Please could you give a brief introduction to the different types of liver disease?
Liver disease is a very broad family of diseases. There are two main categories of liver disease:
Genetic diseases (also known as liver-based metabolic diseases) – these involve a mutation of one of the enzymes of hepatocytes, which is the main types of liver cell. The mutation will cause the enzyme not to function properly and therefore to accumulate toxins in the body, which will impact the health of the individual.
Acquired liver diseases such as liver cirrhosis or fulminant hepatitis – these can be related to external factors such as viruses, alcohol, food intoxification or autoimmune factors. In acquired liver disease there is a breakdown of the function of the liver with time.
Which types of liver disease are Promethera Biosciences developing innovative therapies for?
In the short-term, we are focussing on genetic liver diseases. We are developing a therapy using stem cells coming from the liver of donors.
There are over 250 genetic defects which cause liver disease. We want to start our clinical trials on two of these diseases:
Urea cycle disease – this is a disease affecting the urea cycle which is a very important cycle in the hepatocytes in the metabolism of proteins. When people with this disease eat proteins, they have an accumulation of ammonia in the blood, which has a big impact in the brain. The only way to cure these patients is liver transplantation. Before they receive a liver transplant, they have to have a very severe diet, with very low amounts of protein.
Crigler-Najjar syndrome – this is a specific disease which causes jaundice. Newborns with jaundice are placed under UV to destroy a pigment called bilirubin in the skin. This pigment is very toxic for the brain. It is due to immaturity of the liver. Normally after a few days or weeks, the newborns have a normal life because the liver becomes mature and they don’t need UV treatment anymore. Crigler-Najjar syndrome is a specific disease where the enzyme conjugating this pigment bilirubin is mutated. In this case, the children with this defect have to spend all their lives spending 10-12 hours per day under UV, which destroys the pigment.
Please could you tell us more about the liver disease products that Promethera have developed?
We are a cell therapy company, which means we are developing cells to use as drugs. The cells treat the patients. At the moment, the only way to cure these patients is by liver transplantation. We want to create an alternative treatment to liver transplantation by using specific stem cells that come from a liver donor. We will then infuse these in the portal vein of patients with the genetic defect.
The infused healthy cells will engraft to the liver and will produce the missing enzyme. So essentially we do enzyme replacement. This ensures the level of toxicity in the blood is reduced as the normal enzyme functions are restored.
The value proposition is thanks to the manufacturing of the stem cells in very large quantity. With one liver we treat hundreds of patients instead of one liver one patient with liver transplantations today.
How do these products compare to other therapies that were previously available?
For the diseases we are trying to cure, liver transplantation is the only current way to cure, after this there is only diet and UV.
It is important to remember a liver transplantation is a very heavy and invasive procedure and there can be issues during the procedure. The survival rates vary according to the quality of the centres. For the best centres there may be a survival rate of 85% after 10 years, for the worst it can be 50% survival rate. So there is a risk with liver transplantation, but when it works, it works quite well. You really transform the illness of the patients.
Why did Promethera choose to develop two liver disease products based on the Heterologous Human Adult Liver Progenitor Cells (HHALPC)?
The clinical endpoint to assess the efficacy of the product for the Crigler-Najjar syndrome patient is straightforward. The patient has a high level of bilirubin in the blood. To assess the efficacy of the cells, what we have to do is take a blood sample and see if the level of bilirubin has decreased. The clinical endpoint, or the biomarker, is easy to assess.
Crigler-Najjar syndrome affects a few hundred patients in Europe and a few hundred in the US. Urea cycle disease is more frequent – there are a few thousand patients in both continents. It is an extremely severe disease. If patients with the severe form of the disease do not have a liver transplant by around 12 years old they will die. It is an extremely difficult disease to control with the diet and they have a lot of issues (brain damages), and are likely to have at least 5 to 10 visits to the hospital per year related to complications.
Urea cycle disease has therefore been selected as we believe we can make a serious difference. Also, we think the mass of enzyme activity required for efficacy is in line with the quantity of cells we will infuse.
What do you think the future holds for liver disease therapies?
Liver disease is one of the biggest concerns now in the world – certainly in Asia, which is one of the biggest developing parts of the world, they have a lot of issues concerning liver disease. Providing solutions to these kinds of issues is really answering an unmet need.
I think in the future more and more laboratories and pharmaceutical industries will try find solutions to cure these diseases.
What are Promethera’s plans for the future?
We currently have a team of 46 people based in Belgium and we are conducted our first clinical trial in the UK, France and Belgium. We have a “Good Manufacturing Practice” Facility internally to produce cells batches. We would like to do a second clinical trial in the course of 2014 to validate the efficacy of the cells in the trial. The objective is to do this second study in Europe and the US.
In 2014, we would also like to test two other genetic diseases to have a platform proof of concept. Healthy cells coming from a healthy donor can treat any of the 250 genetic diseases because as each cell contains all liver enzymes required for normal function.
We want to have enough clinical trials on the right diseases to prove to the regulatory bodies that it works.
Would you like to make any further comments?
The technology - the cells and the manufacturing process – has had a patent filed and it was issued in Europe last year.
We are in clinical trials and we are the first company in Europe to start clinical trials with stem cells from the liver.
We are a spin off from a University based in Brussels – Université Catholique de Louvain and the discovery of the cells and the characterization of the cells has been done by Professor Etienne Sokal team who is extremely well known in this area.
We have received a very big round of financing. At the end of March 2012 we received 23.6 million Euros and this is still the biggest financing round for private biotech in Europe. We have several new big and interesting investors like Shire, the biotech company; Boehringer Ingelheim Venture Fund, the giant pharmaceutical company; Mitsui Global Investment, a Japanese investor; and ATMI, a US company developing a bioreactor. They have all invested in the company. We have been well funded and we hope to have everything we need to be successful in the future.
Where can readers find more information?
They can find more information on our website:
About Eric Halioua
Eric Halioua is the CEO of the Belgian Biotechnology company Promethera Biosciences. Promethera® Biosciences' mission is to discover, develop and commercialize cell therapy products to treat liver diseases in an innovative way using stem cell from healthy human livers.
Eric is co-founder of two biotechnology companies called Myosix and Murigenetics. Myosix is a tissue engineering company specialising in musculoskeletal cells culture used in the regeneration of the heart muscle. The company has been sold to Genzyme mid-2002. Murigenetics is a Biotechnology company developing therapies for genetic disorders.
Eric was also a Board Member of a French public biotechnology company called Vivalis, which specializes in the production of avian stem cells lines for the production of vaccines and recombinant proteins.
Eric was as well principal of the international life sciences practice of Arthur D. Little based in Paris and Boston during 11 years. He has led work in the areas of strategy, M&A and technology & innovation management for biotechnology and pharmaceutical companies. Eric also worked as a strategic marketing manager for the “Centre Européen de Bioprospective” and as project leader in the corporate R&D centre of Zeneca in UK.
Eric holds two master degrees (DEA and Magistère) in Pharmacology and Molecular Biology and a MBA from ESSEC business school (Paris, France), with an advanced degree from the Health Care ESSEC chair.