Jacquemin, Emmanuel MD, PhD6; Lopes, Ana Isabel MD7; Gonçalves, Isabel MD8; Mandel, Hanna MD, PhD9; Pawlowska, Joanna MD, PhD10; Kamińska, Diana MD, PhD10; Shteyer, Eyal MD, PhD11; Torre, Giuliano MD12; Shapiro, Riki MD13; Eyskens, François MD, PhD14; Clapuyt, Philippe MD15; Gissen, Paul MD, PhD16; Pariente, Danièle MD, PhD17; Grunewald, Stephanie MD, PhD18; Yudkoff, Marc MD19; Binda, Maria Mercedes PhD20; Najimi, Mustapha PhD21,22; Belmonte, Nathalie PhD20; de Vos, Beatrice MD, PhD20; Thonnard, Joelle MD20; Sokal, Etienne MD, PhD1,20

doi: 10.1097/TP.0000000000002605
Original Clinical Science—Liver
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Background. Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases.

Objective. 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 posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion 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 3 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 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 serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 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.

1 Department of Paediatrics, Paediatric Gastroenterology and Hepatology Unit, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium.

2 Medical Reference Center for Inherited Metabolic Diseases, University Children’s Hospital Jeanne de Flandre and RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, University Lille 2, CHRU Lille, Lille, France.

3 Liver Unit, Birmingham Children’s Hospital, Birmingham, United Kingdom.

4 Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesù di Roma, Roma, Italy.

5 Hépatologie pédiatrique et maladies héréditaires du métabolisme, Centre de compétences maladies héréditaires du métabolisme, Hôpital des enfants, CHU Toulouse, France.

6 Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Rare Liver Diseases, CHU Bicêtre, Assistance Publique, Hôpitaux de Paris, DHU Hepatinov, INSERM 1174, University Paris Sud, Paris, France.

7 Department of Pediatrics, Gastroenterology Unit, Medical Faculty of Lisbon, University Hospital Santa Maria, Lisbon, Portugal.

8 Hospital Pediátrico de Coimbra, Centro Hospitalar da Universidade de Coimbra, Coimbra, Portugal.

9 Department of Pediatrics, Metabolic Unit, Rambam Medical Center, Meyer Children’s Hospital, Haifa, Israel.

10 Department of Gastroenterology, Hepatology and Nutritional Disorders, The Children’s Memorial Health Institute, Warsaw, Poland.

11 Department of Pediatrics, Hadassah Ein-Kerem Medical Center, Jerusalem, Israel.

12 Department of Hepatology, Gastroenterology and Nutrition, Ospedale Pediatrico Bambino Gesù di Roma, Roma, Italy.

13 Liver Transplantation Unit, Institute of Gastroenterology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel.

14 Paediatric department, Universitair Ziekenhuis Antwerpen, Edegem, Belgium.

15 Department of Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

16 GOSH UCL Biomedical Center, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

17 Department of Radiology, CHU Bicêtre, Le Kremlin Bicêtre, France.

18 Centre for Inborn Errors of Metabolism, Great Ormond Street Hospital and Institute of Child Health, UCL, London, United Kingdom.

19 Mass Spectroscopy Center, The Children’s Hospital of Philadelphia, Philadelphia, USA.

20 Promethera Biosciences, Mont-Saint-Guibert, Belgium.

21 Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.

22 Promethera Biosciences, Mont-Saint-Guibert, Belgium.

Received 11 July 2018. Revision received 19 November 2018.

Accepted 10 December 2018.

F.S. and D.D. contributed equally.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

The clinical trial was registered at the EU Clinical Trials Register at EudraCT. EudraCT identification number: 2011-004074-28.

F.S., D.D., P.M., C.D-V., P.B., E.J., A.I.L., I.G., H.M., J.P., E.S., G.T., R.S., F.E., P.C., P.G., D.P., and S.G. were study investigators and participated to the manuscript revision.

M.Y. is the head of the external laboratory who performed the ureagenesis test and participated in the manuscript revision.

B.D.V. and E.S. were responsible for the study design and protocol writing.

B.D.V., J.T., and E.S. were responsible for the study planning, literature search, data extraction and analysis, and manuscript writing. N.B., M.B., and M.N. were responsible for the manuscript writing.

F.S., D.D., C.D-V., D.P., and P.B. have provided consulting services to Promethera Biosciences S.A. B.D.V. was a consultant for Promethera Biosciences SA. J.T. was an employee of Promethera Biosciences SA. M.M.B. and N.B. are employees of Promethera Biosciences S.A. M.N. provides consulting services to Promethera Biosciences S.A. He owns patents and owns stocks in the company. E.S. is the founder and Chief Scientific & Innovation Officer for Promethera Biosciences S.A. He is a member of the board, owns patents, and owns stocks in the company.

P.M., E.J., A.I.L., I.G., H.M., J.P., E.S., G.T., R.S., F.E., P.C., P.G., S.G., and M.Y. declare that they have no conflict of interest.

This study was sponsored by Promethera Biosciences S.A. It has been partly supported by the [Wallonia region]: (grants [6604, 7236, and 7623]).

Correspondence: 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. (francoise.smets@uclouvain.be).

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