Metacrine Reports Positive Results from Phase 1 Trial of MET642
December 17 2020 - 6:30AM
Metacrine, Inc. (Nasdaq: MTCR), a clinical-stage biopharmaceutical
company focused on discovering and developing differentiated
therapies for patients with liver and gastrointestinal diseases,
today reported preliminary results from its Phase 1 trial of
MET642, a farnesoid X receptor (FXR) agonist being developed for
the treatment of non-alcoholic steatohepatitis (NASH) and
inflammatory bowel disease. Findings show that treatment with
MET642 was safe and generally well-tolerated and demonstrated a
sustained pharmacokinetic (PK) profile and robust FXR target
engagement after 14 days of daily oral dosing in healthy
volunteers.
“There are no treatments currently available for NASH patients,
and given FXR agonism works through multiple mechanisms to improve
NASH and fibrosis, I believe that an optimized FXR agonist could
become both a first-line monotherapy and foundation for combination
therapies in the future,” said Stephen A. Harrison, M.D., Visiting
Professor of Hepatology at University of Oxford’s Radcliffe
Department of Medicine, Medical Director of Pinnacle Clinical
Research and President of Summit Clinical Research. “I am
encouraged by the sustained activity and safety demonstrated with
MET642, in particular the lack of pruritis and LDL-cholesterol
increases, which support its continued evaluation in patients with
NASH.”
Metacrine has developed a proprietary FXR platform utilizing a
unique chemical scaffold, which has demonstrated a clinically
differentiated and improved therapeutic profile. The company’s lead
FXR clinical candidate, MET409, has successfully completed a
12-week trial in patients with NASH. MET642, Metacrine’s second
clinical candidate, is derived from the same chemical scaffold as
MET409 and has shown comparable FXR target engagement and
pharmacology in preclinical studies, as well as increased potency
and differentiated pharmaceutical properties.
The MET642 Phase 1 trial was a first-in-human, randomized,
placebo-controlled, double-blind single-ascending dose (SAD) and
multiple-ascending dose (MAD) trial, in which healthy volunteers
received once-daily MET642 doses ranging from 10 mg to 300 mg in
the SAD cohorts and 2.5 mg to 10 mg in the MAD cohorts for 14 days.
The primary objective of the trial was to evaluate safety and
tolerability, and the secondary objectives were to assess PK
parameters and FXR target engagement, the latter through the
measurement of 7α-hydroxy-4-cholesten-3-one (C4), a blood biomarker
of bile acid synthesis that decreases with FXR activation.
Safety FindingsMET642 was safe and generally
well-tolerated, with no serious adverse events reported, and all
adverse events were mild to moderate in severity. Importantly,
pruritus and LDL-cholesterol increases were not seen at any dose
level.
PK and Target Engagement FindingsMET642
exhibited a sustained PK profile as well as robust FXR target
engagement throughout 24 hours after once-daily oral dosing, with
notable C4 repression – up to an approximately 95% decrease in
area-under-the-curve (AUC) relative to placebo – observed after the
last dose in all MAD cohorts of the trial. The magnitude of C4
decrease can be used to project potential levels of liver fat
reduction in NASH patients, with ≥30% relative liver fat reduction
being associated with increased likelihood of histological benefits
upon liver biopsy.
“We are encouraged by the overall safety profile of MET642, and
with meaningful target engagement seen at as low as the 2.5 mg dose
level, we intend to evaluate the 3 mg and 6 mg dose levels in our
upcoming Phase 2a trial in NASH patients,” said Hubert C. Chen,
M.D., chief medical officer of Metacrine. “With the benefit of
greater potency and improved pharmaceutical properties, we believe
MET642 has the potential to be another best-in-class FXR agonist in
our proprietary portfolio.”
