CUPERTINO, Calif., March 9, 2021 /PRNewswire/ -- DURECT
Corporation (Nasdaq: DRRX) today announced the publication of
a peer-reviewed research paper describing the binding sites and
proposed mechanism of action of its lead drug candidate, an
endogenous sulfated oxysterol and epigenetic regulator, DUR-928, in
The Journal of Lipid Research.
DUR-928 is an endogenous sulfated oxysterol that acts as an
epigenetic regulator, a compound that regulates patterns of gene
expression without modifying the DNA sequence. The publication
shows that DUR-928 (referred to in the paper as 25HC3S) binds to
and inhibits the activity of DNA methyltransferases (DNMTs),
DNMT-1, 3a and 3b, epigenetic
regulating enzymes that add methyl groups to DNA (a process called
DNA methylation). As such, by inhibiting DNMT activity, DUR-928
inhibits DNA methylation, thereby regulating the expression of
genes that modulate crucial cellular activities, including those
associated with cell death, stress response, and lipid
biosynthesis. These modulations may lead to improved cell
survival, and reduced lipid accumulation and inflammation, as has
been observed in various in vivo animal models and in results from
DURECT's completed clinical trials in alcohol-associated hepatitis
(AH) and non-alcoholic steatohepatitis (NASH).
"DNA hypermethylation, an example of epigenetic dysregulation,
has been reported to be associated with certain diseases, like AH
and NASH, a life-threatening acute liver disease characterized by
lipid accumulation, severe inflammation and liver cell death, with
an average 90-day mortality rate of 29%," said Norman Sussman, MD, FAASLD, Chief Medical
Officer of DURECT. "DUR-928 has already demonstrated promising
efficacy signals in a Phase 2a study in patients with AH and
encouraging data in a Phase 1b study
in patients with NASH. The proposed mechanism of action of DUR-928
in this publication provides a further scientific rationale for
evaluating DUR-928 as a therapeutic agent for AH and NASH."
James E. Brown, D.V.M., President
and Chief Executive Officer of DURECT, added, "We are focused on
progressing our ongoing Phase 2b
trial of DUR-928 in AH (AHFIRM), and in parallel, exploring
additional indications that could benefit from DUR-928's mechanism
of action."
In a Phase 2a clinical trial in patients with AH, 100% of
patients treated with DUR-928 survived the 28-day follow-up period
compared to a 26% historical average 28-day mortality rate. 74% of
patients treated with DUR-928 were discharged within 4 days or less
of treatment after one dose. In a Phase 1b trial, patients with NASH treated with DUR-928
experienced significant improvements in biomarkers of liver
function and liver health, including liver enzymes and serum lipid
profiles. A reduction in liver fat of more than 10% was observed in
43% of these patients.
The publication, entitled, "25-hydroxycholesterol 3-sulfate is
an endogenous ligand of DNA methyltransferases in hepatocytes" is
available online here:
https://www.jlr.org/article/S0022-2275(21)00045-6/fulltext
About DUR-928
DUR-928 is an endogenous sulfated
oxysterol and an epigenetic regulator. 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 found to be
associated with many acute (e.g. AH) or chronic diseases (e.g.
NASH). As an inhibitor of DNA methyltransferases (DNMT1, DNMT3a and
3b), DUR-928 inhibits DNA methylation
, which subsequently regulates 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
regulator, the proposed mechanism of action provides further
scientific rationale for developing DUR-928 for the treatment of
multiple acute organ injury and certain chronic diseases.
About Epigenetic Regulation
Epigenetic regulation
influences the expression of genes through the silencing or
initiation of gene activity without modifying the DNA
sequence. For instance, methylation of cytosine nucleotides in
promoter regions of DNA, facilitated by DNA
methyltransferases (DNMTs), will generally result in
downregulation of gene expression, while demethylation results in
upregulation. DNA methylation/demethylation can thus regulate the
expression of relevant genes, especially clusters of master genes
that further modulate crucial cellular activities.
About DURECT Corporation
DURECT is a
biopharmaceutical company committed to transforming the treatment
of acute organ injury and chronic liver diseases by advancing novel
and potentially lifesaving therapies based on its endogenous
epigenetic regulator program. DUR-928, the company's lead drug
candidate is in clinical development for the potential treatment of
alcohol-associated hepatitis (AH) for which FDA has granted a Fast
Track Designation. Non-alcoholic steatohepatitis (NASH) is also
being explored. In addition, POSIMIR® (bupivacaine
solution) for infiltration use, a non-opioid analgesic utilizing
the innovative SABER® platform technology, is now
FDA-approved. Full prescribing information about POSIMIR, including
the Boxed Warning, can be found at www.posimir.com. For more
information about DURECT, please visit www.durect.com and follow us
on Twitter https://twitter.com/DURECTCorp.
DURECT Forward-Looking Statement
The statements in
this press release regarding the potential for DUR-928 to treat
patients with AH, NASH, and other diseases, multiple acute organ
injury, ongoing and planned clinical trials of DUR-928, and the
commercial potential of POSIMIR are forward-looking statements
involving risks and uncertainties that can cause actual results to
differ materially from those in such forward-looking statements.
Potential risks and uncertainties include, but are not limited to,
the risks that the clinical trial of DUR-928 in AH takes longer to
conduct than anticipated due to COVID-19 or other factors, the risk
that clinical trials of DUR-928 do not confirm the results from
earlier clinical or pre-clinical trials, or do not demonstrate the
safety or efficacy or the life saving potential of DUR-928 in a
statistically significant manner, risks that we or a third-party
licensee may not commercialize POSIMIR successfully, if at all, and
risks related to our ability to obtain capital to fund operations
and expenses. Further information regarding these and other risks
is included in DURECT's Form 10-K filed on March 5, 2021 under the heading "Risk
Factors."
NOTE: POSIMIR® and SABER® are trademarks
of DURECT Corporation. Other referenced trademarks belong to
their respective owners. DUR-928 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. Full prescribing information
for POSIMIR, including its Boxed Warning, can be found at
www.posimir.com.
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SOURCE DURECT Corporation