The Importance of Clinical Trials in NASH Cirrhosis

Guest blog by Eric Lawitz, MD

Non-alcoholic steatohepatitis (NASH) affects millions of Americans and is a significant and growing problem across the world. NASH is a progressive disease, and, while we don’t yet fully understand the mechanism or are able to predict which patients will progress, a subset of NASH patients will progress to developing NASH cirrhosis, with subsequent potential complications of portal hypertension, liver decompensation and hepatocellular cancer.

People are gradually becoming more aware of NASH. But relatively few understand that the end stage of NASH is NASH cirrhosis, or that NASH cirrhosis requires a completely different approach to treatment than earlier stages of NASH. As I stressed in a recent video on Healio Hepatology, cirrhosis awareness is key to liver health improvement in NASH.

An important complication of portal hypertension in NASH cirrhosis is variceal bleeding, which is the cause of death in about 1/3 of cirrhotic patients. Once varices develop, the one-year risk of bleeding is about 12%. Additionally, each bleeding episode carries a six-week mortality rate of 15 to 20%. This is a significant number. The development of varices reflects the progression of hepatic cirrhosis and portends the development of other cirrhosis complications and outcomes.

Thus, it is important that physicians are vigilant to identify cirrhosis and portal hypertension to prevent further complications. There are easy to use calculators to help determine a patient’s risk for cirrhosis including the FIB4 or the NAFLD fibrosis calculator. These online calculators use the fact that in cirrhosis there is a decline in the platelet count and a rising AST (aspartate transaminase ) with frequently a concurrent flip in the ALT/AST ratio (that is, AST vs ALT).

Once cirrhosis is identified, patients need to be monitored for hepatocellular cancer and other complications of cirrhosis like variceal bleeding. Therapy for NASH cirrhosis is a large, unmet medical need, and we look forward to pharmacologic interventions that may provide benefit to these patients who still so urgently need treatment options.

Today, I would like to review with you one such trial and stress the importance of such trials in advancing our understanding of NASH cirrhosis and finding potential treatments. The NAVIGATE study is an adaptive Phase 2b/Phase 3 randomized placebo-controlled trial looking at the effectiveness of a new potential therapy, named belapectin, in patients with NASH cirrhosis and portal hypertension who have not yet developed varices. The NAVIGATE study looks to prevent the development of these varices and provide a better outcome for patients with NASH cirrhosis. The trial is enrolling in a number of centers across the United States, including the Texas Liver Institute at both our San Antonio and Austin locations.

Belapectin represents a new therapeutic mechanism for treating patients with NASH cirrhosis. A previously reported Phase 2 trial of belapectin enrolled 162 patients with portal hypertension who had a hepatic venous pressure gradient (HVPG) equal to or greater than six millimeters of mercury and compensated NASH cirrhosis. In the 54 patients with mild portal hypertension, defined as an HVPG of less than 10 millimeters of mercury at baseline, the patients on placebo had an increase in their HVPG of 26%, while those in the belapectin treatment group saw a reduction in their HVPG of 2 to 3%.

In addition, this trial demonstrated that in subjects without esophageal varices at baseline, belapectin had a statistically significant reduction in the absolute and percentage change in HVPG. In a post hoc analysis, it was also seen that patients with no varices at baseline, who were then administered the placebo, developed varices at a higher rate than those treated with belapectin. Taken together, these data from the prior trial support the evaluation of belapectin in a Phase 2b/Phase 3 clinical trial to evaluate the use of belapectin in the reduction of incidence of new varices in patients with NASH cirrhosis who have yet to develop esophageal varices.

To enhance both patient and physician awareness of NASH cirrhosis and the NAVIGATE trial, a website was launched called NAVIGATEnash.com. Not only does this website provide general information on NASH cirrhosis, including evaluation and diagnosis, it also supplies resources on where to find trial sites and finally provides a limited-access portal for NAVIGATE trial investigators to share best practices.

We look forward to data readouts on this trial in the future. And finally, I hope you have the opportunity to check out the NAVIGATEnash.com website. It is important for everyone to be aware of the signs and symptoms of NASH cirrhosis and its complications. It is also important that we continue research on potential treatments for this important disease that is increasingly responsible for liver related morbidity and mortality.

Eric Lawitz, MD, FAASLD, AGAF, FAPCR, CPI, is Vice President of Scientific and Research Development at the Texas Liver Institute and a Clinical Professor of Medicine at University of Texas Health San Antonio.