Summary of MET642 Phase 1 Trial Results
Number of subjects |
32 total in SAD cohorts32 total in MAD cohorts |
Serious adverse events |
None |
Severity of treatment-related adverse events |
Mild to moderate only |
Pruritus |
None1 |
LDL-cholesterol |
Mean change from baseline to Day 14:-0.12 to -0.57 mmol/L for
MET642 subjects -0.10 mmol/L for pooled placebo subjects |
Liver function tests |
Sporadic, isolated ALT/AST increases in MAD cohorts; resolved with
continued MET642 dosing/exposure |
Pharmacokinetics |
Mean elimination half-life: ~40-68 hours after 14 days of
dosing |
FXR target engagement |
Mean repression of C4 AUC after last multiple-dose administration:
~55% (2.5 mg) to ~95% (10 mg) relative to placebo |
1One case of localized, overnight itch was reported on Day 7 by
one MET642 subject in the 5 mg cohort, a finding that is atypical
of FXR-associated pruritus; dosing was continued without subsequent
events.
Based on the Phase 1 findings, Metacrine plans to advance two
dose levels of MET642 – 3 mg and 6 mg – in a 16-week, randomized,
placebo-controlled Phase 2a monotherapy trial enrolling up to 180
patients with NASH. The two doses are projected to repress C4 to
levels that are likely to result in meaningful reductions in liver
fat content. The trial is scheduled to start in the first half of
2021, with an interim analysis planned in the second half of 2021,
after approximately 60 patients have completed 16 weeks of
treatment.
About MetacrineMetacrine, Inc. (Nasdaq: MTCR)
is a clinical-stage biopharmaceutical company building a
differentiated pipeline of therapies to treat liver and
gastrointestinal (GI) diseases. The company’s most advanced
programs, MET409 and MET642, target the farnesoid X receptor (FXR),
which is central to modulating liver and GI diseases. Both MET409
and MET642 are currently being investigated in clinical trials as
potential new treatments for non-alcoholic steatohepatitis
(NASH).
Forward-Looking StatementsThis press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. Statements in
this press release that are not purely historical are
forward-looking statements. Forward-looking statements contained in
this press release include statements regarding the therapeutic
potential of MET409 and MET642; Metacrine’s timelines; the
differentiated nature of Metacrine’s FXR program; plans underlying
Metacrine’s clinical trials; plans underlying Metacrine’s clinical
trials in NASH; plans for advancing the clinical development of
Metacrine’s FXR program; and the potential best-in-class nature of
Metacrine’s FXR program; and the potential for its FXR product
candidates to be long-term therapies for NASH. Words such as “may,”
“will,” “expect,” “likely,” “plan,” “aim,” “anticipate,”
“estimate,” “intend,” “potential,” “preliminary,” “prepare,”
“projected,” “scheduled,” and similar expressions (as well as other
words or expressions referencing future events, conditions or
circumstances) are intended to identify forward-looking statements.
These forward-looking statements are based on Metacrine’s
expectations and assumptions that may never materialize or prove to
be incorrect. Each of these forward-looking statements involves
risks and uncertainties. Actual results may differ materially from
those projected in any forward-looking statements due to numerous
risks and uncertainties, including but not limited to: the risk
that the preliminary analysis may change upon further evaluation or
may not be able to be replicated in a larger patient sample and
other risks and uncertainties inherent in early-stage clinical
trials; risks and uncertainties regarding regulatory approvals for
MET409 or MET642; potential delays in initiating, enrolling or
completing any clinical trials; unexpected safety or efficacy data
observed during preclinical or clinical studies, potential adverse
side effects or other safety risks associated with Metacrine’s
product candidates; competition from third parties that are
developing products for similar uses; and Metacrine’s ability to
obtain, maintain and protect its intellectual property. Information
regarding the foregoing and additional risks may be found in the
section entitled “Risk Factors” in Metacrine’s Quarterly Report on
Form 10-Q filed with the Securities and Exchange Commission (the
“SEC”) on November 12, 2020, and in Metacrine’s other filings with
the SEC. All forward-looking statements contained in this press
release speak only as of the date on which they were made. Except
as required by law, Metacrine assumes no obligation to update any
forward-looking statements contained herein to reflect any change
in expectations, even as new information becomes available.
Contact:Chelcie ListerTHRUST Strategic
Communications910.777.3049investors@metacrine.com
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