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

Françoise Smets, Dries Dobbelaere, Patrick McKiernan, Carlo Dionisi-Vici, Pierre Broué, Emmanuel Jacquemin, Ana Isabel Lopes, Isabel Gonçalves, Hanna Mandel, Joanna Pawlowska, Diana Kamińska, Eyal Shteyer, Giuliano Torre, Riki Shapiro, François Eyskens, Philippe Clapuyt, Paul Gissen, Danièle Pariente, Stephanie Grunewald, Marc Yudkoff & 6 others Maria Mercedes Binda, Mustapha Najimi, Nathalie Belmonte, Beatrice De Vos, Joelle Thonnard, Etienne Sokal

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalTransplantation
DOIs
Publication statusE-pub ahead of print - Feb 18 2019

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Crigler-Najjar Syndrome
Inborn Urea Cycle Disorder
Mesenchymal Stromal Cells
Stem Cells
Pediatrics
Safety
Liver
Portal Vein
Thrombosis
Regenerative Medicine
HLA Antigens
Multicenter Studies
Liver Diseases
Catheters
Transplantation
Hemodynamics
Body Weight
Clinical Trials
Technology
Antibodies

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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; Dobbelaere, Dries; McKiernan, Patrick; Dionisi-Vici, Carlo; Broué, Pierre; Jacquemin, Emmanuel; Lopes, Ana Isabel; Gonçalves, Isabel; Mandel, Hanna; Pawlowska, Joanna; Kamińska, Diana; Shteyer, Eyal; Torre, Giuliano; Shapiro, Riki; Eyskens, François; Clapuyt, Philippe; Gissen, Paul; Pariente, Danièle; Grunewald, Stephanie; Yudkoff, Marc; Binda, Maria Mercedes; Najimi, Mustapha; Belmonte, Nathalie; Vos, Beatrice De; Thonnard, Joelle; Sokal, Etienne.

In: Transplantation, 18.02.2019.

Research output: Contribution to journalArticle

Smets, F, Dobbelaere, D, McKiernan, P, Dionisi-Vici, C, Broué, P, Jacquemin, E, Lopes, AI, Gonçalves, I, Mandel, H, Pawlowska, J, Kamińska, D, Shteyer, E, Torre, G, Shapiro, R, Eyskens, F, Clapuyt, P, Gissen, P, Pariente, D, Grunewald, S, Yudkoff, M, Binda, MM, Najimi, M, Belmonte, N, Vos, BD, Thonnard, J & Sokal, E 2019, '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', Transplantation. https://doi.org/10.1097/TP.0000000000002605
Smets, Françoise ; Dobbelaere, Dries ; McKiernan, Patrick ; Dionisi-Vici, Carlo ; Broué, Pierre ; Jacquemin, Emmanuel ; Lopes, Ana Isabel ; Gonçalves, Isabel ; Mandel, Hanna ; Pawlowska, Joanna ; Kamińska, Diana ; Shteyer, Eyal ; Torre, Giuliano ; Shapiro, Riki ; Eyskens, François ; Clapuyt, Philippe ; Gissen, Paul ; Pariente, Danièle ; Grunewald, Stephanie ; Yudkoff, Marc ; Binda, Maria Mercedes ; Najimi, Mustapha ; Belmonte, Nathalie ; Vos, Beatrice De ; Thonnard, Joelle ; Sokal, Etienne. / 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. In: Transplantation. 2019.
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title = "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{\circledR}) in Urea Cycle Disorders and Crigler-Najjar Syndrome patients",
abstract = "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.",
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TY - JOUR

T1 - Phase I/II Trial of Liver Derived Mesenchymal Stem Cells in Pediatric Liver Based Metabolic Disorders

T2 - 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

AU - Smets, Françoise

AU - Dobbelaere, Dries

AU - McKiernan, Patrick

AU - Dionisi-Vici, Carlo

AU - Broué, Pierre

AU - Jacquemin, Emmanuel

AU - Lopes, Ana Isabel

AU - Gonçalves, Isabel

AU - Mandel, Hanna

AU - Pawlowska, Joanna

AU - Kamińska, Diana

AU - Shteyer, Eyal

AU - Torre, Giuliano

AU - Shapiro, Riki

AU - Eyskens, François

AU - Clapuyt, Philippe

AU - Gissen, Paul

AU - Pariente, Danièle

AU - Grunewald, Stephanie

AU - Yudkoff, Marc

AU - Binda, Maria Mercedes

AU - Najimi, Mustapha

AU - Belmonte, Nathalie

AU - Vos, Beatrice De

AU - Thonnard, Joelle

AU - Sokal, Etienne

PY - 2019/2/18

Y1 - 2019/2/18

N2 - 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.

AB - 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.

U2 - 10.1097/TP.0000000000002605

DO - 10.1097/TP.0000000000002605

M3 - Article

JO - Transplantation

JF - Transplantation

SN - 0041-1337

ER -