October 15, 2016 (Vol. 36, No. 18)
Using Heterologous Human Adult Liver-Derived Progenitor Cells rather than Mesenchymal Cells
Belgian company Promethera Biosciences claims to be the world’s first clinical-phase company treating liver diseases with liver cells and derived stem cells. It uses heterologous human adult liver-derived progenitor cells (HHALPC) to treat liver disease, rather than the more common mesenchymal cells that are derived from bone marrow or adipose tissue.
“Because HHALPCs are derived from the liver, they already are dedicated to the liver lineage,” Etienne Sokal, M.D., Ph.D., founder and chief innovation and scientific officer, explains.
“Each hepatocyte is a comprehensive metabolic unit—a microscopic liver, in effect —each containing all the proteins and enzymes of the liver. Introducing healthy cells into diseased livers will restore any missing function,” Dr. Sokal explains. “Our aim at Promethera is to produce functional cells derived from liver stem cells, expanded in vitro. As a major advantage over gene therapy, the same cell-based medicinal product can treat many different conditions.
“When we infuse those cells, either intravenously or by direct intraportal injection, they home into their original organ and, therefore, have a greater propensity to become functioning liver cells.”
A Platform Approach
HHALPCs can differentiate into mature hepatocytes and be used for enzyme replacement, and the undifferentiated cells also have therapeutic value. Undifferentiated HHALPCs produce a wide variety of cytokines with strong immunomodulatory effects and, therefore, can control inflammation, immune disorders, and fibrosis. These properties form the basis of a platform approach capable of treating multiple liver diseases in which inflammation and fibrosis play a role in progressive loss of function.
“In any liver disease, the mechanism of disease is the same,” Dr. Sokal stresses. “When you have liver disease, you have damage to the hepatocytes, which cause inflammation. That activates cells that produce extracellular matrix in excess, such as collagen. If you over-produce collagen, the liver hardens and fibrotic conditions develop. The end stage is cirrhosis of the liver.”
Products in Development
Promethera has three products in development: Heparesc®, HepaStem, and H2Stem. Heparesc is the furthest along. Made from mature hepatocytes, engraftment typically occurs within 10 to 28 days. At that point, cell and enzyme activity is evident in the organ. “It’s a relatively quick efficacy profile, which is critical for patients with urea cycle disorders,” according to Torsten Hombeck, Ph.D., chief commercial and strategy officer.
Heparesc has completed two multicenter clinical trials in North America and Europe to treat children with neonatal urea cycle defects—an ultra-orphan indication. Dr. Hombeck says he plans to submit a new drug application to Health Canada by year’s end.
Canada, he says, is an area of particular unmet need. “We found a certain population in Canada that seems to have a higher incidence of urea cycle disorder than other Western countries,” Dr. Hombeck says. The inborn errors that cause this condition correlate to consanguinity, which is an issue for remote communities. “We made a strategic decision to see if we could help them,” he adds.
One of the greatest challenges in conducting these trials, obviously, was locating enough patients to generate statistically significant data to assess safety and efficacy. Beyond that, the life science industry is realizing that determining dosages for children involves more than adjusting doses for body weight.
“Children’s bodies react to medications differently than adults’, so one almost has to do separate trials for children. Gaining approval for pediatric trials was a big achievement. When we begin trials for large indications like nonalcoholic steatohepatitis (NASH), we will start trials in adults. But, for urea cycle disorders, there is no adult version of the disease,” Dr. Sokal says.
HepaStem and H2Stem
Promethera’s other two pipeline drugs are based on progenitor cells. HepaStem, is in Phase IIb trials for urea cycle disorder. It is ready to enter clinical trials for acute-on-chronic liver failure (ACLF) and in preclinical trials for NASH.
H2Stem also is based on progenitor stem cells. “This is a cell we can take from the liver and expand in vitro,” Dr. Sokal continues. “It has more differentiated properties than HepaStem, so is being developed for use with specific metabolic indications—notably alpha 1 antitrypsin deficiency.”
In that condition, Dr. Sokal says, patients have both liver and lung disease. The necessary protein, historically, can only be produced by plasma extraction. “Therefore, it’s extremely expensive, very rare, and very difficult to produce. H2Stem produces large quantities of protein in vitro with expanded cells. This is the next-generation hepatocyte.”
Promethera broadened its pipeline April 2016 when it acquired the key assets of Cytonet. It plans to continue to strengthen its emerging product line by optimizing its three cell lines in ways that are most likely to achieve regulatory approval and commercialization. The development of Heparesc exemplifies that approach. Heparesc is tackling an orphan disease while Promethera expands HepaStem to larger indications such as ACLF and NASH.
As Dr. Hombeck says, “We have several shots on goal with different cell lines to target large indications and, therefore, de-risk the business by not depending on one or two trials.” The objective is to commercialize products “with or without partners.”
Those plans include eventually launching products wherever there is great need. In addition to Canada, there is interest from the Middle-East and also in Asia where, Dr. Hombeck says, “liver disease is an essential problem.”
Location: Watson & Crick Hill, Rue Granbonpre, 11, B-1435 Mont-Saint-Guibert, Belgium
Phone: 32(0) 10 39 43 00
Principal: John Tchelingerian, Ph.D., CEO
Number of Employees: 60
Focus: Promethera is developing cell therapies to treat liver disease. Products are expanded from heterologous human adult liver-derived progenitor cells.