CC: Room 24/25
There has been no new class of drugs approved to treat portal hypertension since the first beta blockers won the indication nearly three decades ago. That will likely change as new discoveries in the pathophysiology of portal hypertension and its potential regression continue.
“It is now known from large-scale clinical trials of antiviral therapy for chronic hepatitis B and hepatitis C that fibrosis and portal hypertension can regress,” said Jonathan Fallowfield, BSc, BM, PhD, Professor of Translational Liver Research at the University of Edinburgh Centre for Inflammation Research in Edinburgh, UK. “It could just be because liver inflammation and scarring is getting better. But we suspect there are more subtle effects happening at the cellular and molecular level. There is a lot of basic research going on, animal models and in vitro systems to understand the different molecules and mechanisms that are involved in portal hypertension. The potential for targeted therapy is increasingly promising in terms of the new biology we are learning.”
Dr. Fallowfield will co-chair “Mechanisms of Regression of Portal Hypertension” from 10:30 am – 12:30 pm on Friday in Room 24/25, Moscone North/South. Jordi Gracia Sancho, PhD, Head of the Liver Vascular Biology Research Group at the Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain, will also co-chair the program.
“There have been substantial recent advances in both basic and clinical research,” Dr. Fallowfield said. “This session is an opportunity to crystalize the state of the art and see where the priority areas are for clinical development.”
Portal hypertension is already accepted as a pivotal prognostic factor in chronic liver disease. Defined thresholds of severity accurately predict the risk of complications, clinical deterioration and death. Dr. Fallowfield noted that the two major areas of unmet need are noninvasive methods to diagnose and monitor changes in portal hypertension and new therapies that target specific biologic or mechanistic pathways.
There is no question that beta blockers can effectively treat chronic portal hypertension. They can, but only in about 60 percent of patients. The other 40 percent either do not respond adequately or cannot tolerate the treatment. But there are no noninvasive, easy to use and affordable methods to monitor response to therapy, he explained.
“We need to be able to monitor patients so we can treat them more effectively,” Dr. Fallowfield said. “If the drug isn’t working on portal pressure, we should probably stop it.
Patients who do not respond to beta blockers or do not tolerate them will need a second line agent. And for now, there is no licensed second line treatment.
“The trouble with portal hypertension is that the pathophysiology is very complex,” Dr. Fallowfield said. “There are a number of factors that contribute including fibrosis and vascular distortion, angiogenesis, and active contraction of perisinusoidal hepatic myofibroblasts. To be able to assess pressure changes using blood biomarkers, imaging or some other noninvasive method would be extremely useful clinically as well as in research studies.”
Multiparametric MRI is one promising technique for noninvasive measurement as it measures both structural and hemodynamic components in a single scan. Dr. Fallowfield and other researchers are exploring a variety of biomarker strategies. There are also studies investigating the use of serum analytes to assess changes in portal hypertension.
One of the key goals is to discover new druggable disease targets. Basic research is beginning to pay off, Dr. Fallowfield said.
“We see highly effective targeted treatments in oncology. That kind of approach to treatment in hepatology could make an important change in patient outcomes,” he said.
Some of the most interesting developments did not originate in portal hypertension research. There is growing evidence that statins can have an effect on portal hypertension pathways. Farnesoid X receptor (FXR) agonists and Janus kinase (JAK) inhibitors are other candidate drugs that may also have useful activity.
“There are multiple feasible targets that are emerging from basic research,” Dr. Fallowfield said.