- Type B meeting with FDA held under
Breakthrough Therapy designation resulted in agreement on key
aspects of Phase 3 trial design
- Single Phase 3 trial designed to enroll
200 U.S. patients with a 90-day survival primary endpoint;
topline results expected within two years of trial
initiation
- Protocol for Phase 3 trial builds on
data from the AHFIRM Phase 2b trial;
30 mg and 90 mg doses of larsucosterol reduced 90-day mortality in
U.S. patients by 57% and 58%, respectively, compared with
placebo
CUPERTINO, Calif. ,
Sept. 25,
2024 /PRNewswire/ -- DURECT Corporation (Nasdaq:
DRRX), a late-stage biopharmaceutical company pioneering the
development of epigenetic therapies to transform the treatment of
serious and life-threatening conditions such as acute organ injury,
today provided details on the design of its upcoming registrational
Phase 3 trial which will evaluate larsucosterol for the treatment
of patients with severe alcohol-associated hepatitis (AH).
"We are pleased with the collaborative interactions with the
U.S. Food and Drug Administration (FDA), including our recent Type
B meeting held under Breakthrough Therapy designation, that allowed
us to reach agreement on key elements of the protocol for the
upcoming Phase 3 trial," said James E.
Brown, D.V.M., President and Chief Executive Officer of
DURECT. "We believe the primary endpoint of 90-day survival is
clinically meaningful and provides the greatest probability of
success based on the AHFIRM data. In the completed AHFIRM trial,
larsucosterol showed the ability to reduce mortality in AH patients
compared to standard of care, particularly in the U.S., where we
observed nearly 60% lower mortality at 90-days in both the 30 mg
and 90 mg dose groups. We look forward to initiating the Phase 3
trial as soon as possible, subject to obtaining sufficient funds,
which should enable us to report topline data within two years of
trial initiation. The FDA also agreed that a single Phase 3 trial
would be sufficient to support a New Drug Application (NDA).
Larsucosterol's Breakthrough Therapy designation for the
treatment of AH gives us the opportunity to file an NDA as a
rolling submission. As we continue to advance our development
program for larsucosterol in AH, we look forward to additional
discussions with the FDA under this designation."
Norman Sussman, M.D., FAASLD,
Chief Medical Officer of DURECT, added, "As cases of AH continue to
rise, there is an urgent need for an effective therapy to
significantly reduce the high mortality rate, which is
approximately 30% at 90 days. Based on our Phase 2b AHFIRM data, we believe larsucosterol has the
potential to save the lives of tens of thousands of patients yearly
who currently have very limited options. We have ongoing
discussions with a range of U.S. clinical sites and hepatologists,
including those who participated in AHFIRM, to streamline the
process of initiating our Phase 3 trial. We are pleased to have the
opportunity to work again with a high quality network of sites and
investigators who are enthusiastic about larsucosterol and eager to
participate in the Phase 3 trial."
The proposed Phase 3 trial design incorporates feedback from the
Type B meeting held with the FDA under the Breakthrough Therapy
designation. It is designed as a randomized, double-blind,
placebo-controlled, multi-center study conducted in the U.S., which
will evaluate the safety and efficacy of larsucosterol for the
treatment of patients with severe AH. The primary outcome measure
will be a 90-day survival endpoint. The Phase 3 trial is planned to
enroll approximately 200 patients randomized in a 1:1 ratio across
two arms: 1) larsucosterol (30 mg) or 2) placebo, which will be
added to the current standard of care, with or without
methylprednisolone capsules at the investigators' discretion.
Patients enrolled in the trial will be followed for a total of up
to 180 days to collect additional safety and outcomes data.
