HepaStem (heterologous human adult liver-derived mesenchymal stem cells) / Cellaion - LARVOL DELTA

PROLONGSTEM: HepaStem Long-Term Safety Registry (clinicaltrials.gov) - P=N/A | N=44 | Terminated | Sponsor: Cellaion SA | N=22 ➔ 44 | Trial completion date: Jul 2028 ➔ May 2024 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Jul 2028 ➔ May 2024; Sponsor decision related to product development prioritisation.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2 | N=133 | Terminated | Sponsor: Cellaion SA | Trial completion date: Dec 2024 ➔ May 2024 | Active, not recruiting ➔ Terminated; Sponsor decision

Trial completion date • Trial termination • Hepatology • Liver Failure

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2 | N=130 | Active, not recruiting | Sponsor: Cellaion SA | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Liver Failure

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: Cellaion SA | Phase classification: P2b ➔ P2 | N=363 ➔ 130 | Trial completion date: Jan 2023 ➔ Dec 2024 | Trial primary completion date: Jan 2023 ➔ Jul 2024

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Hepatology • Liver Failure

PERSISTENT ACLF: CHARACTERISTICS OF THE PATIENTS IN THE PHASE IIb HEP 102-DHELIVER STUDY (AASLD 2023) - "The DHELIVER study is an ongoing multicenter Phase IIb RCT double-blinded POC trial that aims to demonstrate the efficacy of Human Allogeneic Liver-derived Progenitor Cells (HepaStem®) on overall survival in patients with persistent ACLF grades (G) 1 and 2... Patients with persistent ACLF enrolled in DHELIVER study were characterized mainly by presence of liver failure (in G1) associated with coagulation failure (in G2). High level of bilirubin and significant systemic inflammation were recorded. Predominant etiology of cirrhosis was alcohol-related liver disease."

Clinical • P2b data • CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure

Safety, tolerability, and preliminary efficacy of ascending doses of Human Allogeneic Liver-derived Progenitor Cells (HepaStem®) in patients with cirrhotic and pre-cirrhotic non-alcoholic steatohepatitis (NASH) (EASL-ILC 2023) - "This first dose-finding, safety, and preliminary efficacy study of HepaStem in adult NASH patients with F3 or cirrhosis confirmed previous safety findings. Preliminary indicators of efficacy on liver health, metabolic and inflammation markers support further study of HepaStem’s potential to prevent progression towards cirrhosis and decompensation"

Clinical • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immune Modulation • Immunology • Inflammation • Ischemic stroke • Non-alcoholic Steatohepatitis • Obesity • IFNG • IL6 • TNFA

Safety, tolerability, and preliminary efficacy of ascending doses of Human Allogeneic Liver-derived Progenitor Cells (HepaStem®) in patients with cirrhotic and pre-cirrhotic non-alcoholic steatohepatitis (NASH) (EASL-ILC 2023) - "This first dose-finding, safety, and preliminary efficacy study of HepaStem in adult NASH patients with F3 or cirrhosis confirmed previous safety findings. Preliminary indicators of efficacy on liver health, metabolic and inflammation markers support further study of HepaStem’s potential to prevent progression towards cirrhosis and decompensation. Figure: YI bursary request: No Plagia Similarity: Status: Comments: Source: Average Grade: 15.2 Reviewing Comments: Average score value: Comment: Suggested type: Rejection Suggested: Reason for rejection: Comment for rejection: :"

Clinical • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immune Modulation • Immunology • Inflammation • Ischemic stroke • Non-alcoholic Steatohepatitis • Obesity • IFNG • IL6 • TNFA

ACLF course profiles over screening period in the phase IIb DHELIVER study (EASL-ILC 2023) - "DHELIVER study is an ongoing Phase IIb RCT double-blinded POC trial that aims to demonstrate the efficacy of HepaStem® on overall survival in patients with persistent ACLF G1 and G2... This prospective study confirms the variable and highly dynamic course of the disease in patients with ACLF G1 and G2 over the 3 to 7-day period post initial diagnosis. Improvement was most commonly observed in patients with ACLF G1 (39.3% vs 8.6% in G2). The most common etiology of cirrhosis was alcohol-related liver disease."

P2b data • CNS Disorders • Fibrosis • Gastroenterology • Genetic Disorders • Hematological Disorders • Hepatic Encephalopathy • Hepatitis B • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis

PROLONGSTEM: HepaStem Long-Term Safety Registry (clinicaltrials.gov) - P=N/A; N=22; Enrolling by invitation; Sponsor: Promethera Therapeutics; Trial completion date: Jul 2023 ➔ Jul 2028; Trial primary completion date: Jul 2023 ➔ Jul 2028

Clinical • Trial completion date • Trial primary completion date • Genetic Disorders • Hepatology • Liver Failure • Metabolic Disorders

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2b; N=363; Recruiting; Sponsor: Promethera Biosciences; Trial completion date: Nov 2023 ➔ Jan 2023; Trial primary completion date: Feb 2022 ➔ Jan 2023

Clinical • Trial completion date • Trial primary completion date • Hepatology • Liver Failure

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation. (PubMed, JHEP Rep) - P2 | "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)...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."

