The experimental caspase inhibitor
emricasan did not meet the statistical threshold for improvement of portal
hypertension in people with non-alcoholic steatohepatitis (NASH), but it did
appear to have some benefit for those at high risk for decompensated liver
disease, according to a report at the EASL International Liver Congress
this month in Vienna.
"Although the primary endpoint was
not met in this study, the reductions in HVPG [hepatic venous pressure gradient] observed in patients with
compensated NASH cirrhosis and very severe portal hypertension are encouraging
and support additional exploration in these patients. This group of patients is
at greatest risk of progressing to decompensation and there are currently no
approved treatments available to them," said presenter Prof. Guadalupe
Garcia-Tsao of Yale University.
Non-alcoholic fatty liver disease (NAFLD) and its more severe form,
NASH, are responsible for a growing
proportion of advanced liver disease. The build-up of fat in the liver
triggers inflammation, which over time can lead to the development of fibrosis,
cirrhosis and liver cancer. In people with advanced cirrhosis, scar tissue
replaces functional liver cells and can block the flow of blood through the
liver, causing high blood pressure in the portal vein coming from the gastrointestinal
tract. This can cause ascites (abdominal fluid accumulation) and bleeding
varicose veins in the oesophagus and stomach – signs of liver decompensation.
An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis.
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
The phase IIb ENCORE-PH trial evaluated whether emricasan
would decrease portal pressure in people with cirrhosis related to NASH. Emricasan
is a first-in-class pan-caspase inhibitor that was shown
to improve biomarkers of liver health and decrease
portal vein pressure in earlier studies. Caspases are protease enzymes that
play a role in cell suicide and inflammation.
This interim analysis included 263 people
from more than 50 sites in Europe and the US. More than half (57%) were women
and the mean age was approximately 61 years. Many were obese and more than 80%
At baseline, the participants had an HVPG of 12 mmHg or higher (median 17). An
HVPG above 10 to 12 mmHg is considered severe portal hypertension, and above 16 indicates a high risk for
decompensation. Most were classified as Child-Pugh A,
meaning not at high risk for death due to liver disease. About a quarter
already had early decompensated cirrhosis, but they'd had only one prior event
and were stable at study entry.
Participants were randomly assigned to
receive various doses of oral emricasan (5, 25 or 50mg) or placebo twice daily
for 48 weeks. HVPG was measured at study entry and again at 24 weeks, which was
the study's primary endpoint.
HVPG declined by -0.5, -0.8 and -0.7 mmHg,
respectively, in the emricasan 5, 25 and 50mg arms, compared with -0.2 mmHg in
the placebo group. Overall, the decreases in HVPG in all three emricasan dose
arms did differ enough from the placebo arm to reach the threshold for
statistical significance, meaning the changes could have been due to chance.
However, a post hoc analysis showed that HVPG
was significantly reduced in the subset of participants with compensated cirrhosis
and worse portal hypertension at baseline (≥16 mmHg), with declines of around
-1.5 mmHg in all emricasan dose arms. This much improvement is considered "clinically
meaningful," according to Prof. Garcia-Tsao.
In addition, emricasan recipients showed
significantly more improvement in biomarkers of liver health including ALT and
AST liver enzyme levels.
Treatment was generally safe and well
tolerated. Adverse events were common, but occurred with similar frequency in
the emricasan and placebo groups (both 82%). Fewer than 5% stopped taking
emricasan due to side-effects.
The study is ongoing and HVPG will be
assessed again at the end of treatment at 48 weeks, Prof. Garcia-Tsao said.