Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD) and is characterized by a fatty liver, inflammation, and liver cell damage. If left untreated, NASH can further develop into liver fibrosis, the formation of scar tissue in the liver, and liver cirrhosis. To date, a patient’s only option at the final stage of liver disease is a liver transplant. There is no alternative available yet.
This year alone has already seen a number of disappointments within the NASH clinical trial landscape. In April, Gilead announced that it’s anti-fibrosis compound selonsertib failed to reach the endpoint in phase III. In June, Conatus’ and Novartis’ NASH cirrhosis treatment emricasan also missed its primary endpoint in a phase IIb trial. And although Intercept’s Ocaliva showed an effect on fibrosis in phase III, the results were overshadowed by strong side effects.
Current approaches to NASH
The therapy landscape for NASH is currently dominated by small molecules that address defined targets. Many of the currently ongoing trials are focusing on the earlier stages of NASH, covering the fibrotic stages F1 and F2. The later stages of NASH, F3 and F4, on the other hand, are receiving attention at the clinical stage but are difficult to treat.
“If you look at the number of therapies in development for cirrhotic NASH F4 and indications further down the disease progression path, you will find a blue ocean,” says Henrik Luessen, CBO at Promethera. “There is not much competition to be found in that space. NASH is a spectrum disease in which many factors play a role, including inflammation, immune activation, stellate cell activation, lipid metabolism, and fibrosis. Most molecules can only target one of these factors and the action is therefore very limited. In later stages, where many more factors are involved, there is a need for an approach that addresses more than one target. That is the key challenge in NASH.”
Entering the NASH space
Promethera has taken a leap into the blue ocean and has developed a cell therapy in which liver-derived cells can address several factors of the disease. These cells have a potent paracrine effect and are able to respond to the cause of the disease by secreting or expressing various molecules, including hepatic growth factor (HGF), indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 (PGE2), to reduce inflammation, inhibit stellate cell activation, and to further interrupt the fibrotic or cirrhotic process and restore liver function.
“Based on the behavior of our cells observed over more than six years of intense clinical research following the inception of Promethera, we decided to focus on end-stage NASH and acute-on-chronic liver failure (ACLF), the end-stages of the disease where patients are suffering from at least one organ failure and have a very low prognosis to survive the next three months,” Luessen explains. “When we found promising signs of efficacy and safety in ACLF we decided to move further into the NASH field and focus on the late stages of the disease where there is a strong unmet medical need. In both cases, we are positioning our cells as an alternative to liver transplantation.”
The data of the completed HEP101 study in ACLF patients will be published at the upcoming American Association for the Study of Liver Diseases (AASLD) meeting in Boston on 10th November 2019, for the first time.
Moreover, in May 2019, Promethera started the PANASH study, which is evaluating the safety of HepaStem in NASH F3 and F4 patients at different dosages. Efficacy markers will also be investigated as a study outcome.
Cell therapies and antibodies against late-stage NASH
Promethera’s pipeline is comprised of two allogeneic cell therapies and one antibody. Designed to target the tumor necrosis factor receptor 1 (TNF-R1), the company’s antibody Atrosimab is currently in preclinical development. TNF is known to interact with receptors one (R1) and two (R2). While R1 is responsible for triggering inflammatory responses and apoptosis, R2 is actually a type of regenerative receptor.
“Classical TNF inhibitors inhibit all systemic TNF, including all interactions with R2,” Luessen says. “Atrosimab only inhibits R1, which allows the regenerative properties of R2 to be maintained. It can also be potentially used in combination with our HepaStem technology.”
HepaStem, currently in phase II, is a cell therapy that addresses different components of the NASH disease progression. Consisting of liver-derived mesenchymal stem cells (MSC), HepaStem is administered intravenously without the need for immunosuppressants and enters the liver via the bloodstream, where it then targets multiple changed pathways. HepaStem can reduce tissue fibrosis and promote the restoration of liver function by lowering inflammation, deactivating stellate cells, and reducing fibrosis.
Promethera’s second cell therapy, H2Stem, is currently at a preclinical stage. H2Stem are liver-derived progenitor cells from the hepatobiliary tract that can express various markers, can differentiate into hepatocyte-like cells in vitro and have been observed to home and repopulate the liver of humanized mice. “H2Stem has shown good signs of engraftment in mice, which allows us to assume that it might have strong regenerative or repair properties, but we are still collecting evidence,” says Luessen.
The future of the NASH therapy landscape
Promethera’s allogeneic cell line is unique in that it also has the potential for liver homing, meaning the cells have a liver imprint and remain in the liver where they can fight the cause of the disease. Moreover, the cells do not provoke immunogenic responses, which enables the intravenous injection of the therapy without needing immune suppression. Even a second injection, triggers no acute immunogenicity or toxicity.
“Our product has undergone the chemistry, manufacturing, and controls (CMC) part of development,” Luessen explains. “This means that we have a very scalable product. We are now moving to bioreactors, which will allow us to treat thousands of patients with only one liver. We are confident that we can meet global demand with our new in-house process, in particular when we move to our state-of-the-art facilities in Gosselies, Belgium, in 2020. At the moment, the only option for end-stage liver disease patients is a liver transplant, so with one liver we could avoid a very high number of liver transplants, at least exceeding the currently recorded global numbers of transplants. That’s what makes our technology unique and very promising.”
Many companies are now becoming increasingly aware that addressing only one target in early-stage NASH does not add many benefits to patients, Luessen says. In fact, patients often have to take several medications continuously, which can come with unpleasant side effects. Furthermore, early-stage NASH patients can greatly benefit from lifestyle changes, including dietary measures and physical exercise.
In the early stages of NASH, during F1 and F2, many patients are not aware of their disease because they do not show any symptoms. “Once the disease is felt, patients are often already in the later stages, F3 and F4, and here, the medicinal landscape becomes very poor,” Luessen explains. “Looking at the future, I think this will be recognized and there will be a greater focus on the fibrotic and cirrhotic stages of NASH. We can already see different pharma companies, who are usually competitors, working together. They are combining their compounds to have a more efficient treatment. This will be the only way to address the disease outside of cell therapy.”
Images via Promethera and Shutterstock.com
Author: Larissa Warneck, Science Journalist, Labiotech.eu