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The HepaRG-Bio-Artificial Liver: Feasibility of commercialization and expansion of business plan

Periodic Reporting for period 1 - BALXPAND (The HepaRG-Bio-Artificial Liver: Feasibility of commercialization and expansion of business plan)

Reporting period: 2017-03-01 to 2017-08-31

End-stage liver disease patients have insufficient mass of functional liver, due to different causes as intoxication, and liver infections. Within a few weeks, their condition can deteriorate to such extent that only 20%-50% of the patients survive. In the Western world, there is an incidence of 0.29-0.41 per 10.000 patients per year. Emergency liver transplantation is the only life-saving therapy, even though this invasive procedure is associated with considerable mortality and morbidity and requires life-long medicinal immunosuppression. The health care costs for patients that undergo a transplantation are huge: ±120 k€ for the transplantation and 10 k€/yr. per patient for medical immunosuppression. Treatment of morbidities associated with liver transplantation requires intensive care treatment and this will further raise health care costs for end-stage liver patients.
Due to a shortage of donor livers, more than 30,000 patients are on the liver transplant waiting list in Europe and the US. Strikingly, each year, there are only about 12,000 donor livers available in these regions and the average waiting time of patients on the waiting list is 115 days in Europe and 232 days in the US. A significant share of the patients die while being placed on the waiting list. An even larger share of patients suffers from the effects of late transplantation because, while waiting before reaching the criteria for liver transplantation and subsequent availability of a donor liver, their condition worsens and morbidity and mortality after transplantation will increase. There is no treatment available to reverse the disease progress substantially and prevent transplantation.
The SME Hep-Art has, together with academic partners, developed a BAL, named HepaRG-AMC-BAL, which is a bioreactor embedded with HepaRG cells, from a human liver stem cell line, that mature to high level inside the BAL. This HepaRG-AMC-BAL is developed to treat the plasma of the end-stage liver disease patients (Fig. 1) and temporarily replace liver function to bridge the period towards transplantation, or to support liver restoration until transplantation will become superfluous. A preclinical test showed that the HepaRG-AMC-BAL-prototype treatment provided effective liver support during liver failure.
The overall objective of the BAL2B project was to prepare the HepaRG-AMC-BAL for a clinical trial to eventually test the safety and efficacy of this treatment modality. To that means Hep-Art aimed to improve the production of cells for the HepaRG-AMC-BAL, obtain insight into the production costs of the HepaRG-AMC-BAL in the clinical implementation phase, to map suitable Contract Manufacturing Organisations (CMOs) with cleanroom production facilities for producing quality-tested HepaRG-AMC-BALs, and to develop a feasibility plan with the results of the study.
The expansion of liver cells was tested with an automated and closed culture system. In addition, following the outcome of sessions with a coach, a new strategy for the production of the final BAL was developed, with the aim to simplify the logistical process, reduce risks and limit the number of CMO’s required per continent. The ultimate goal is to reduce the supply chain costs (costs of goods (cells), costs of transport (requirements), costs of waste (lost BALs), etc), which would improve the business proposition. This is essential for Hep-Art in its business strategy to attract a partner for end-stage development and commercialization. As costs of goods determine a large part of selling price, process improvement is essential and when successful with large impact, potentially benefiting both company’s business as well as society costs (price reductions possible).

The main results:
• Data from 6 runs with the automated culture system: the system was easy to operate and cells harvested from the system were comparable in their functionality as cells harvested from parallel culture flasks, however the system was not cost-effective, as the expansion of the cells was limited;
• A first pilot experiment showing that considerable simplification of the logistics is within reach;
• Development of a strategy for the most cost-effective and simple process from cell to BAL at bedside with an indication of the costs, and with the requirement of only one CMO per continent, showing feasibility of the business;
• Identification of a suitable CMO for Europe to start with, which is willing and capable to quality-controlled production of the cells and BAL cultures and the transport to the clinic;
• Identification of a suitable large medical device company for partnering with Hep-Art;
• A feasibility report implementing the findings of the BALXPAND project.
The BALXPAND project has substantially increased the feasibility of Hep-Arts business project.
This opens new perspectives for end-stage liver disease patients by bridging them to liver transplantation with less morbidity or even by stimulating restoration, making liver transplantation superfluous. This may also reduce the health care burden for society, saving the high costs for liver transplantation. For Hep-Art it is a break-through, as it brings a small clinical trial within reach, which is essential to make Hep-Art attractive for partnering with a large medical company, which is needed for a follow-up clinical trial with a large number of patients to show efficacy of the BAL treatment.
The actions to be undertaken up to the first (small) clinical trial:
• Scale up the expansion of cells for the simplified logistical process;
• Scale up the transport process of the BAL cultures;
• Make the whole production and transport process quality-controlled by the CMO;
• Prepare and conduct a clinical trial in 5-10 end-stage liver disease patients to show safety and feasibility of the BAL treatment;
• Refine the business plan to inform and attract a suitable partner;
• Obtain financing for these activities.