CUPERTINO, Calif., Nov. 12, 2019 /PRNewswire/ -- DURECT
Corporation (Nasdaq: DRRX) today announced the results from
its Phase 2a clinical trial of DUR-928 in alcoholic hepatitis (AH),
presented as a late-breaking oral presentation at The Liver
Meeting®. The study results were also selected for
inclusion in the 'Best of The Liver Meeting' summary slide
presentation in the alcohol-related liver disease category.
Today at Noon Eastern Time,
DURECT will host a Key Opinion Leader (KOL) webcast featuring a
presentation of the results delivered by one of the principal
investigators of the trial, Tarek
Hassanein, M.D. Dr. Hassanein will be available for a
question and answer session following the presentation.
Results
All patients treated with DUR-928 in
this trial survived the 28-day follow-up period and there were no
drug-related serious adverse events. Patients treated with
DUR-928 had a statistically significant reduction from baseline in
bilirubin at day 7 and 28 and MELD at day 28. Lille scores
were also statistically significantly lower than those from a
well-matched group of patients in a contemporary ongoing trial as
well as several published historical controls. 74% of all
DUR-928 treated patients and 67% of those with severe AH were
discharged from the hospital within four days of receiving a single
dose of DUR-928.
"The results of this study are remarkable and much was learned
from this Phase 2a clinical trial," stated Dr. Tarek Hassanein, a principal investigator in the
trial. "The low Lille
scores, the early reduction in bilirubin and the number of severe
AH patients who were able to be discharged after a single dose of
DUR-928 is striking and the safety profile looks very promising as
well."
Lille
Lille scores are used in clinical
practice to help determine the prognosis and response of AH
patients after seven days of treatment. The lower the
Lille score, the better the
prognosis. Patients with a Lille score below 0.45 have a six-month
survival rate of 85% compared to those with Lille scores above 0.45, with only a 25%
six-month survival rate.[1] The chart below shows the
Lille scores for individual AH
patients treated with DUR-928 plotted as a function of their
baseline MELD scores. In our study, the median Lille score for patients treated with DUR-928
was 0.10. The median Lille
score among a cohort of 15 patients treated with standard of care
at the University of Louisville
(UL) was 0.41 (shown as historical control).
The chart below shows individual patient Lille scores plotted as a function of their
baseline MELD scores.
- Our advisor, Dr. Craig McClain from the University of Louisville (UL), shared anonymized
data from his study, in which 15 AH patients with initial MELD
scores ranging from 15-30 received either supportive care alone
(n=8 moderate AH patients) or supportive care with corticosteroids
(n=7 severe AH patients). Two of these patients died by day
28.
- One patient in the DUR-928 group did not return for the day
7 visit.
- Lille scores in the DUR-928
patients were significantly lower than that of the UL patients
(p=0.01; Wilcoxon's Rank Sum Test).
As shown below, 100% of patients in the 30mg and 90mg DUR-928
dosing groups were treatment responders based on their Lille scores. 89% of the overall DUR-928
patient population were treatment responders. Patients with
severe AH, as defined by Maddrey's Discriminant Function >32 or
MELD 21-30, and baseline serum bilirubin above 8 mg/dL, had
similarly high response rates to DUR-928 treatment.
AH Patient
Category
|
n1
|
Responders
(Lille<0.45)
|
Lille
Median
(Quartile)
|
All
Patients2
30 or 90mg
DUR-9283
|
18
14
|
89%
100%
|
0.10 (0.04,
0.20)
0.05 (0.04,
0.19)
|
DF>32
(SAH)2
30 or 90mg
DUR-9283
|
15
11
|
87%
100%
|
0.19 (0.05,
0.22)
0.12 (0.05,
0.19)
|
MELD
21-302
30 or 90mg
DUR-9283
|
12
8
|
83%
100%
|
0.19 (0.11,
0.25)
0.19 (0.10,
0.19)
|
Baseline bilirubin
>8mg/dl2
30 or 90mg
DUR-9283
|
11
8
|
82%
100%
|
0.10 (0.05,
0.20)
0.10 (0.05,
0.19)
|
1 One patient did
not return for Day 7 visit; 2 Including patients
receiving 30, 90 and 150mg of DUR-928; 3
Excluding patients receiving 150mg of DUR-928.
|
|
Maddrey's
Discriminant Function (DF) is calculated using the patient's
prothrombin time and serum bilirubin level.
|
The Lille scores of patients
treated with DUR-928 in this trial were also significantly lower
than several selected published historical studies (Hepatology
2007, 45:1348-1354; Gut 2011, 60:255-260), in which patients
had similar baseline bilirubin, albumin, Creatinine, prothrombin
time and DF scores, and were treated with standard of care with or
without corticosteroids. Of course, due to the historical
nature of these studies, such comparisons should be taken
cautiously.
