The novel caspase inhibitor emricasan led to
improvements in various biomarkers and decreases in MELD scores in patients
with liver cirrhosis due to hepatitis C, heavy alcohol use or other causes, with
significant declines among those who started with worse liver dysfunction,
according to a late-breaking presentation at the International Liver Congress last month in
Caspases are protease enzymes that play a role in
apoptosis (programmed cell death) and inflammation, contributing to progression
of chronic liver disease. Emricasan (IDN-6556) is a
first-in-class pan-caspase inhibitor that has been shown to decrease biomarkers
of apoptosis and inflammation in people with liver disease.
Catherine Frenette of the Scripps Clinic in San Diego, and colleagues, evaluated the
effects of emricasan in people with cirrhosis who had MELD scores between 11
and 18. The MELD score is an
indicator of liver disease severity calculated using bilirubin and creatinine
levels and blood clotting capacity (INR), used to predict how urgently a
patient needs a liver transplant. Scores of 10-19 predicted three-month
mortality of 6%, rising to more than 70% with a score above 40.
An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis.
A disease or infection affecting the brain.
Stretched veins which may burst and cause severe bleeding; a complication of cirrhosis.
This multicentre phase 2 study enrolled 86
participants with liver cirrhosis. Nearly two-thirds were men, most were white
and the mean age was 58 years. The main causes of liver disease were heavy
alcohol use (38%), hepatitis C (29%) and non-alcoholic steatohepatitis (23%).
The mean MELD score at study entry was 12.8, though
22% had MELD >15. The mean Child-Pugh score was 6.9, with 56% being classified
as Child-Pugh class B, indicating significant functional impairment but not yet
decompensation. Mean alanine aminotransferase and aspartate aminotransferase (ALT
and AST) levels were 30.9 and 52.2 U/l, respectively.
Hepatitis C patients receiving or planning antiviral
treatment, hepatitis B patients on therapy for less than three months and
HIV-positive people were excluded, as were those with very advanced liver
disease (e.g. recent bleeding varices, uncontrolled ascites, serious
encephalopathy or Child-Pugh class C).
Participants were randomly assigned to receive 25mg
oral emricasan or placebo twice-daily for three months, followed by a second
three-month open-label phase in which everyone received emricasan.
A total of 74 participants completed the three-month
randomised treatment phase, while 12 discontinued early (four on emricasan and eight
After three months of therapy, emricasan was
associated with significant decreases in the serum apoptosis and inflammation
markers caspase 3/7 and cCK18, with the former change being significant overall
and the latter for people with high baseline MELD scores.
MELD scores decreased overall in the emricasan group
while rising slightly in the placebo group (-0.1 vs +0.1), but the difference
did not reach statistical significance (p = 0.50). Child-Pugh scores also fell
overall in the emricasan group and rose in the placebo group (-0.2 vs +0.1),
but again this was not significant (p = 0.1).
However, in a pre-specified analysis looking at
patients with more advanced disease who had baseline MELD scores of 15 or
higher, those who received emricasan did show significant improvement compared
to placebo in MELD scores, Child-Pugh scores, bilirubin levels and blood
A similar proportion of patients experienced clinical
worsening events in the emricasan and placebo groups (both 14%), including
development or worsening of ascites or encephalopathy.
Treatment was generally safe and well tolerated, with
similar adverse events, serious events, laboratory abnormalities, vital signs
and incidence of cancer and infections in the emricasan and placebo groups. The
most common adverse events in the emricasan group were headache (16%), nausea (14%)
and fatigue (9%).
These findings confirmed the mechanism of action and
showed that emricasan "improved measures of liver function in patients
with baseline MELD >15" and had a "reassuring safety profile,"
the researchers concluded. These results support further study of emricasan in
patients with cirrhosis and liver impairment, they said.
Asked about evidence from other diseases suggesting that caspase
inhibitors are associated with increased risk for infections, Frenette noted
that emricasan is a liver-specific drug and in this study infections did not
occur more often in the emricasan compared to the placebo group.