Journal • P2 data • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure

This trial will evaluate the safety and efficacy of HepaStem compared toplacebo in patients with a cirrhotic liver condition called Acute on ChronicLiver Failure (ACLF). The study will be performed in multiple centers and ina double-blinded manner, meaning neither the patients nor the treatingphysicians know who is on placebo or the study drug. (clinicaltrialsregister.eu) - P2; N=363; Ongoing; Sponsor: Promethera Biosciences

Clinical • New P2 trial • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • CXCL8 • IL6

A Safety and Efficacy Study of Infusions of HepaStem in Urea Cycle Disorders Pediatric Patients (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: HLB Cell Co., Ltd.; Recruiting ➔ Withdrawn

Clinical • Trial withdrawal • Metabolic Disorders • Pediatrics

Study to Evaluate the Efficacy of HepaStem in Urea Cycle Disorders Paediatric Patients (HEP002) (clinicaltrials.gov) - P2; N=5; Completed; Sponsor: Promethera Biosciences; Recruiting ➔ Completed; N=20 ➔ 5

Clinical • Enrollment change • Trial completion • Metabolic Disorders • Pediatrics

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2b; N=363; Recruiting; Sponsor: Promethera Biosciences; Not yet recruiting ➔ Recruiting; Trial primary completion date: Feb 2023 ➔ Feb 2022

Clinical • Enrollment open • Trial primary completion date • Hepatology • Liver Failure

Phase II Safety Study of 2 Dose Regimens of HepaStem in Patients With ACLF (clinicaltrials.gov) - P2; N=24; Completed; Sponsor: Promethera Biosciences; Active, not recruiting ➔ Completed

Clinical • Trial completion • Hepatology • Liver Failure

PANASH: Safety and Tolerability of HepaStem in Patients With Cirrhotic and Pre-cirrhotic NASH Patients (clinicaltrials.gov) - P1/2; N=23; Completed; Sponsor: Promethera Biosciences; Recruiting ➔ Completed; Trial primary completion date: Feb 2020 ➔ May 2020

Clinical • Trial completion • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis

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. (PubMed, Transplantation) - "This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses."

Clinical • Journal • P1/2 data • Cardiovascular • Hematological Disorders • Hepatology • Metabolic Disorders • Pediatrics • Thrombosis • Venous Thromboembolism

Clinical Protocol to Prevent Thrombogenic Effect of Liver-Derived Mesenchymal Cells for Cell-Based Therapies. (PubMed, Cells) - "This phenomenon however, could be controlled using either a low, or a high cell dose combined with anticoagulants. In clinical practice, this points to the suitability of a low HHALPC dose infusion to cirrhotic patients, provided that platelet and fibrinogen levels are monitored."

Clinical • Clinical protocol • Journal

CIRRHOTIQUE01: Effect of Liver MSCs in Blood of Patients With Liver Disease. (clinicaltrials.gov) - P=N/A; N=9; Completed; Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Enrolling by invitation ➔ Completed; N=15 ➔ 9

Enrollment change • Trial completion

Safety and preliminary efficacy of human adult liver progenitor cells (HepaStem™) in patients with acute-on-chronic liver failure (ACLF) or acute decompensation (AD) at risk of developing ACLF (BWG 2020) - "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."

Clinical • CRP

Infusion-related thrombogenesis by liver-derived mesenchymal stem cells controlled by anticoagulant drugs in 11 patients with liver-based metabolic disorders. (PubMed, Stem Cell Res Ther) - P1/2; "The safety- and the infusion-related pro-coagulant activity remains a concern in MSC transplantation. In our study, a combination of heparin and bivalirudin was added to prevent the thrombogenic risk induced by HepaStem infusions in 11 patients. A significant decrease in platelet and increase in D-dimer levels were observed, suggesting the activation of coagulation in these patients; however, this was spontaneously reversible in time. We can conclude that adding this combination of anticoagulants is safe and limits infusion-related thrombogenesis to subclinical signs in most of the patients."

Clinical • Journal

DHELIVER: Study to Evaluate the Efficacy and Safety of HepaStem in Patients With Acute on Chronic Liver Failure (ACLF) (clinicaltrials.gov) - P2b; N=363; Not yet recruiting; Sponsor: Promethera Biosciences

Clinical • New P2b trial

Phase II Safety Study of 2 Dose Regimens of HepaStem in Patients With ACLF (clinicaltrials.gov) - P2; N=24; Active, not recruiting; Sponsor: Promethera Biosciences; Recruiting ➔ Active, not recruiting; N=12 ➔ 24

Clinical • Enrollment change • Enrollment closed

PANASH: Safety and Tolerability of HepaStem in Patients With Cirrhotic and Pre-cirrhotic NASH Patients (clinicaltrials.gov) - P1/2; N=24; Recruiting; Sponsor: Promethera Biosciences; Trial completion date: Mar 2020 ➔ Jul 2020; Trial primary completion date: Sep 2019 ➔ Feb 2020

Clinical • Trial completion date • Trial primary completion date