However, some of the single agents and combinations led to significant
improvements in various secondary endpoints. Prof. Rohit Loomba of the University of
California at San Diego described these findings in more detail at the
recent conference, focusing on the best-performing combination, firsocostat plus cilofexor.
At 48 weeks, the proportions of people with at least a one-stage improvement in fibrosis without worsening NASH were as
- firsocostat monotherapy: 12%
cilofexor monotherapy: 12%
- placebo: 11%
The likelihood of progression to cirrhosis was lower in all treatment
groups (15%, 20%, 15%, 8%, and 23%, respectively) compared with the placebo
NASH resolution without worsening fibrosis was
uncommon in all treatment groups. No one in the cilofexor monotherapy or
placebo group achieved this endpoint, rising to 1.4%
with selonsertib/firsocostat, 1.5% with selonsertib/cilofexor, 3.0% with firsocostat monotherapy and 4.5% with firsocostat/cilofexor.
People assigned to firsocostat/cilofexor were most likely to see at least a 2-point reduction in NAFLD activity score
(35% vs 9-29% across the other arms) and at least one grade of improvement in
components of that score:
- steatosis (fat accumulation):
26% vs 6-29%
- lobular inflammation: 57% vs
- ballooning of hepatocytes:
29% vs 13-24%
fibrosis and bile duct proliferation were assessed using a machine learning
algorithm, firsocostat/cilofexor led to significantly greater improvements than the placebo.
Firsocostat monotherapy also performed well on fibrosis measures while
cilofexor monotherapy did well on the bile duct measure.
Fibroscan liver stiffness scores and enhanced liver function (ELF) scores declined most in the firsocostat monotherapy arm. For liver stiffness, 55%
of firsocostat recipients, 45% of firsocostat/cilofexor recipients and 38% of cilofexor recipients were classified as responders,
compared with 20% in the placebo group. For ELF scores, the corresponding
proportions were 44%, 31%, 24% and 19%.
Participants who received firsocostat/cilofexor
also had significant reductions in biomarkers of liver injury, inflammation and
liver function, including ALT and AST liver enzymes, bilirubin, total bile
acids and CK18 protein fragments, while those taking either drug alone saw
Finally, people who received
had significantly greater reductions in body weight and insulin levels and
greater improvement in kidney function compared with the placebo group.
All treatments were generally safe
and well tolerated. Severe (grade 3 or 4) drug-related adverse events were
uncommon, seen in just two people (3%) in the firsocostat/cilofexor arm, one (1%) in the selonsertib/cilofexor
arm and none in the other groups. Three people (4%) taking firsocostat/cilofexor discontinued treatment due to adverse events, similar to the
rates in the other treatment arms.
The most common adverse event overall
was pruritus, or itching, which can be a symptom of cirrhosis itself. This was
most common in the selonsertib/cilofexor groups (29%) and the firsocostat/cilofexor group (28%); pruritus rates were 18-20% in the other
treatment arms and 15% in the placebo group.
Triglyceride levels rose in all
treatment groups while there was no change in the placebo arm. The largest
changes were seen in the firsocostat/cilofexor
and firsocostat monotherapy arms (44 and 42 mg/dl). However, none of the groups
had a significant increase in harmful LDL cholesterol. Both pruritus and
triglyceride increases were considered "manageable," according to the
Although it has been difficult for
experimental therapies to meet the endpoint of fibrosis improvement without
worsening NASH, they do lead to beneficial changes in other indicators of liver
health, especially when used in combination. These results suggest that further
studies of combination therapies for advanced fibrosis due to NASH – in
particular firsocostat/cilofexor – are warranted, Prof. Loomba said.