CUPERTINO, Calif., May 26, 2020 /PRNewswire/ -- DURECT Corporation
(Nasdaq: DRRX) today announced positive topline results from
its Phase 1b clinical study of orally
administered DUR-928 in nonalcoholic steatohepatitis (NASH)
patients.
A total of 65 patients completed the study, in which DUR-928 was
orally administered daily for 4 weeks at 50 mg (n=23), 150 mg
(n=21), or 600 mg (300 mg BID (n=21)). Both the 50 mg and 600 mg
dose groups showed a statistically significant median reduction at
day 28 from baseline of serum alanine aminotransferase (ALT) levels
at -16% and -17%, respectively. The 600 mg dose group also showed
statistically significant median reductions at day 28 from baseline
of serum aspartate aminotransferase (AST) (-18%) and gamma-glutamyl
transferase (GGT) (-8%), and the 50 mg dose group had a
statistically significant reduction at day 28 from baseline in
liver stiffness as measured by Fibroscan (-10%).
Patients in the 50 mg or 150 mg dose groups also had
statistically significant median reduction at day 28 from baseline
of serum triglycerides (-13% in the 50 mg group) or LDL-C (-11% in
the 150mg group). Patients with elevated baseline triglycerides
(≥200 mg/dL; n=16) across all dose groups had a median reduction at
day 28 from baseline of -24% (p <0.01).
At day 28, 43% of patients in all three dose groups showed ≥ 10%
liver fat reduction from baseline as measured by magnetic
resonance imaging - proton density fat
fraction (MRI-PDFF). In this subgroup, there was a
significant reduction from baseline in median liver fat content
(-18%, -19%, and -23%, in the 50 mg, 150 mg and 600 mg groups
respectively). The reduction of liver fat content was accompanied
by a significant median reduction from baseline of serum ALT (-21%,
-19%, and -32%, in the 50 mg, 150 mg and 600 mg groups
respectively).
DUR-928 was well tolerated at all three doses evaluated. There
were no serious adverse events reported during the study.
Pharmacokinetic (PK) parameters after repeat dosing were comparable
to those after a single dose (from a prior study), indicating no
accumulation after repeat dosing. Drug exposure was dose
dependent.
Results, including biomarker data, are still being analyzed.
DURECT plans to present additional results and data analyses at a
future scientific meeting.
"The results from this trial are encouraging given the short
treatment course of 4 weeks to establish proof of concept," stated
Dr. Eric Lawitz, Texas Liver Institute, University of Texas Health San Antonio
and principal investigator of the study. "I look forward to
further development of what appears to be a well-tolerated drug
with the potential to treat NASH patients through modulation of
multiple biologic pathways."
"It is impressive to see these improvements after such a short
treatment period," stated James E.
Brown, D.V.M., President and CEO of DURECT. "Multiple
important liver enzymes, plasma lipids and imaging results moving
in the same direction is a very promising indication of DUR-928's
potential in NASH."
Topline Data Summary (Day 28 vs Baseline)
For all tables below, * Indicates p-value <0.05;
** indicates p < 0.01; *** indicates p
<0.001
Clinical
Chemistry
|
Median
|
50 mg
QD
|
150 mg
QD
|
300 mg
BID
|
ALT
|
-16%*
(n=22)
|
-10%
(n=20)
|
-17%***
(n=20)
|
AST
|
-14%
(n=22)
|
-9%
(n=20)
|
-18%**
(n=20)
|
GGT
|
-6%
(n=23)
|
-1%
(n=20)
|
-8%*
(n=21)
|
LDL-C
|
-6%
(n=22)
|
-11%*
(n=20)
|
-7%
(n=21)
|
Non-HDL-C
|
-8%
(n=23)
|
-5%
(n=20)
|
-1%
(n=21)
|
Triglycerides
|
-13%*
(n=23)
|
-3%
(n=20)
|
-2%
(n=21)
|
ALT (alanine
aminotransferase); AST (aspartate aminotransferase);
GGT (gamma-glutamyl transferase);
LDL-C ( Low-Density Lipoprotein
– Cholesterol); Non-HDL-C (Total cholesterol excluding
High-Density Lipoprotein – Cholesterol);
QD (once a day); BID
(twice a day)
|
Non-Invasive
Imaging
|
Median
|
50 mg
QD
|
150 mg
QD
|
300 mg
BID
|
MRI-PDFF
|
-7%
(n=21)
|
-7%
(n=21)
|
-4%
(n=21)
|
Fibroscan
|
-10%**
(n=22)
|
-9%
(n=20)
|
-1%
(n=21)
|
MRI-PDFF (Magnetic
Resonance Imaging - Proton Density Fat Fraction) is a
non-invasive measure of the proportion
of liver tissue which is composed of fat; FibroScan is
a specialized ultrasound machine that measures the stiffness of
liver tissue.
