Enanta Pharmaceuticals Announces Positive Phase 1 a/b Clinical Results for its Lead FXR Agonist, EDP-305
October 23 2017 - 7:30AM
Business Wire
- EDP-305 was generally safe and well
tolerated over a broad range of single and multiple doses with
pharmacokinetic (PK) data supporting once daily oral dosing
- EDP-305 exhibited strong engagement of
the FXR receptor as evidenced by increased FGF19 levels and reduced
C4 levels
- Results support the ability to
administer EDP-305 in future trials at doses that neither elicit
clinically significant changes in lipids nor result in
pruritus
Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA), a chemistry-driven
biotechnology company dedicated to creating small molecule drugs
for viral infections and liver diseases, today announced positive
results from its Phase 1 clinical study of EDP-305, Enanta’s lead
FXR agonist for non-alcoholic steatohepatitis (NASH) and primary
biliary cholangitis (PBC). The objective of this double-blind,
placebo-controlled study in adult healthy volunteer (HV) subjects
and subjects with presumed non-alcoholic fatty liver disease
(NAFLD) (PN)* was to evaluate the safety, tolerability and
pharmacokinetics of single ascending dose (SAD) and multiple
ascending dose (MAD) levels of EDP-305. Pharmacodynamic (PD)
markers of FXR activity (FGF19, C4) and lipids were measured in all
dose groups.
Summary of results:
- A total of 146 subjects received at
least one dose of EDP-305 (n=110) or placebo (n=36) including 50 HV
subjects in SAD and 96 (48 HV, and 48PN) in the MAD phases of the
study. Overall, mean BMI in the PN cohort was 32 (29,35). SAD had 6
cohorts at doses of 1, 5, 10, 20, 40 and 80 mg EDP-305/placebo, and
MAD had 6 cohorts at doses of 0.5, 1, 2.5, 5, 10 and 20 mg
EDP-305/placebo for 14 days.
- Strong FXR target engagement was
demonstrated, with doses of EDP-305 > 1 mg increasing FGF19 and
reducing C4 in all subjects, while PN subjects were even more
sensitive with significant effects also observed in both parameters
at the lowest multiple doses of 0.5 and 1 mg.
- Pharmacokinetic analysis revealed a PK
profile suitable for once daily oral dosing.
- Dose proportional increases in exposure
were observed, with median t1/2 from 11-23 hours in HV and from
10-18 hours in PN subjects following multiple doses.
- Longer t1/2 (2-fold) and more drug
accumulation (~3 to 4-fold) were observed following the multiple 20
mg dose compared to lower doses.
- No serious adverse events (SAEs) were
reported, and EDP-305 was generally well tolerated at all doses
tested.
- Treatment-emergent adverse events
occurring in ≥ 2 EDP-305 treated subjects in MAD cohorts were:
headache and pruritus in HV subjects, and constipation and pruritus
in PN subjects.
- Of the cases of pruritus noted (9% for
EDP-305, 3% in placebo), the majority were mild or moderate and
occurred at multiple doses of 20 mg, with no cases below 10mg.
Notably, EDP-305 demonstrated potent engagement of the FXR receptor
across the lower dose range where there was no pruritus.
- Two subjects discontinued treatment in
the MAD phase at the 20 mg dose level, one for a transient grade 2
ALT/AST elevation, and one for moderate pruritus.
- No dose-related changes in lipids were
observed in HV subjects at any doses; and no dose-related changes
in lipids were observed in PN subjects except for reductions of
total cholesterol and HDL cholesterol at the multiple 20mg dose,
with no concomitant increase in LDL cholesterol.
- These results support further clinical
evaluation of EDP-305 in NASH and PBC patients.
- Enanta plans to present detailed
results at a future scientific conference.
“We are very encouraged by our Phase 1 a/b results demonstrating
a good safety profile as well as strong target engagement in our PN
subjects in the lower multiple dose range of 0.5 to 5 mg,” stated
Jay R. Luly, Ph.D., President and CEO, Enanta. “Enanta plans to
initiate a Phase 2 dose-ranging study in PBC patients by the end of
2017 and a Phase 2 dose-ranging study in NASH patients by early
2018 utilizing doses in that dose range.”
* Presumed NAFLD (PN) subjects are obese, with or without
pre-diabetes or type 2 diabetes mellitus.
About EDP-305, a Farnesoid X Receptor (FXR) Agonist
EDP-305 is a potent FXR agonist and Enanta’s lead product
candidate being developed for the treatment of NASH and PBC.
EDP-305 represents a new class of FXR agonists that has been
designed to take advantage of increased binding interactions with
the receptor. Further, this non-bile acid class contains steroidal
and non-steroidal components, and does not contain the carboxylic
acid group that can lead to the formation of taurine and glycine
conjugates normally associated with bile acids, which may also be
present in other classes of FXR agonists.
About NAFLD, NASH, and FXR
Non-alcoholic fatty liver disease (NAFLD) is the accumulation of
excessive fat in the form of triglycerides in patients’ liver cells
(steatosis) that is not caused by alcohol. NAFLD is widely
considered to be the liver expression of metabolic disease
associated with type 2 diabetes, insulin resistance, obesity, and
hyperlipidemia. A subgroup of NAFLD patients has liver cell injury
and inflammation in addition to excessive fat (steatohepatitis).
Progression of this condition leads to non-alcoholic
steatohepatitis (NASH). Patients with NASH can develop fibrosis and
ultimately cirrhosis of the liver, potentially leading to
hepatocellular carcinoma (HCC) or requiring a liver transplant.
Farnesoid X receptor (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.
About Enanta
Enanta Pharmaceuticals has used its robust, chemistry-driven
approach and drug discovery capabilities to become a leader in the
discovery of small molecule drugs for the treatment of viral
infections and liver diseases. Two protease inhibitors,
paritaprevir and glecaprevir, discovered and developed through
Enanta’s collaboration with AbbVie, have now been approved in
jurisdictions around the world as part of AbbVie’s direct-acting
antiviral (DAA) regimens for the treatment of hepatitis C virus
(HCV) infection, including the U.S.-marketed regimens MAVYRET™
(glecaprevir/pibrentasvir) and VIEKIRA PAK®
(paritaprevir/ritonavir/ombitasvir/dasabuvir).
Royalties and milestone payments from the AbbVie collaboration
are helping to fund Enanta’s research and development efforts,
which are currently focused on the following disease targets:
non-alcoholic steatohepatitis (NASH)/ primary biliary cholangitis
(PBC), respiratory syncytial virus (RSV) and hepatitis B virus
(HBV). Please visit www.enanta.com for more information.
Forward Looking Statements
This press release contains forward-looking statements,
including statements with respect to the prospects for development
of EDP-305 for the treatment of NASH and PBC. 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
discovery and development risks of early stage development efforts
in disease areas such as NASH that currently have no therapeutic
treatment; potential competition from the development efforts of
others in this disease area; Enanta’s level of 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-K for the fiscal year ended September
30, 2016 and 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20171023005324/en/
InvestorsEnanta Pharmaceuticals, Inc.Carol Miceli,
617-607-0710cmiceli@enanta.comorMediaMacDougall Biomedical
CommunicationsKari Watson, 781-235-3060kwatson@macbiocom.com
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