Challenges in developing an off-the-shelf cell therapy for ACLF and NASH

Abstract

Background & Aim Promethera is a biopharma company focused on the research, development and commercialization of stem cell-based therapies and technologies for acute and chronic liver diseases. Our lead clinical program, an allogenic human liver derived mesenchymal stem cell product derived from our patented cell technology platform HepaStem, is currently being used in Phase IIa clinical trials for ACLF (acute on chronic liver failure) with the company also preparing clinical trials for NASH. Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic liver diseases (NAFLD), is one of the prominent liver diseases worldwide. There is currently no approved drug for its treatment and liver transplantation is the only therapeutic approach for advanced NASH. Mesenchymal stem cells (MSCs) are promising candidates to modulate the pro-inflammatory and pro-fibrogenic environment of chronic liver because of their immunomodulatory properties. Recent data obtained in preclinical models of early and advanced stage NASH provided significant evidences to open new phase I/II clinical studies in NASH. Methods, Results & Conclusion The dosing for this indication is likely to be in the order of 100 million cells per infusion. Large numbers of cells thus need to be manufactured and using standard cell culture techniques would make it too expensive and labour intensive. A standard expansion protocol in flasks or cell factories is an open process, and therefore run in expensive clean rooms to avoid the risk of contamination. We have explored several state-of-the art-bioreactor systems, and various types of microcarriers in stirred tanks from different manufacturers. We have tested these systems to optimize the complete workflow of HepaStem culture, including stem cell isolation from livers and expansion up to the scale of many clinical doses. Quality control and comparability studies were performed to verify that the characteristics of HepaStem cells harvested from the different procedures were maintained. We have built a production platform, almost entirely in closed system, that can provide the large numbers of clinical doses that would be needed for the treatment of NASH. This platform functions with a strong reduction of human labour and it also modular and flexible to anticipate growing demand. In parallel we have developed serum-free and xenofree culture methods to be able to abandon the use of animal-derived products, for the related risks and because animal sera become scarce and expensive.