- Oral ACC Inhibitor Led to Significant
Reductions in Measures of Liver Fat and Fibrosis -
- Results from the GS-0976 Phase 2 Study and
18 Other Abstracts from Across Gilead’s Liver Fibrosis Pipeline
Presented at The Liver Meeting® 2017 -
Gilead Sciences, Inc. (Nasdaq: GILD) today announced results
from a Phase 2, randomized, placebo-controlled trial evaluating two
doses of GS-0976, an oral, investigational inhibitor of Acetyl-CoA
carboxylase (ACC), in patients with nonalcoholic steatohepatitis
(NASH). The data demonstrate that the higher dose of GS-0976 (20 mg
taken orally once daily) when administered for 12 weeks was
associated with statistically significant reductions in hepatic
steatosis (buildup of fat in the liver) and a noninvasive marker of
fibrosis (TIMP-1) compared to placebo. These results are being
presented during a late-breaking abstract session at The Liver
Meeting® 2017 in Washington, D.C. (Abstract #LB-9). Eighteen
other abstracts on Gilead’s NASH and liver fibrosis pipeline were
also presented at the meeting.
“In patients with advanced fibrosis, NASH may lead to severe
complications including end-stage liver disease, hepatocellular
carcinoma and the requirement for liver transplantation,” said
Rohit Loomba, MD, MHSc, lead study author, Director of the NAFLD
Research Center, Director of Hepatology, Professor of Medicine, and
Vice Chief of the Division of Gastroenterology at University of
California San Diego School of Medicine. “Unfortunately, there are
no treatments available for these patients. In this first
randomized, placebo-controlled, Phase 2 study of an ACC inhibitor
in NASH, the data suggest that GS-0976 has the potential to play an
important role in treating patients with this disease.”
ACC plays a role in one of several biologically relevant
pathways associated with disease progression in NASH. ACC catalyzes
the first step in hepatic de novo lipogenesis, the synthesis of
fatty acids that contribute to hepatic steatosis and, subsequently,
inflammation and liver fibrosis.
The study included 126 patients who were randomized to receive
GS-0976 20 mg (n=49), GS-0976 5 mg (n=51), or placebo (n=26) once
daily for 12 weeks. All patients in the study were diagnosed with
NASH and liver fibrosis stages F1 through F3 based on biopsy, or by
magnetic resonance elastography (MRE) and MRI proton density fat
fraction (MRI-PDFF).
Patients receiving GS-0976 20 mg demonstrated significant
decreases in liver fat content (measured by MRI-PDFF) compared to
placebo after 12 weeks of treatment. Patients treated with GS-0976
20 mg also experienced a significant decrease in TIMP-1, a serum
marker associated with liver fibrosis. Differences between GS-0976
5 mg and placebo were not statistically significant. Data for these
efficacy endpoints are summarized in the table below.
Relative (%) Changes in Imaging, ALT and Serum Fibrosis
Markers at Week 12*
Endpoint (Week 12)
GS-0976
20 mg
(n=49)
GS-0976
5 mg
(n=51)
Placebo
(n=26)
P-values
20 mg vs.Placebo
5 mg vs.Placebo
MRI-PDFF -28.9 -13.0 -8.4
0.002 0.142 ≥30% reduction in
MRI-PDFF, % (n/N)
48%(22/46)
23%(11/47)
15%(4/26)
0.004 0.433 MRE-stiffness -5.5 -9.6 -12.5 0.100 0.743 Liver
stiffness by FibroScan -11.1 -8.4 -3.1 0.212 0.364 ALT -20.5 -9.8
-6.7 0.176 0.765 TIMP-1 -7.9 -2.9 -1.5
0.022 0.301 PIII-NP
-13.9 -7.0 -0.5 0.107 0.605
*Unless indicated, all data are median relative (%) changes from
baseline.
In other measures, including liver stiffness by FibroScan, liver
stiffness by MRE, serum ALT and PIII-NP, a serum marker of
fibrogenesis, no statistically significant differences were
observed between the treatment and placebo arms of the study.
At week 12, a median relative change in triglycerides (TG) from
baseline of +11 percent, +13 percent and -4 percent was observed in
patients receiving GS-0976 20 mg, GS-0976 5 mg and placebo,
respectively. Asymptomatic Grade 3 or 4 TG elevations (>500
mg/dL) were observed in 16 patients receiving GS-0976 20 mg (n=7)
or 5 mg (n=9); the primary factor associated with such elevations
was a baseline TG level >250 mg/dL (p<0.001). The majority of
patients with such elevations either responded to fibrate or fish
oil therapy (n=4) or resolved without additional treatment or
cessation of GS-0976 (n=7). GS-0976 was well-tolerated. Nausea,
abdominal pain and diarrhea were the most common adverse
events.
