Compelling efficacy signal in favor of
larsucosterol in the key secondary endpoint of mortality at 90
days. Clinically relevant reduction in 90-day mortality of
41% for 30 mg dose and 35% for 90 mg dose compared with standard of
care (SOC)
Numerical improvement in primary endpoint of
mortality or transplant at 90 days did not achieve statistical
significance
More pronounced effect in the U.S. trial
population of 232 patients, representing 76% of the trial
population, with a clinically meaningful 90-day mortality reduction
of 57% for 30 mg dose and 58% for 90 mg dose compared with
SOC
Larsucosterol was well-tolerated and both 30
mg and 90 mg dose groups had numerically fewer adverse events than
SOC
Strong rationale for advancing larsucosterol
in a Phase 3 registration trial in alcohol-associated hepatitis
with reduction in 90-day mortality as the primary endpoint
DURECT will host a conference call and webcast
at 5 p.m. ET today
CUPERTINO, Calif., Nov. 7, 2023
/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, including acute organ injury and
cancer, today announced topline results from its AHFIRM trial, a
Phase 2b randomized, double-blind, placebo-controlled
study evaluating the safety and efficacy of larsucosterol in 307
patients with severe alcohol-associated hepatitis (AH).
Topline data from AHFIRM showed:
- Both the 30 mg and 90 mg larsucosterol doses demonstrated a
compelling and clinically meaningful trend in reduction of
mortality at 90 days, the key secondary endpoint, with mortality
reductions of 41% (p=0.070) in the 30 mg arm and 35% (p=0.126) in
the 90 mg arm compared with SOC.
- The numerical improvement in the primary endpoint of mortality
or transplant at 90 days did not achieve statistical significance
for either dose of larsucosterol.
- Both doses of larsucosterol showed a more pronounced reduction
in mortality in patients enrolled in the U.S., representing 76% of
patients enrolled in the trial. The reductions in mortality at 90
days were 57% (p=0.014) for the 30 mg arm and 58% (p=0.008) for the
90 mg arm compared with SOC.
- Larsucosterol was safe and well tolerated. There were fewer
treatment-emergent adverse events (TEAEs) in the larsucosterol arms
compared with SOC.
DURECT intends to have an End of Phase 2 (EOP2) meeting with the
U.S. Food and Drug Administration (FDA) to discuss the trial
results and the Phase 3 registration trial design in the first
quarter of 2024. DURECT also intends to present the results
of AHFIRM at an upcoming medical meeting.
"The topline results from AHFIRM provide compelling evidence
that administration of larsucosterol can reduce mortality at 90
days in this devastating disease," said James E. Brown,
D.V.M., President and CEO of DURECT. "We have strong
rationale to advance larsucosterol into a Phase 3 registration
trial designed with adequate power to detect a statistically
significant result using 90-day mortality as the primary endpoint.
We look forward to meeting with the FDA to discuss next
steps. Based on the strength of the clinical data generated
to date, if approved, larsucosterol could save many patient lives.
We extend our thanks to all the patients, families, clinical
trial investigators, and staff across the multiple sites globally
who have worked with the DURECT team to bring larsucosterol to this
advanced stage."
Craig McClain, M.D., AGAF, FACG,
FAASLD, FACN, Professor of Medicine and Pharmacology &
Toxicology at University of Louisville
School of Medicine, commented, "In my practice, I treat AH patients
frequently and can personally attest to the frustration of the
hepatology community at the lack of effective treatment options for
these critically ill patients. The AHFIRM trial results represent
the most promising data set I have seen on new therapy for severe
AH with no important toxicity and a trend toward reducing
mortality."
Norman Sussman, M.D., FAASLD,
Chief Medical Officer at DURECT, added, "Patients with
alcohol-associated hepatitis are extremely ill and have a high
mortality in the three months following hospital admission. The
AHFIRM trial provides strong evidence that larsucosterol has the
potential to reduce 90-day mortality and has demonstrated an
excellent safety profile to date. We are continuing to
analyze the AHFIRM data to fully understand the results and to
inform future trials and our discussion with the FDA."
Key AHFIRM trial results:
Mortality or Liver Transplantation at 90 Days
The primary endpoint for the AHFIRM trial was the reduction in
mortality or liver transplantation at 90 days. The endpoint
was analyzed using a hierarchical assessment of patient outcomes to
calculate a win probability for each of the 30 mg and 90 mg dose of
larsucosterol compared with SOC. The results for the primary
endpoint were not statistically significant for either the 30 mg or
90 mg doses compared with SOC, though a numerical improvement was
observed.
