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Boston 2016: NASH
Why I am Encouraged by Data on NASH Management From the 2016 Boston Hepatology Meeting

Released: March 10, 2017

Expiration: March 09, 2018

Brent A. Neuschwander-Tetri
Brent A. Neuschwander-Tetri, MD
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The 2016 hepatology meeting in Boston brought us encouraging news on many fronts. The progress towards eradicating chronic hepatitis C virus (HCV) infection over the past 3-4 years has been nothing short of remarkable, and I look forward to the day when we will begin to see similar results in clinical trials for NASH.

However, the treatment of NASH has challenges not seen in patients with HCV infection. Patients likely exhibit the disease phenotype that we label as NASH through a variety of genetic, epigenetic, and environmental reasons, and thus, I don’t expect that any single treatment will work for all patients. Moreover, diagnosing NASH is much more complex than measuring viral titers in the blood.

In the future, I expect that we will be using combination therapies with a personalized medicine approach where we can decide on appropriate treatments for specific patients based on their genes and clinical phenotype.

Unfortunately, we are far short of that goal now. We have yet to find good clinical or genetic predictors of who will respond to current treatments such as vitamin E, pioglitazone, obeticholic acid, and elafibranor.

Encouraging data were presented on several newer agents at the 2016 Boston Hepatology meeting including the CCR2/5 chemokine receptor antagonist, cenicriviroc, and the ASK1 inhibitor, selonsertib.

Improvements in Fibrosis or NASH?
The CENTAUR study of cenicriviroc for patients with NASH and F1-3 fibrosis was anticipated to show improvement in NASH because of cenicriviroc’s antiinflammatory mechanism, but instead it showed improvement in fibrosis (≥ 1 NASH CRN stage at year 1 vs placebo; P = .023).

The lack of improvement in NASH may not be surprising, as we have yet to show that inflammation in NASH contributes meaningfully to the hepatocellular injury that characterizes steatohepatitis. In fact, an earlier study of a PDE4 inhibitor was similarly shown to be ineffective in improving NASH even though it reduced circulating tumor necrosis factor-α levels.

However, the improvement in fibrosis observed with cenicriviroc may be explained by its blockade of CCR2 and CCR5, which interferes with hepatocellular injury signaling and stellate cell activation, thus promoting an antifibrotic response.

These antifibrotic results are encouraging, and cenicriviroc may soon be evaluated in the phase III STELLARIS trial.

Shorter Trials?
The results of a phase II trial of selonsertib with or without simtuzumab in patients with NASH and F2/F3 fibrosis were also encouraging and provide a bit of a paradigm shift.

Although we’ve become accustomed to the idea that fibrosis is likely reversible, the prevailing thought has been that this reversal would likely take a year or more of effective therapy. Yet, in this trial, patients receiving selonsertib showed a measurable improvement in fibrosis after only 6 months of treatment. This result is already changing how we think about clinical trial design in NASH and whether we can shorten trials to accelerate drug discovery. Two phase III trials of selonsertib have started: STELLAR-3 and STELLAR-4 (names which may cause some confusion with the STELLARIS trial of cenicriveroc).

Alcohol Consumption
The Boston Hepatology meeting also clarified how we might advise patients about the effect of moderate alcohol consumption on NAFLD.

A prior cross-sectional analysis had shown that patients with NAFLD who consume small amounts of alcohol had less severe liver histology than those who were fully abstinent.

However, at the Boston Hepatology meeting, data on longitudinal changes in liver histology suggested that modest alcohol consumption is not protective. Compared with nondrinkers, those who drank 1-2 drinks per day were less likely to have improved steatosis, improved serum AST levels, or interim NASH resolution.

Based on these longitudinal results, in my practice, I will continue to tell my patients who don’t have a proclivity to alcohol abuse that an occasional single drink, but nothing more, is acceptable.

Your Thoughts
How will these and other new data from the Boston Hepatology meeting influence your approach to treating patients with NASH? I encourage you to answer the polling question and post your thoughts in the comments section below.

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