Clinical Development of Medicinal Signaling Cells (HepaStem®) for Liver Regenerative Therapy

Human Allogeneic Liver-derived Progenitor Cells (HALPC; HepaStemTM) are an advanced therapy medicinal product composed of medicinal signaling cells derived and expanded from healthy human liver. Their mesenchymal and hepatocytic features make them promising cell therapy candidates for the treatment of life-threatening fibro-inflammatory liver diseases.

Safety, tolerability, and preliminary efficacy of HALPC infusion have been shown in 3 different trial:

1. A phase IIa prospective, open label, multi-center, randomized clinical trial in paediatric patients suffering from metabolic disorders, such as urea cycle disorders or Crigler-Najjar syndrome (HEP001 – NCT01765283; Smets et al., 2019).
2. In adults with Non Alcoholic Steato Hepatitis (NASH)
3 In adult with Acute decompensation and Acute on chronic Liver Failure (ACLF). HALPC act as a cargo inducing a hit-and-run decreasing of systemic and local inflammation and deactivation of stellate cells through paracrine activity. In vitro studies have shown a significant secretion of anti-inflammatory and anti-fibrotic cytokines including prostaglandin E2 (PGE2), indoleamine 2,3- dioxygenase (IDO), and hepatocyte growth factor (HGF), upon incubation of HALPC with an inflammatory cocktail.
ACLF is a life-threatening complication of cirrhosis, associated with deterioration of liver function followed by multiple organ failures. ACLF is linked to multiple cell type dysfunction, immunological imbalance and increased local and systemic inflammation. It is expected that HALPC exert immunomodulatory effects by interacting with immune cells of the patient and by paracrine effects through the various factors they secrete.

The phase IIa clinical trial (HEP101 – NCT02946554) assessed the safety and preliminary efficacy of repeated infusions and intermediate doses in cirrhotic patients with ACLF or AD. (Nevens et al., 2018). An ongoing phase IIb, proof of concept trial, is currently recruiting patients across multiple centers in Europe (HEP102 – NCT04229901). This is an interventional, double blind, randomized, and placebo- controlled study of 1 dose regimen of HALPC intravenously infused in patients newly diagnosed with ACLF grade 1 or 2 on top of Standard of Care (SoC).

Pre-clinical data coupled with clinical data support a continued investigation in the context of a clinical development platform program, targeting ACLF, NASH, Acute Alcoholic Hepatitis, Acute decompensation of cirrhosis and other fibro inflammatory liver diseases.
 

Learning Objectives:

1. Classify the principle of paracrine mechanism of action.

2. Describe the process of bench to bedside clinical development.

3. Identify the design of a clinical trial.