Harrison also reported disappointing findings
from two phase 3 studies of selonsertib (formerly GS-4997). This drug inhibits apoptosis
signal-regulating kinase 1 (ASK1), which promotes inflammation, liver cell
injury and fibrosis.
After an earlier phase 2 trial showed that a substantial number of NASH
patients who took selonsertib experienced at least a one-stage decrease in fibrosis and a
reduction in liver fat, Gilead Sciences initiated a pair of larger phase 3 trials,
STELLAR-3 and STELLAR-4.
Together these studies enrolled 1679 participants at 450 sites in 27
countries. STELLAR-3 included 802 people with bridging fibrosis (stage F3)
while STELLAR-4 included 877 people with compensated cirrhosis (stage F4).
Across both studies, about 60% were women, most were white and the median
age was 59 years. More than half were classified as obese and three-quarters
had diabetes. All had biopsy-confirmed NASH and more than 80% had NAS scores of
5 or higher.
Participants were randomly assigned to received selonsertib at doses of
6mg or 18mg taken by mouth once daily or a placebo for 48 week, at which point
they received a second biopsy.
The trials were originally planned to last for five years, but they were
halted at week 48 after biopsy results at that point showed a lack of efficacy,
as Gilead announced earlier this year.
In STELLAR-3, 12% of participants treated with the lower
dose of selonsertib and 10% of those who received the higher dose had at least
a one-stage improvement in fibrosis without NASH worsening, Harrison reported. These
percentages did not differ significantly from that of the placebo group (13%).
Likewise, 13% of
STELLAR-4 participants randomised to receive 6mg of selonsertib and 14% of those
treated with the higher dose achieve the primary endpoint, again not significantly
different from the placebo group (13%).
Looking at other histological endpoints in STELLAR-3, 4% in the low-dose
group and 5% in the high-dose group experienced NASH resolution without
worsening fibrosis, compared with 9% in the placebo group. Both improvement in
fibrosis (14%, 13% and 16%, respectively) and progression to cirrhosis (16%,
13% and 16%) occurred at statistically similar rates across all three groups.
The same pattern was seen in STELLAR-4. Fibrosis improvement (17%, 19%
and 16%, respectively) and NASH resolution without worsening fibrosis (4%, 2%
and 4%) were again statistically similar across all groups.
What's more, selonsertib had no beneficial effects on liver
biochemistry, non-invasive tests or other biomarkers, according to Harrison.
Overall, 3% of participants experienced liver-related clinical events during
about 16 months of follow-up; these were numerically more frequent in the
selonsertib groups compared with the placebo group, but differences were not
As with emricasan, biochemical analyses revealed that selonsertib did
inhibit ASK1, as intended, but again this did not lead to the desired
improvement in clinical outcomes.
Selonsertib monotherapy was also safe and well tolerated. Approximately
15% of participants across treatment groups in both studies experienced grade 3
or 4 adverse events. Discontinuation due to adverse events was rare in all
treatment arms (3% or less).
Given the number of
different biological processes that play a role in the development of fatty
liver disease, optimal treatment may involve drugs that work by different
mechanisms. Agents that do not work well on their own but show positive effects
on biomarkers may still have potential as components of combination therapy,
Gilead is currently testing selonsertib in combination
with the nonsteroidal farnesoid X receptor (FXR) agonist cilofexor (formerly
GS-9674) and the acetyl-CoA carboxylase inhibitor firsocostat (GS-0976) in the phase 2 ATLAS
FXR regulates bile acid synthesis
and plays a role in lipid metabolism, while ACC is involved in de novo lipogenesis, or conversion of carbohydrates to fatty acids in