Data from the AHFIRM trial showed a compelling efficacy signal
in favor of larsucosterol in the key secondary endpoint of
mortality at 90 days. Both the 30 mg and 90 mg larsucosterol
doses demonstrated clinically meaningful trends in reduction of
mortality at 90 days with mortality reductions of 41% (p=0.068) in
the 30 mg arm and 35% (p=0.124) in the 90 mg arm compared with
placebo. The reductions in mortality at 90 days were more
pronounced in U.S. patients, who comprised 76% of the trial
population, with reductions of 57% (p=0.014) in the 30 mg arm and
58% (p=0.008) in the 90 mg arm compared with placebo. The
numerical improvement in the primary endpoint of mortality or liver
transplant at 90 days did not achieve statistical significance for
either dose of larsucosterol. Reflecting the life-threatening
nature of AH and the lack of therapeutic options, the FDA granted
larsucosterol Fast Track and Breakthrough Therapy designations for
the treatment of AH.
About Alcohol-associated Hepatitis (AH)
AH is an acute
form of alcohol-associated liver disease (ALD) associated with
long-term heavy alcohol intake, often following a recent period of
increased consumption (i.e., a binge). AH is typically
characterized by severe inflammation and liver cell damage,
potentially leading to life-threatening complications including
liver failure, acute kidney injury and multi-organ failure. There
are no FDA approved therapies for AH, and a retrospective analysis
of 77 studies published between 1971 and 2016, which included data
from 8,184 patients, showed the overall mortality from AH was 26%
at 28 days, 29% at 90 days and 44% at 180 days. A subsequent global
study published in December 2021, which included 85 tertiary
centers in 11 countries across 3 continents, prospectively enrolled
2,581 AH patients with a median Model of End-Stage Liver Disease
(MELD) score of 23.5, reported mortality at 28 and 90 days of
approximately 20% and 31%, respectively. Stopping alcohol
consumption is necessary, but frequently not sufficient for
recovery in many moderate (defined as MELD scores of 11-20) and
severe (defined as MELD scores >20) patients, and therapies that
reduce liver inflammation, such as corticosteroids, are limited by
contraindications, have not been shown to improve survival at 90
days or one year, and have demonstrated an increased risk of
infection. While liver transplantation is becoming more common for
ALD patients, including AH patients, the total number of such
transplants is still relatively small and limited by organ
availability. Average costs for a liver transplant
exceed $875,000, and patients require lifelong
immunosuppressive therapy to prevent organ rejection.
About the AHFIRM Trial
AHFIRM was a Phase 2b randomized, double-blind, placebo-controlled,
international, multi-center study conducted in subjects with severe
alcohol-associated hepatitis (AH) to evaluate the saFety and
effIcacy of laRsucosterol treatMent (AHFIRM). The study was
comprised of three arms and enrolled 307 patients, with
approximately 100 patients in each arm: (1) Placebo, which consists
of standard of care, with or without methylprednisolone capsules at
the investigators' discretion; (2) larsucosterol (30 mg); and (3)
larsucosterol (90 mg). Patients in the larsucosterol arms received
the same supportive care without steroids. The primary outcome
measure was the 90-day incidence of mortality or liver
transplantation for patients treated with larsucosterol compared to
those treated with placebo, and the key secondary endpoint was
90-Day survival. The Company enrolled patients at clinical trial
sites across the U.S., EU, U.K., and Australia. In November
2023, the Company announced topline data for the AHFIRM
Trial. Reflecting the life-threatening nature of AH and the lack of
therapeutic options, the U.S. Food and Drug Administration (FDA)
has granted larsucosterol Fast Track Designation and Breakthrough
Therapy Designation for the treatment of AH. For more information,
refer to ClinicalTrials.gov Identifier: NCT04563026.
About Larsucosterol
Larsucosterol is an
endogenous sulfated oxysterol and an epigenetic modulator.
