-- Combination Therapy Data Presented from
First 12-Week Study --
-- Enrollment Complete for Phase 3 STELLAR
Trials of ASK1 Inhibitor Selonsertib --
Gilead Sciences, Inc. (Nasdaq: GILD) today presented data from a
proof-of-concept study of investigational combination therapies for
patients with advanced fibrosis due to nonalcoholic steatohepatitis
(NASH), combining the apoptosis signal-regulating kinase 1 (ASK1)
inhibitor selonsertib with either the Acetyl-CoA carboxylase (ACC)
inhibitor GS-0976 or the selective, non-steroidal Farnesoid X
receptor (FXR) agonist GS-9674. The data were presented at The
International Liver Congress™ 2018 in Paris.
More than 25 additional Gilead abstracts on NASH and other
fibrotic liver diseases are also being presented, including data
from predictive modeling studies using noninvasive tests for the
diagnosis and monitoring of NASH that aim to reduce the need for
liver biopsy.
“Gilead is focused on addressing the greatest unmet need in
NASH, which is in patients with advanced fibrosis. Reflective of
this unmet need, the STELLAR-3 and STELLAR-4 studies of selonsertib
in patients with F3 and F4 fibrosis have completed enrollment ahead
of schedule. We expect data from these Phase 3 studies in the first
half of 2019,” said Norbert Bischofberger, PhD, Executive Vice
President of Research and Development and Chief Scientific Officer
at Gilead. “We are now exploring combination therapy approaches
with compounds with distinct and potentially complementary
mechanisms of action. The initial data presented today are
important advances toward our goal of improving outcomes for
patients with advanced fibrosis due to NASH.”
Investigational Combination Therapies in Patients with
NASH
The proof-of-concept study (Oral #105) included 70 patients
treated with either selonsertib 18 mg plus GS-0976 20 mg (n=20),
selonsertib 18 mg plus GS-9674 30 mg (n=20), or each monotherapy
(n=10 per group) once daily for 12 weeks. All patients in the study
were diagnosed with NASH and liver fibrosis stages F2 to F3 based
on biopsy, or by magnetic resonance elastography (MRE) and MRI
proton density fat fraction (MRI-PDFF). The greatest changes
observed after 12 weeks of treatment in the study were decreases in
liver fat content (measured by MRI-PDFF), which occurred in
regimens containing GS-0976. Improvements in liver biochemistry
and/or markers of fibrosis were also observed across both
combination arms of the study compared to baseline. In patients
treated with selonsertib plus GS-0976, kinetic labeling revealed
the largest reduction in the fractional synthesis rate of lumican,
a marker of fibrogenesis. Similar rates of adverse events were
observed between patients treated with single-agent and combination
therapies. No patient discontinued treatment prematurely.
“These encouraging results suggest that combination therapy with
selonsertib and either GS-0976 or GS-9674 warrants further
exploration in longer-term studies in patients with NASH and F3 and
F4 fibrosis,” said Stephen Harrison, MD, presenting author and
Visiting Professor of Hepatology at the Radcliffe Department of
Medicine, University of Oxford, UK. “Patients 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. Combination therapy
may be a way forward to achieving greater benefit for this patient
population.”
Gilead also presented data from a pre-clinical study of another
combination treatment approach for NASH, evaluating GS-9674 and
GS-0976 together and as single-agents in rodent models of NASH and
liver fibrosis (Poster #077). The data indicate that combining
agents had greater anti-fibrotic and anti-steatotic effects and led
to greater improvements in liver biochemistry and fibrosis markers,
compared with either agent alone.
Based on these promising pre-clinical results and data from the
proof-of-concept clinical study, Gilead has initiated a larger
Phase 2b study of combination treatment with selonsertib, and/or
GS-0976, and/or GS-9674 in patients with advanced fibrosis due to
NASH.
Data from Noninvasive Tests Help Predict Histological
Severity and Clinical Outcomes in Patients with NASH
Currently, the diagnosis and monitoring of NASH requires liver
biopsy, an invasive and costly procedure with the potential for
serious complications. At the meeting, Gilead presented results
from two studies utilizing machine learning techniques which
suggest that noninvasive tests perform as effectively as liver
biopsy for predicting clinical outcomes in patients with advanced
fibrosis due to NASH. Both studies utilized data from two previous
Phase 2b trials of simtuzumab that involved 477 NASH patients with
F3-F4 fibrosis. While simtuzumab was ineffective, data from these
trials have revealed important insights into the natural history of
disease progression and the potential utility of noninvasive
fibrosis markers.
One study (Poster #466) showed that models using noninvasive
testing data can predict the risk of clinical disease progression
in patients with advanced fibrosis due to NASH. Another study (Oral
#178) identified models that can predict which patients are most
likely to experience spontaneous fibrosis improvement. Both studies
incorporated noninvasive tests such as Enhanced Liver Fibrosis
(ELF) score, FIB-4 and NAFLD fibrosis score.
Additional presentations at The International Liver Congress™
describe the accuracy of other noninvasive markers, including
proteomics (Poster #432), serum bile acids (Poster #422),
micro-RNAs (Poster #463), and the stool microbiome (Poster #004) to
predict liver histology and/or its change over time. These novel
approaches will be evaluated in future Gilead studies.
About Gilead’s Clinical Programs in
NASH
NASH is a chronic and progressive liver disease characterized by
the accumulation of fat in the liver, as well as inflammation,
which can lead to liver damage and fibrosis. Gilead is advancing
multiple novel investigational compounds for the treatment of
advanced fibrosis due to NASH.
Gilead is currently planning or conducting Phase 2 and 3
clinical trials evaluating single-agent and combination therapy
approaches against multiple biologically relevant pathways
associated with NASH – metabolic dysregulation, inflammation and
fibrosis. Compounds in development include:
- Selonsertib (formerly GS-4997) –
A small-molecule inhibitor of apoptosis signal-regulating kinase 1
(ASK1), which promotes inflammation, apoptosis and fibrosis in
settings of increased oxidative stress, which is characteristic of
NASH and associated with its pathogenesis.
- GS-9674 – A selective,
non-steroidal agonist of the Farnesoid X receptor (FXR), a nuclear
hormone receptor that is highly expressed in the gastrointestinal
tract and liver. FXR is the primary regulator of bile acid
synthesis and plays important roles in glucose and lipid
metabolism.
- GS-0976 – A small-molecule
inhibitor of Acetyl-CoA carboxylase (ACC), an enzyme that is
involved in de novo lipogenesis, which is the synthesis of lipids,
including mediators of inflammation and fibrosis. ACC also
upregulates the burning of fat in the liver through beta
oxidation.
Selonsertib, GS-9674 and GS-0976, alone and in combination, are
investigational therapies and their efficacy and safety have not
been determined.
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 35 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 single-agent and combination
therapy approaches, including selonsertib, and/or GS-9674 and/or
GS-0976, 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 selonsertib, and/or GS-9674
and/or GS-0976 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 Annual Report on Form 10-K for the
year ended December 31, 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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