A sub-group analysis was conducted to compare severe AH patients
in the 30mg and 90mg dosing groups (n=8) with well-matched severe
AH patients (n=13) who received corticosteroids for 28 days in a
contemporaneous study at the University of
Louisville (UL). Patients shown below in the UL
steroid group had a mean baseline MELD of 24.46 and mean Maddrey's
DF score of 62.98. The 8 patients in the DUR-928 group had baseline
mean MELD of 24.50 and mean Maddrey's DF score of 61.25. All
patients treated with DUR-928 survived the 28-day follow up period,
while 3 patients in the UL steroid group died within the first 28
days.
The steroid group in the above graph includes the 7 severe AH
patients treated with steroids from the UL group shown in the MELD
vs Lille graph above plus an additional 6 severe AH patients
subsequently treated in the UL study.
Bilirubin
Bilirubin is formed by the breakdown
of red blood cells in the body. The level of total bilirubin
in the blood is an indication of how the liver is functioning.
In this trial, patients treated with DUR-928 had a
significant early reduction from baseline in bilirubin by day 7.
Patients with more elevated bilirubin at baseline (serum
bilirubin >8 mg/dL) had a median reduction from baseline of 25%
by day 7 and 48% by day 28.
*p<0.05 compared to baseline (Wilcoxon's Signed Rank
Test)
Model of End-Stage Liver Disease (MELD)
MELD
is another common scoring system used to assess the severity and
prognosis of AH patients. Patients with MELD scores of 11-20
are classified as having moderate AH and patients with MELD scores
of 21-30 are classified as having severe AH. As with
Lille scores, the lower the MELD
score, the better the prognosis for the AH patient. In this
study (shown in the chart below), the median reduction from
baseline in MELD among all DUR-928 treated patients was over 2
points and among those with baseline bilirubin levels >8 mg/dL
was 5 points by day 28.
*p<0.05 compared to baseline (Wilcoxon's Signed Rank
Test)
MELD is calculated based on (a) bilirubin, (b) serum
creatinine (sCr), and (c) International Normalized Ratio (INR),
which is a measure of prothrombin time.
Safety and Pharmacokinetics
DUR-928 was well
tolerated at all doses tested. There were no drug-related
serious adverse events and only three adverse events designated as
possibly related to DUR-928: one occurrence of moderate generalized
pruritus, one mild rash and one grade two alkaline phosphatase.
There were no discontinuations, early withdrawals or
termination of study drug or study participation due to adverse
events. All patients treated with DUR-928 survived through
the 28-day follow-up period. Drug exposures were dose proportional
and were not affected by the severity of the disease.
About the DUR-928 Alcoholic Hepatitis Phase 2a
Trial
The open-label, dose escalation,
multi-center study was designed to determine the safety,
pharmacokinetics and pharmacodynamics of DUR-928 in AH patients
following treatment. This included assessing liver
biochemistry, biomarkers, and prognostic scores such as the
Lille score. Final
enrollment included 19 patients with moderate and severe AH, who
were administered DUR-928 intravenously at three different doses.
Eight patients (four moderate and four severe) were dosed at
30mg, seven patients (three moderate and four severe) were dosed at
90mg and four patients (all severe) were dosed at 150mg.
After being discharged on day two, one patient did not return
for the scheduled day seven and day 28 follow-up visits; therefore
Lille, bilirubin and model of
end-stage liver disease (MELD) data reported above are based on 18
patients.
Next Steps
DURECT is planning to conduct a
double-blind, placebo-controlled, Phase 2b clinical trial evaluating DUR-928 in AH
patients beginning mid-2020. Assuming reasonable enrollment rates,
top line data from this trial would be available in 2022.
Conference Call and Webcast with Slides
Tuesday, November12 at Noon Eastern
Time/9:00 a.m. Pacific
Time
Dial-In and Webcast
Information
Tuesday, November
12 at 12 noon EST
Domestic (Free): 1-877-407-0784
Toll / International: 1-201-689-8560
Conference ID: 13696593
Webcast with slides:
http://public.viavid.com/index.php?id=137023
A replay of the webcast and data slide presentation will be
available on the Investor section of the DURECT website at
https://investors.durect.com/ after the call.
About Dr. Tarek I.
