Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA), a clinical-stage
biotechnology company dedicated to creating small molecule drugs
for viral infections and liver diseases, today announced topline
results from its INTREPID Phase 2 study of EDP-305, a Farnesoid X
receptor (FXR), in subjects with primary biliary cholangitis
(PBC).
The INTREPID study was a 12-week, randomized, double-blind,
placebo-controlled study evaluating the safety, tolerability,
pharmacokinetics and efficacy of EDP-305 in subjects with PBC, with
or without an inadequate response to ursodeoxycholic acid. The
primary endpoint of the study was to evaluate the proportion of
subjects with at least 20% reduction in alkaline phosphatase (ALP)
from pre-treatment value (ALP response), or normalization of ALP,
at week 12.
In the intent-to-treat (ITT) analysis, EDP-305 1 mg and 2.5 mg
treatment arms resulted in 45% (n=14/31, p=0.106) and 46% (n=13/28,
p=0.063) ALP response, respectively, compared to 11% (n=1/9) in the
placebo arm. Absolute changes from baseline in ALP at week 12 in
both the EDP-305 1 mg arm (p=0.017) and the 2.5 mg arm (p= 0.021)
compared to the change from baseline in the placebo arm were
statistically significant. In a post-hoc analysis, the proportions
of ALP responders among those who completed treatment with no
missing value at week 12 were 50% (n=14/28, p=0.039) and 62%
(n=13/21, p=0.011), respectively, compared to 11% in placebo
(n=1/9).
In the ITT analysis, key secondary endpoints, which included
changes from baseline in liver enzymes alanine aminotransferase
(ALT), aspartate aminotransferase (AST) and gamma-glutamyl
transferase (GGT) at week 12, were met with a statistically
significant difference compared to placebo in both the EDP-305 1 mg
arm and the 2.5 mg arm. Absolute changes from baseline at week 12
in these key secondary endpoints in the EDP-305 1 mg and 2.5 mg
arms compared to placebo were respectively: ALT (p=0.001, p=0.009),
AST (p=0.000, p=0.001) and GGT (p=0.000, p=0.000). A statistically
significant difference in the percent change from baseline of these
key biomarkers at week 12 was also observed in both EDP-305 arms
compared to placebo.
Overall, EDP-305 was generally safe in subjects with PBC, with
the majority of treatment-emergent adverse events (TEAEs) being
mild to moderate. Five patients in the 2.5 mg arm experienced
severe pruritus. The most common (≥10% or >1 subject/arm) TEAEs
included pruritus, gastrointestinal-related symptoms (abdominal
pain, diarrhea, gastro-esophageal reflux), headache and insomnia.
These TEAEs are consistent with the safety profile observed across
more than 400 subjects exposed to EDP-305 for up to 12 weeks. The
incidence of treatment discontinuation due to pruritus in INTREPID
was approximately 3% for the 1 mg EDP-305 treatment group and 18%
for the 2.5 mg EDP-305 treatment group. Treatment with EDP-305 had
no apparent effect on lipids, including cholesterol, low-density
lipoproteins, high-density lipoproteins and triglycerides.
“While INTREPID did not meet the primary endpoint in subjects
with PBC, as defined by at least a 20% reduction in ALP in the ITT
set analysis, there were numerically higher response rates with 1
mg and 2.5 mg compared to placebo,” said Jay Luly, Ph.D., President
and Chief Executive Officer of Enanta Pharmaceuticals. “In
addition, as shown in the completer analysis, those subjects who
finished treatment had a significant ALP response. We were also
able to obtain actionable data from this study to help us advance
EDP-305 and were encouraged that the lower dose of 1 mg could
achieve much better tolerability, in terms of pruritus, without
reducing the number of ALP responders or key biomarkers of target
engagement also achieved at the 2.5 mg dose. This is an encouraging
finding, particularly for the intermediate doses of 1.5 mg and 2.0
mg that we plan to take into our ARGON-2 study in non-alcoholic
steatohepatitis (NASH) patients. One of those two doses in NASH
could potentially achieve an efficacy and tolerability profile
acceptable in NASH patients.”
Dr. Luly continued, “Rather than conducting further dose
selection studies with EDP-305 in PBC, a disease for which there is
already an approved second-line FXR agonist therapy, we intend to
focus our future efforts with EDP-305 on NASH, a disease where FXR
agonists like EDP-305 have the potential to be important components
of drug combinations designed to give maximum benefit to patients.
Our ARGON-2 study in NASH will explore new intermediate doses with
the potential to optimize efficacy and tolerability, thereby
maximizing the opportunity to develop EDP-305 in combination with
other mechanisms of action against NASH.”
