Promethera’s development portfolio contains innovative product candidates for multiple therapies based on human liver-derived cell therapy technologies. These are allogeneic cell therapies developed as off-the-shelf pharmaceutical grade products.
HepaStem is a human liver derived mesenchymal stem cell with the potential to differentiate into hepatocyte like cells and displaying anti-inflammatory and anti-fibrotic properties. HepaStem is today developed in ACLF and NASH/Fibrosis. Promethera Biosciences has started a phase IIa trial in ACLF to establish the safety of the peripheral intravenous infusion of HepaStem as a primary endpoint and explore clinical and biological parameters as secondary endpoints.
The Company is also exploring the possibility to use HepaStem as a distinct cell-based gene therapy platform after genetic modification of this cell. Currently this approach is using the Hemophilia B indication for a general proof of concept before designing tailored cells for its core programs. HepaStem will be administered intravenously, a customary injection method in stem-cell based medicines.
Acute-on-chronic liver failure (ACLF)
ACLF is a recently recognized syndrome characterized by acute decompensation of cirrhosis associated with organ/system failure(s) (liver, kidney, brain, coagulation, circulation and/or lung) and poor survival. (27)
Common precipitants of acute decompensation of liver function include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40 % of patients, no precipitating event is identified.
Epidemiological studies indicate that there is an increasing prevalence of liver cirrhosis related to chronic infection by hepatitis C or B virus, alcohol consumption and non-alcoholic steatohepatitis worldwide (28). The natural course of cirrhosis is from compensated to decompensated disease. Decompensation is characterized by the development of complications related to portal hypertension and liver failure (variceal bleeding, ascites, hepatic encephalopathy and bacterial infections) and is associated with poor prognosis.
Approximately 31% of patients admitted to a hospital for acute decompensation of cirrhosis have ACLF at admission (20%) or develop the syndrome during hospitalization (11%).
It is estimated that the incidence of ACLF patients in Europe (EMA), the U.S. and Japan is more than 70,000 patients annually.
27. Bernal, W. et al. Acute-on-chronic liver failure. Lancet 386, 1576-1587, doi:10.1016/S0140-6736(15)00309-8 (2015).
28. Murray, C. J. et al. GBD 2010: a multi-investigator collaboration for global comparative descriptive epidemiology. Lancet 380, 2055-2058, doi:10.1016/S0140-6736(12)62134-5 S0140-6736(12)62134-5 [pii] (2012)
Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic fatty liver disease (“NAFLD”) is one of the world’s most significant liver-related health problems. Being overweight or obese is a primary risk factor for NAFLD, with 80% of obese people and a high proportion of diabetics (40-70%) estimated to have NAFLD. The severity of the disease is assessed histologically using the NAFLD Activity Score (“NAS”), which consists of the unweighted sum of scores of steatosis, hepatocyte ballooning, and lobular inflammation.
Nonalcoholic steatohepatitis (“NASH”) is defined as a sub-form of NAFLD when the simultaneous presence of any degree of steatosis, lobular inflammation, and ballooning of the liver can be observed as a result of liver inflammation and damage caused by a build-up of fat in the liver. In simple steatosis, fat accumulates in the liver with no presence of significant inflammation or liver fibrosis, whereas in NASH, liver steatosis is associated with hepatic inflammation, hepatocellular ballooning, and fibrosis, which can render it indistinguishable from alcoholic steatohepatitis. As NASH is the progressive form of liver disease, it carries the risk of progressive fibrosis, cirrhosis, and end-stage liver disease, and is primarily characterized by hepatic necro-inflammation. NASH is a slow developing condition and, as a result, the intensity of a patient suffering from NASH can vary and NASH therefore often goes undiagnosed in the larger population.
The prevalence of NAFLD is increasing worldwide in parallel with the obesity epidemic. It is estimated that the prevalence of NAFLD in the adult US population is 30%-40%, while studies from other parts of the world report a prevalence ranging from 6% to 35% (median approximately 20%). Furthermore, it has been estimated that 15%-20% of patients with NAFLD have NASH. This translates into a NASH prevalence in the general population of 3%-5%. A more recent study from the US observed an even higher prevalence of NAFLD and NASH in the general population (46% and 12%, respectively), and 2.7% in the entire cohort had established, advanced NASH related liver fibrosis, leading to an estimated > 2 million US adults with NASH related, advanced liver disease
6. Miyajima, A., Tanaka, M. & Itoh, T. Stem/Progenitor Cells in Liver Development, Homeostasis, Regeneration, and Reprogramming. Cell Stem Cell 14, 561-574, doi:10.1016/j.stem.2014.04.010 (2014).
8. HEPAMAP. A roadmap for hepatology research in Europe: An overview for policy makers. (2016).
H2Stem is a human liver derived progenitor cell that has the potential to differentiate towards the hepatocyte lineage. The Company is currently advancing the platform towards the clinic by improving the manufacturing process and further characterization of the cell type’s therapeutic potential.
H2Stem technology platform
H2stem are liver derived progenitor cells characterized by the expression of biliary, endoderm, hepatocytic and mesenchymal markers. In addition, they retain the capability of differentiating in vitro into hepatocyte-like cells and show a high capacity to home and repopulate the liver of FRG mice, an established model for human xenografts, with mature functional hepatocytes. These results suggest a liver stem cells role of H2stem.
H2stem can be differentiated in vitro towards hepatocyte lineage and differentiated cells are characterized by the expression and secretion of albumin and alpha 1-antitrypsin.
Heparesc is Promethera’s most advanced pre-commercial product. The cell technology, which was one of the assets Promethera gained access to when it acquired Cytonet in 2015, is comprised of liver-derived primary, mature hepatocytes. Two clinical studies have successfully been completed and Promethera is preparing to file for market approval with the regulatory authorities in Canada in the first half of 2017.
Heparesc is a cell therapy product derived from donors that has been developed for the treatment of patients with urea cycle disorders. The product consists of a cryopreserved suspension of human liver cells, which are isolated from non-transplantable donor organs and prepared in a standardized manufacturing process under Good Manufacturing Practice conditions.
Heparesc for the treatment of Urea Cycle Disorder
Heparesc was developed for the treatment of deficient liver cell function in patients with inborn liver-based metabolic disorders such as urea cycle defects. In these medical conditions the patient may profit either from partial correction of the defect and /or in a “bridge to transplantation” setting from a transient functional support until a liver transplantation can be performed.
Stéphenne, Xavier, Mustapha Najimi, Catherine Sibille, Marie-Cécile Nassogne, Françoise Smets, and Etienne M Sokal. "Sustained Engraftment and Tissue Enzyme Activity After Liver Cell Transplantation for Argininosuccinate Lyase Deficiency." Gastroenterology 130, no. 4 (2006): doi:10.1053/j.gastro.2006.01.008