Other Gilead studies being presented at The Liver Meeting
include preclinical data examining the combination of inhibitors of
ACC and apoptosis signal-regulating kinase 1 (ASK1) in rodent
models of NASH. These data suggest that the combination of agents
resulted in greater anti-fibrotic and anti-steatotic efficacy than
either agent alone (Abstract #425; named a Presidential Poster of
Distinction). Gilead is currently conducting clinical studies
evaluating combinations of the ASK1 inhibitor selonsertib, ACC
inhibitor GS-0976 and the selective, non-steroidal Farnesoid X
receptor (FXR) agonist GS-9674 in patients with NASH. Additional
abstracts describe the accuracy of noninvasive markers to predict
improvements in liver histology in response to treatment in a Phase
2 study of selonsertib, including reductions in fibrosis with MRE
(Abstract #2104) and liver fat with MRI-PDFF (Abstract #2169).
Phase 3 studies are ongoing with selonsertib in patients with
advanced fibrosis due to NASH.
Gilead is also presenting multiple abstracts regarding primary
sclerosing cholangitis (PSC), a progressive cholestatic liver
disease with no approved therapies. These include presentations on
the role of magnetic resonance cholangiopancreatography (MRCP) in
PSC including a Presidential Plenary Oral Presentation (Abstract
#140) describing a novel MRCP-based risk score for predicting
PSC-related complications; an innovative technique for quantifying
biliary tree volume in PSC (Abstract #292); prospective data
describing the natural history of radiologic progression in PSC
(Abstract #279; a Presidential Poster of Distinction); and the
development and validation of a PSC-specific patient reported
outcome (PRO) measure (Abstract #1351; a Presidential Poster of
Distinction). These studies will enhance our understanding of PSC
and aid in the development of novel therapies. Gilead is currently
conducting a Phase 2 study of the FXR agonist GS-9674 in patients
with PSC.
About Gilead’s Clinical Programs in
NASH
NASH is a chronic liver disease associated with steatosis, or
accumulation of fat within the liver, which can lead to
inflammation, progressive fibrosis and cirrhosis. Gilead is
advancing multiple novel investigational compounds for the
treatment of NASH with advanced fibrosis. Gilead is currently
planning or conducting Phase 2 and 3 clinical trials evaluating
single-agent and combination therapy approaches against multiple
core pathways associated with NASH – metabolic dysregulation,
inflammation and fibrosis. Compounds in development include the
ASK1 inhibitor selonsertib; the selective, non-steroidal FXR
agonist GS-9674; and the ACC inhibitor GS-0976. The STELLAR Phase 3
trial program evaluating selonsertib among NASH patients with
bridging fibrosis (F3) or cirrhosis (F4) is ongoing. GS-9674 and
GS-0976 are currently in Phase 2 studies in NASH.
Selonsertib, GS-9674 and GS-0976, alone and in combination, are
investigational therapies and have not been determined to be safe
or efficacious.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers,
develops and commercializes innovative therapeutics in areas of
unmet medical need. The company’s mission is to advance the care of
patients suffering from life-threatening diseases. Gilead has
operations in more than 30 countries worldwide, with headquarters
in Foster City, California.
Forward-Looking
Statement
This press release includes forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of 1995
that are subject to risks, uncertainties and other factors,
including Gilead’s ability to complete its Phase 2 and Phase 3
clinical trial programs evaluating GS-0976, selonsertib and GS-9674
in patients with NASH in the currently anticipated timelines or at
all. In addition, there is the possibility of unfavorable results
from further clinical trials involving these compounds. Further, it
is possible that Gilead may make a strategic decision to
discontinue development of GS-0976, selonsertib and/or GS-9674 if,
for example, Gilead believes commercialization will be difficult
relative to other opportunities in its pipeline. As a result, the
compounds may never be successfully commercialized. These risks,
uncertainties and other factors could cause actual results to
differ materially from those referred to in the forward-looking
statements. The reader is cautioned not to rely on these
forward-looking statements. These and other risks are described in
detail in Gilead’s Quarterly Report on Form 10-Q for the quarter
ended June 30, 2017, as filed with the U.S. Securities and Exchange
Commission. All forward-looking statements are based on information
currently available to Gilead, and Gilead assumes no obligation to
update any such forward-looking statements.
For more information on Gilead Sciences, please
visit the company’s website at www.gilead.com, follow Gilead on Twitter
(@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5
or 1-650-574-3000.
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Gilead Sciences, Inc.Sung Lee, 650-524-7792 (Investors)Nathan
Kaiser, 650-522-1853 (Media)
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