“Based on these data, it’s clear that EDP-305 demonstrated
evidence of target engagement with robust reductions in markers of
liver injury,” said Kris Kowdley, M.D., FACP, FACG, AGAF, FAASLD,
Director, Liver Institute Northwest and Clinical Professor, Elson
S. Floyd College of Medicine, Washington State University, the
Principal Investigator for the study. “These data suggest that a
dose between 1.0 mg and 2.5 mg could hit an optimal level of
efficacy and tolerability, which could bode well for future studies
in NASH. I look forward to seeing future data on EDP-305.”
About Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is a chronic disease of the
liver that slowly destroys the medium-sized bile ducts within the
liver. Bile is a digestive liquid that is made in the liver. It
travels through the bile ducts to the small intestine, where it
helps digest fats and fatty vitamins.
In patients with PBC, the bile ducts are destroyed by
inflammation. This causes bile to remain in the liver, where its
increased levels gradually damage liver cells and cause cirrhosis
or scarring of the liver. As cirrhosis progresses and the amount of
scar tissue in the liver increases, the liver loses its ability to
function, leading to potential liver failure, liver transplantation
or hepatocellular carcinoma. PBC affects mostly women, but more men
are now being diagnosed. The disorder usually becomes apparent
during middle age, initially affecting most individuals between the
ages of 45 to 65 years. However, the disorder has been diagnosed in
females as young as 22 years of age and in females in their early
90s. It has been estimated that PBC is one of the most common
autoimmune diseases, affecting nearly 1 in 1000 women over the age
of 40.1
About EDP-305, a Farnesoid X Receptor Agonist
EDP-305 is a potent Farnesoid X receptor (FXR) agonist and
Enanta’s lead product candidate being developed primarily for the
treatment of NASH. FXR is a nuclear receptor and a main regulator
of bile acid levels in the liver and small intestine. It responds
to bile acids by regulating gene transcription of key enzymes and
transporters, many of which play important roles in lipid
metabolism, insulin resistance, inflammation, and fibrosis. EDP-305
represents a class of FXR agonists that has been designed to take
advantage of increased binding interactions with the receptor. This
non-bile acid class contains steroid and non-steroid components and
does not contain the carboxylic acid group normally present in
other classes of FXR agonists and natural bile acids that can lead
to the formation of taurine and glycine conjugates.
About Enanta Pharmaceuticals, Inc.
Enanta is using its robust, chemistry-driven approach and drug
discovery capabilities to become a leader in the discovery and
development of small molecule drugs for the treatment of viral
infections and liver diseases. Enanta’s research and development
efforts have produced clinical candidates for the following disease
targets: respiratory syncytial virus (RSV), non-alcoholic
steatohepatitis (NASH) and hepatitis B virus (HBV). Enanta is also
conducting research in human metapneumovirus (hMPV) and emerging
coronaviruses, including SARS-CoV-2.
Enanta’s research and development activities are funded by
royalties from hepatitis C virus (HCV) products developed under its
collaboration with AbbVie. Glecaprevir, a protease inhibitor
discovered by Enanta and now marketed by AbbVie as part of its
leading treatment for chronic HCV infection, is sold under the
brand names MAVYRET® (U.S.) and MAVIRET® (ex-U.S.)
(glecaprevir/pibrentasvir). Please visit www.enanta.com for more
information.
Forward Looking Statements Disclaimer
This press release contains forward-looking statements,
including statements with respect to the prospects for further
development of EDP-305. Statements that are not historical facts
are based on management’s current expectations, estimates,
forecasts and projections about Enanta’s business and the industry
in which it operates and management’s beliefs and assumptions. The
statements contained in this release are not guarantees of future
performance and involve certain risks, uncertainties and
assumptions, which are difficult to predict. Therefore, actual
outcomes and results may differ materially from what is expressed
in such forward-looking statements. Important factors and risks
that may affect actual results include: the development risks of
early stage discovery efforts in the disease areas in Enanta’s
research and development pipeline, such as NASH; the impact of
development, regulatory and marketing efforts of others with
respect to competitive treatments for NASH; Enanta’s limited
clinical development experience; Enanta’s need to attract and
retain senior management and key scientific personnel; Enanta’s
need to obtain and maintain patent protection for its product
candidates and avoid potential infringement of the intellectual
property rights of others; and other risk factors described or
referred to in “Risk Factors” in Enanta’s most recent Form 10-Q for
the fiscal quarter ended December 31, 2019 and any other periodic
reports filed more recently with the Securities and Exchange
Commission. Enanta cautions investors not to place undue reliance
on the forward-looking statements contained in this release. These
statements speak only as of the date of this release, and Enanta
undertakes no obligation to update or revise these statements,
except as may be required by law.
1
https://rarediseases.org/rare-diseases/primary-biliary-cholangitis/
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Jennifer Viera 617-744-3848 jviera@enanta.com
Enanta Pharmaceuticals (NASDAQ:ENTA)
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