number of different biological processes that play a role in the development of
fatty liver disease, optimal treatment may involve agents that work by
again, presented findings from a proof-of-concept study evaluating combinations
of three experimental drugs from Gilead Sciences: the apoptosis
signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997), the acetyl-CoA carboxylase (ACC) inhibitor
GS-0976 and the selective non-steroidal farnesoid X receptor (FXR) agonist
ASK1 promotes inflammation and fibrosis, ACC is
involved in de novo
lipogenesis (conversion of carbohydrates
into fatty acids in the liver) and FXR regulates bile acid synthesis and plays
a role in lipid metabolism.
An earlier phase 2
that up to 43% of people with NASH taking selonsertib saw at least a one-stage reduction in
liver fibrosis and up to 26% had at least a 30% reduction in liver fat
according to MRI-PDFF. Another study, presented at last year's AASLD Liver Meeting, showed that GS-0976 led to significant decreases in liver fat
accumulation and improved fibrosis in people with NASH.
analysis included 70 people with NASH and stage F2-F3 fibrosis. Two-thirds
were women and the median age was about 55 years.
were randomly assigned to receive either selonsertib, GS-0976, GS-9674,
selonsertib plus GS-0976, or selonsertib plus GS-9674, all once daily for 12
weeks. (Harrison did not report results from a triple therapy arm using all
results were seen in people treated with GS-0976. De novo lipogenesis declined
significantly in the groups taking GS-0976 alone or with selonsertib. Those
taking selonsertib plus GS-0976 showed the greatest decrease in lumican
fractional synthesis rate, a marker of fibrosis.
in liver fat content according to MRI-PDFF were -43% in the GS-0976 monotherapy
arm, -32% in the selonsertib plus GS-0976 arm, -16% in the GS-9674 monotherapy
arm and -9% in the selonsertib plus GS-9674 arm. However, fat content rose by
7% in those taking selonsertib alone. Seventy per cent of GS-0976 monotherapy recipients and
50% of those taking selonsertib plus GS-0976 saw their liver fat decrease by at
ALT levels fell
in the groups taking GS-0976 (alone or in combination) or GS-9674 monotherapy.
GS-9674 (alone or in combination) led to declines in another liver enzyme, GGT.
were generally safe and well tolerated. There were only two serious adverse
events, neither of which appeared treatment-related. Three people taking
GS-0976 had severe triglyceride elevations.
Based on these
findings, Gilead has initiated a phase IIb study of selonsertib with the ACC
inhibitor and the FXR agonist, the company said in a press release. The phase III STELLAR-3 and STELLAR-4 trials
are currently evaluating selonsertib monotherapy. A preclinical study presented
at the conference showed that GS-0976 plus GS-9674 showed better activity than
either drug alone in mice and rats.
As previously reported, another drug in the fatty
liver disease pipeline, cenicriviroc, continues to show anti-fibrosis activity in
people with NASH after two years of follow-up. Cenicriviroc
is also being studied in combination with an FXR agonist from Novartis.
with advanced fibrosis due to NASH urgently need effective therapeutic options
because they may face more serious health risks, including development of
complications of end-stage liver disease, liver cancer and the need for liver
transplantation," Harrison said in the Gilead press release.
"Combination therapy may be a way forward to achieving greater benefit for
this patient population."