DURECT plans to confirm the efficacy and
safety of larsucosterol in a registrational Phase 3 clinical
trial
CUPERTINO, Calif., May 21, 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 and cancer,
today announced that the U.S. Food and Drug Administration (FDA)
has granted Breakthrough Therapy designation (BTD) to larsucosterol
for the treatment of patients with severe alcohol-associated
hepatitis (AH).
"We're pleased with the FDA's decision to grant Breakthrough
Therapy designation to larsucosterol, as it further recognizes its
potential to save the lives of AH patients," said James E. Brown, D.V.M., President and CEO of
DURECT. "AH has a high mortality rate and no currently approved
treatments, so there is a great need for a safe and effective
therapy. We continue to finalize the design of our planned
registrational Phase 3 trial for larsucosterol, incorporating the
recent FDA feedback and promising data from our completed Phase
2b AHFIRM trial. We look forward to
releasing additional clinical data on larsucosterol and potentially
bringing this therapy to patients as soon as possible."
The BTD is supported by clinical evidence from the Phase
2b AHFIRM trial, a double-blind,
placebo-controlled, international, multi-center study, which
evaluated the safety and efficacy of larsucosterol as a treatment
for patients with severe AH. Topline data from the study were
announced in 2023, and further details will be shared in a
late-breaking oral presentation at the European Association for the
Study of the Liver (EASL) Congress 2024 on June 8, 2024 in Milan,
Italy.
BTD is designed to expedite the development and review of
therapies intended to treat a serious or life-threatening condition
and whose preliminary clinical evidence indicates that the drug may
demonstrate substantial improvement on one or more clinically
significant endpoints over existing available therapies. BTD
provides therapeutics with all the benefits from a Fast Track
designation, such as early and frequent communication with the FDA,
eligibility for rolling review and other actions to expedite
review, in addition to intensive guidance and organizational
commitment involving senior FDA managers. BTD does not change the
standards for product approval but may expedite the process.
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 consisted 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. Topline data from AHFIRM were
announced in November 2023. 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 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 charges for a liver transplant
exceed $875,000, and patients require lifelong
immunosuppressive therapy to prevent organ rejection.
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.,
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 and cancer. Larsucosterol, DURECT's lead drug
candidate, binds to and inhibits the activity of DNA
methyltransferases (DNMTs), epigenetic enzymes that are elevated
and associated with hypermethylation found in alcohol-associated
hepatitis (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; metabolic
dysfunction-associated steatohepatitis (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:
the potential benefits of Breakthrough Therapy designation, and the
potential uses and benefits of laruscosterol in 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 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; risks that Innocoll
may not commercialize POSIMIR successfully; and risks related to
the sufficiency of our cash resources, our anticipated capital
requirements, our need or desire for additional financing, our
ability to continue to meet the minimum bid price for continued
listing on Nasdaq, our ability to obtain capital to fund our
operations and expenses, 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
March 31, 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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