Patient
Outcomes
|
|
|
SOC
|
Larsucosterol
30 mg
|
Larsucosterol
90 mg
|
Number of patients
randomized
|
103
|
102
|
102
|
Number of patients with
90-day outcome data
|
102
|
99
|
101
|
|
|
|
|
Deaths (%)
|
25
(24.5 %)
|
15
(15.2 %)
|
17
(16.8 %)
|
Transplants
(%)
|
4
(3.9 %)
|
6
(6.1 %)
|
9
(8.9 %)
|
Alive &
Transplant-free (%)
|
73
(71.6 %)
|
78
(78.8 %)
|
75
(74.3 %)
|
Win Probability
Analysis
|
|
|
Larsucosterol 30 mg
vs. SOC
|
|
Larsucosterol 90 mg
vs. SOC
|
|
SOC
|
30 mg
|
|
SOC
|
90 mg
|
Win Probability
%1
|
15.8 %
|
23.6 %
|
|
19.2 %
|
23.1 %
|
p-value
|
|
0.196
|
|
|
0.533
|
|
1 Win
probability was calculated based on the hierarchy of alive and
transplant-free being superior to transplant and death and
transplant being superior to death. Comparisons of the same
outcome were included in the denominator as ties.
|
Mortality at 90 Days
Mortality at 90 Days was a key secondary endpoint for the AHFIRM
trial. In this analysis, the 30 mg and 90 mg doses of
larsucosterol showed numerical trends toward a clinically
meaningful survival benefit with 90-day mortality reductions of 41%
and 35%, respectively, when compared to SOC, although these results
were not statistically significant.
Group
|
Mortality at 90
Days
|
% Reduction vs.
SOC
|
Difference vs.
SOC
|
p-value
|
Larsucosterol 30 mg
(n=102)
|
15.3 %
|
-40.7 %
|
-10.5 %
|
0.070
|
SOC (n=103)
|
25.8 %
|
|
|
|
|
|
|
|
|
Larsucosterol 90 mg
(n=102)
|
16.2 %
|
-34.9 %
|
-8.7 %
|
0.126
|
SOC (n=103)
|
24.9 %
|
|
|
|
Mortality at 90 Days (U.S. patients)
When further analyzed by geography, both the 30 mg and 90 mg
doses showed an enhanced survival benefit at 90 days with
reductions in 90-day mortality of 57% and 58%, respectively, in
patients enrolled in the U.S., which represented 76% of the total
patients enrolled.
Group
|
Mortality at 90
Days
|
% Reduction vs.
SOC
|
Difference vs.
SOC
|
p-value
|
Larsucosterol 30 mg
(n=76)
|
12.3 %
|
-56.8 %
|
-16.1 %
|
0.014
|
SOC (n=78)
|
28.5 %
|
|
|
|
|
|
|
|
|
Larsucosterol 90 mg
(n=78)
|
11.7 %
|
-58.1 %
|
-16.2 %
|
0.008
|
SOC (n=78)
|
27.9 %
|
|
|
|
Safety and Tolerability
Both the 30 mg and 90 mg doses of larsucosterol were well
tolerated. There were fewer TEAEs in the larsucosterol arms
compared with SOC.
|
SOC
|
Larsucosterol
30 mg
|
Larsucosterol
90 mg
|
Number of
TEAEs
|
721
|
545
|
567
|
Dial-In and Webcast
Information, 5pm ET Today
|
|
Toll Free:
|
1-877-407-4018
|
International:
|
1-201-689-8471
|
Conference
ID:
|
13742589
|
Call me™:
|
click here
|
Participants can use
guest dial-in numbers above to reach an operator or they can click
the Call me™ link for instant telephone access to the event
(dial-out). The Call me™ link will be made active 15 minutes
prior to the scheduled start time.
|
Webcast:
|
https://viavid.webcasts.com/starthere.jsp?ei=1642726&tp_key=3921e455c2
|
|
A replay of the webcast
will be available on the Investor section of
the DURECT website at
https://www.durect.com/investors/ after the
call.
|
About the AHFIRM trial
AHFIRM was a
Phase 2b randomized, double-blind, placebo-controlled,
international, multi-center study designed 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
comprising 307 total patients, with approximately 100 patients in
each arm: (1) SOC, which consists of placebo plus supportive 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. In order to maintain
blinding, patients in the two active arms received matching placebo
capsules if the investigator prescribed 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 SOC. The Company enrolled patients at clinical
trial sites across the U.S., EU, U.K., and Australia.
Reflecting the life-threatening nature of AH and the lack of
therapeutic options, the U.S. Food and Drug Administration (FDA)
granted larsucosterol Fast Track 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 intake of alcohol and often occurs
after a recent period of increased alcohol consumption (i.e., a
binge). AH is typically characterized by severe inflammation and
destruction of liver tissue (i.e., necrosis), 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 a total
of 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. 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 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), larsucosterol inhibits DNA methylation, which
subsequently modulates 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 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 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://twitter.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 for larsucosterol to demonstrate a reduction
in mortality or liver transplant in patients with AH and to save
lives, our plans to meet with the FDA and other regulatory agencies
to review the results of AHFIRM trial, the potential
FDA or other regulatory approval of larsucosterol for
the treatment of AH, the commercialization of POSIMIR
by Innocoll, the potential to develop
larsucosterol for AH, NASH or other indications, and the
potential benefits, if any, of our product candidates. 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 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 it for the
treatment of AH, risks that Innocoll may not
commercialize POSIMIR successfully, and risks related
to the sufficiency of our cash resources, our anticipated capital
requirements and capital expenditures, our need or desire for
additional financing, 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,
2022 and quarterly report on Form 10-Q for the quarter ended
September 30, 2023, when filed, under
the heading "Risk Factors." These reports are available on
our website www.durect.comunder
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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