|
The following tables show Day 28 vs Baseline data from
patients with ≥ 10% Reduction in MRI-PDFF
Clinical
Chemistry
Patients with ≥
10% Reduction in MRI-PDFF
|
Median
|
50 mg
QD
(n=9)
|
150 mg
QD
(n=8)
|
300 mg
BID
(n=9)
|
ALT
|
-21%**
|
-19%*
|
-32%***
|
AST
|
-24%**
|
-21%
|
-39%***
|
GGT
|
-13%***
|
-16%*
|
-14%
|
LDL-C
|
-7%
|
-11%
|
-8%*
|
Non-HDL-C
|
-10%
|
-8%*
|
-12%*
|
Triglycerides
|
-9%
|
0%
|
-8%
|
ALT (alanine
aminotransferase); AST (aspartate aminotransferase);
GGT (gamma-glutamyl transferase);
LDL-C ( Low-Density Lipoprotein
– Cholesterol); Non-HDL-C (Total cholesterol excluding
High-Density Lipoprotein-Cholesterol);
QD (once a day); BID
(twice a day)
|
Non-Invasive
Imaging
Patients with ≥
10% Reduction in MRI-PDFF
|
Median
|
50 mg
QD
(n=9)
|
150 mg
QD
(n=9)
|
300 mg
BID
(n=9)
|
MRI-PDFF
|
-18%***
|
-19%***
|
-23%***
|
Fibroscan
|
-7%
|
-9%**
|
-9%
|
MRI-PDFF (Magnetic
Resonance Imaging - Proton Density Fat Fraction) is a
non-invasive measure of the proportion
of liver tissue which is composed of fat; FibroScan is
a specialized ultrasound machine that measures the stiffness of
liver tissue.
|
About the Study
The study was a randomized, open
label, multi center US study to evaluate safety, pharmacokinetics
and signals of biological activity of DUR-928 in NASH patients with
stage 1-3 fibrosis. A total of 65 patients completed the study.
DUR-928 was orally administered daily at 50 mg (n=23), 150 mg
(n=21), or 600 mg (300 mg BID (n=21)). Patients in this trial were
dosed daily for 4 weeks and followed up for an additional 4
weeks.
About DUR-928
DUR‑928 is a new chemical entity and the
first endogenous epigenetic regulator clinically tested for
difficult-to-treat liver diseases. It is the lead candidate in
DURECT's Epigenetic Regulator Program and is currently being tested
in Phase 1 and Phase 2 development. An endogenous, orally
bioavailable, small molecule, DUR-928 has been shown in preclinical
studies to play an important regulatory role in lipid homeostasis,
inflammation, and cell survival. Human applications may include
acute organ injury such as alcoholic hepatitis (AH), acute liver or
kidney injury in COVID-19 patients, and chronic metabolic diseases
such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty
liver disease (NAFLD), and other liver diseases.
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. DURECT's lead candidate, DUR-928, has
demonstrated the ability to regulate the expression of genes
involved in lipid metabolism, inflammatory responses and cell
survival. This drug candidate is currently in Phase 2 development
for the treatment of alcoholic hepatitis (AH), and Phase 1
development for the treatment of nonalcoholic steatohepatitis
(NASH). We are also working with the FDA on the design of a
proof-of-concept Phase 2 trial of DUR-928 in COVID-19 patients with
acute liver or kidney injury. DURECT's proprietary drug delivery
technologies are designed to enable new indications and enhanced
attributes for small-molecule and biologic drugs. A key product
candidate in this category is POSIMIR® (bupivacaine
extended-release solution), an investigational locally-acting,
non-opioid analgesic intended to provide up to three days of
continuous pain relief after surgery. DURECT has also entered into
an agreement with Gilead Sciences to develop and commercialize a
long-acting injectable HIV investigational product using DURECT's
SABER® technology. For more information about
DURECT, please visit www.durect.com.
DURECT Forward-Looking Statement
The statements in this press release regarding the potential for
DUR-928 to treat NASH patients and other plans for clinical
development of DUR-928, including plans to conduct a Phase 2
clinical trial of DUR-928 in COVID-19 patients, and the potential
benefits and uses of our drug candidates, including the potential
use of DUR-928 to treat acute organ injuries such as AH and
COVID-19 patients with acute liver or kidney injury, 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 future clinical
trials of DUR-928 do not confirm the results of trials conducted on
small numbers of patients, are not started when anticipated, take
longer to conduct than anticipated, do not generate similar
positive results as generated in earlier clinical or pre-clinical
trials, or do not demonstrate the safety or efficacy of DUR-928 in
a statistically significant manner, the risk that the remaining
data from the Phase 1b NASH trial
reported in this press release is not consistent with the topline
data reported here, the risk of disruptions to our business
operations resulting from the COVID-19 pandemic, the risk that
additional time and resources may be required for development,
testing and regulatory approval of DUR-928, potential adverse
effects arising from the testing or use of our drug candidates, our
potential failure to maintain our collaborative agreements with
third parties such as Gilead or consummate new collaborations 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-Q filed on May 11, 2020 under the heading "Risk
Factors."
NOTE: POSIMIR® and SABER® are trademarks of
DURECT Corporation. Other referenced trademarks belong to
their respective owners. DUR-928 and POSIMIR are
investigational drug candidates under development and have not been
approved for commercialization by the U.S. Food and Drug
Administration or other health authorities for any indication.
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SOURCE DURECT Corporation