Hassanein
Dr. Hassanein is one of the
investigators of the Phase 2a AH clinical trial and is
board-certified in internal medicine, gastroenterology and
transplant hepatology. He is currently a professor of
medicine and director of outreach services for liver
transplantation at the School of Medicine, University of California San Diego (UCSD). He
has been instrumental in establishing three major liver
transplantation programs. Dr. Hassanein established the Southern
California Liver Centers in 2009 to care for patients with advanced
and complicated liver diseases, including alcoholic hepatitis,
liver cancer, HCV and cirrhosis. He is also the director of
the Southern California Research Center, medical director of UCSD
Sharp Liver Transplant Outreach Program and chief of
gastroenterology and hepatology at Sharp Coronado Hospital in
Coronado, California. Dr.
Hassanein has been the principal investigator on multiple
international trials and has authored numerous publications.
Dr. Hassanein earned his medical degree from Alexandria University in Alexandria, Egypt. He completed his
residency training at Wayne State
University in Detroit,
Michigan, and a research fellowship and a clinical
fellowship in gastroenterology, hepatology and transplantation at
the University of Pittsburgh School of
Medicine.
About Alcoholic Hepatitis (AH)
AH is an acute form of
alcoholic liver disease (ALD), associated with long-term heavy
intake of alcohol, and often occurs after a recent period of
increased alcohol consumption. AH is typically characterized
by recent onset jaundice and hepatic failure. An 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. According to the most recent data
provided by the Agency for Healthcare Research and Quality (AHRQ),
a part of the US Department of Health and Human Services (HHS),
there were over 117,000 hospitalizations for patients with
alcoholic hepatitis in 2016. From a recent publication
analyzing the mortality and costs associated with alcoholic
hepatitis, the cost per patient is estimated at over $50,000 in the first year. ALD is one of
the leading causes of liver transplants in the U.S., each of which
costs over $800,000.
About DURECT Corporation
DURECT is a
biopharmaceutical company actively developing therapeutics based on
its Epigenetic Regulator Program and proprietary drug delivery
platforms. DUR‑928, a new chemical entity in Phase 2
development, is the lead candidate in DURECT's Epigenetic Regulator
Program. 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 AH and acute kidney injury (AKI), chronic hepatic diseases
such as NASH, and inflammatory skin conditions such as psoriasis
and atopic dermatitis. DURECT's advanced oral and injectable
delivery technologies are designed to enable new indications and
enhanced attributes for small-molecule and biologic drugs.
Key product candidates in this category include POSIMIR®
(bupivacaine extended-release solution), an investigational
locally-acting, non-opioid analgesic intended to provide up to 3
days of continuous pain relief after surgery, and a long-acting
injectable SABER-based HIV investigational product being developed
with Gilead. For more information about DURECT, please visit
www.durect.com.
DURECT Forward-Looking Statement
The statements
in this press release regarding the potential benefits and uses of
DUR-928 to treat AH and about other potential uses of DUR-928 to
treat renal diseases, such as NASH and AKI, and inflammatory skin
conditions such as psoriasis and atopic dermatitis, the potential
use of POSIMIR to treat post-operative pain, and the potential
development of a long-acting injectable SABER-based HIV product
with Gilead 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 risk
of delays in clinical trials or adverse safety events from patients
administered with DUR-928, the risk that the ongoing clinical
trials of DUR-928 in NASH or psoriasis do not successfully achieve
their endpoints, the risk that placebo controlled studies of
DUR-928 required for regulatory approval will not replicate results
from open label clinical trials or trials with small numbers
of patients or historical controls, the risk that reductions in
bilirubin, Lille scores or MELD
scores do not predict efficacy of therapy for AH, the risks that
the long-acting injectable SABER-based HIV investigational product
being developed with Gilead will not succeed or that Gilead will
abandon this program, the risk that the FDA Advisory Committee will
not recommend approval of POSIMIR or that the FDA will not approve
POSIMIR, and the risk of delays and costs due to additional work or
other requirements imposed by regulatory agencies for continued
development, approval or sale of any of our product
candidates. Further information regarding these and other
risks related to DURECT is included in DURECT's Form 10-Q filed on
November 5, 2019 under the heading
"Risk Factors" and in subsequent reports that we file with the
Securities and Exchange Commission.
NOTE: POSIMIR® and SABER® are trademarks
of DURECT Corporation. Other referenced trademarks belong to
their respective owners. DUR-928 and POSIMIR are drug
candidates under development and have not been approved for
commercialization by the U.S. Food and Drug Administration or other
health authorities.
[1] Louvet A et al. Hepatology 2007; 45:
1348-54.
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