Epigenetic regulators are compounds that regulate patterns of gene
expression without modifying the DNA sequence. DNA
hypermethylation, an example of epigenetic dysregulation, results
in transcriptomic reprogramming and cellular dysfunction, and has
been reported in many acute (e.g., AH) and chronic diseases (e.g.,
metabolic dysfunction-associated steatohepatitis (MASH)). As an
inhibitor of DNA methyltransferases (DNMT1, DNMT3a and 3b),
larsucosterol inhibits DNA methylation, which subsequently
modulates the expression of genes that are involved in cell
signaling pathways associated with stress responses, cell death and
survival, and lipid biosynthesis. This may ultimately lead to
improved cell survival, reduced inflammation, and decreased
lipotoxicity. As an epigenetic modulator, the proposed mechanism of
action provides further scientific rationale for developing
larsucosterol for the treatment of acute organ injury and certain
chronic diseases.
About DURECT Corporation
DURECT is a late-stage
biopharmaceutical company pioneering the development of epigenetic
therapies that target dysregulated DNA methylation to transform the
treatment of serious and life-threatening conditions, including
acute organ injury. Larsucosterol, DURECT's lead drug candidate,
binds to and inhibits the activity of DNA methyltransferases,
epigenetic enzymes that are elevated and associated with
hypermethylation found in AH patients. Larsucosterol is in clinical
development for the potential treatment of AH, for which the FDA
has granted a Fast Track and a Breakthrough Therapy designation;
MASH is also being explored. In addition,
POSIMIR® (bupivacaine solution) for infiltration
use, a non-opioid analgesic utilizing the innovative
SABER® platform technology, is FDA-approved and is
exclusively licensed to Innocoll Pharmaceuticals for sale and
distribution in the United States.
For more information about DURECT, please
visit www.durect.com and follow us on X (formerly
Twitter) at https://x.com/DURECTCorp.
DURECT Forward-Looking Statements
This press release
contains forward-looking statements, including statements made
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995, relating to: our plans to initiate
and enroll patients in a Phase 3 trial of larsucosterol in AH in
2024 and present top-line data in the second half of 2026, our
ability to confirm the efficacy and safety of larsucosterol in AH
patients to support an NDA filing with the FDA, the potential
benefits of Breakthrough Therapy designation, and the potential
uses of laruscosterol to treat patients with AH and potentially
other indications. Actual results may differ materially from those
contained in the forward-looking statements contained in this press
release, and reported results should not be considered as an
indication of future performance. The potential risks and
uncertainties that could cause actual results to differ from those
projected include, among other things, the risk that future
clinical trials of larsucosterol are delayed or do not confirm the
results from subset analyses of the AHFIRM trial, including
geographic or other segmentation, or of earlier clinical or
pre-clinical trials, or do not demonstrate the safety or efficacy
of larsucosterol in a statistically significant manner; the risk
that we do not raise sufficient capital to commence or complete the
Phase 3 trial of larsucosterol in patients with AH or continue to
fund our operations, the risk that the FDA or other government
agencies may require additional clinical trials for larsucosterol
before approving larsucosterol for the treatment of AH, the risk
that Breakthrough Therapy designation does not expedite the process
for FDA approval and that larsucosterol may never be approved; and
risks related to the sufficiency of our cash resources, our
anticipated capital requirements, our ability to continue to meet
the minimum bid price for continued listing on Nasdaq, and our
ability to continue to operate as a going concern. Further
information regarding these and other risks is included in DURECT's
most recent Securities and Exchange Commission (SEC) filings,
including its annual report on Form 10-K for the year ended
December 31, 2023 and quarterly
report on Form 10-Q for the quarter ended June 30, 2024, under the heading "Risk
Factors." These reports are available on our website
www.durect.com under the "Investors" tab and on the SEC's website
at www.sec.gov. All information provided in this press release and
in the attachments is based on information available to DURECT as
of the date hereof, and DURECT assumes no obligation to update this
information as a result of future events or developments, except as
required by law.
NOTE: POSIMIR® is a trademark of Innocoll
Pharmaceuticals, Ltd. in the U.S. and a trademark of DURECT
Corporation outside of the U.S. SABER® is a trademark of
DURECT Corporation. Other referenced trademarks belong to their
respective owners. Larsucosterol is an investigational drug
candidate under development and has not been approved for
commercialization by the U.S. Food and Drug Administration or other
health authorities for any indication.
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