- New results from the Phase 2a STAMP-NAFLD trial show
consistently greater response in high-risk patients with coexisting
type 2 diabetes (T2DM), estimated to be approximately 50% of NASH
patients1
- Clinically meaningful improvements (p<0.05) in liver fat
content, liver enzymes alanine transaminase (ALT) and aspartate
transaminase (AST), fasting glucose and hemoglobin A1c (HbA1c) were
observed in PXL770-treated patients with T2DM
- New preclinical results demonstrated PXL770 produced direct
beneficial effects on human cells which mediate fibrosis (stellate
cells) and inflammation (macrophages)
- Poxel plans to conduct a 52-week Phase 2b trial evaluating
up to two doses of PXL770 in up to 120 patients per study arm with
biopsy-proven NASH and pre-diabetes or T2DM; primary endpoint to
measure NASH resolution with no worsening of fibrosis
- Poxel to host virtual NASH investor event today from
8:30-10:00 am EST / 2:30-4:00 pm CET featuring presentations from
Kenneth Cusi, MD, Chief of the Division of Endocrinology, Diabetes
& Metabolism in the Department of Medicine at the University of
Florida and Stephen A. Harrison, MD, Director, Summit Clinical
Research and company management
POXEL SA (Euronext: POXEL - FR0012432516), a biopharmaceutical
company focused on the development of innovative treatments for
metabolic disorders, including type 2 diabetes and non-alcoholic
steatohepatitis (NASH), today announced an update on results from
the PXL770 Phase 2a STAMP-NAFLD trial in NASH. The STAMP-NAFLD
trial was a 12-week, randomized, parallel group study in 120
presumed NASH patients with or without type 2 diabetes (T2DM). The
Company additionally announced new preclinical results and plans
for a Phase 2b trial focused on patients with noncirrhotic
biopsy-proven NASH and coexisting prediabetes or T2DM. PXL770 is a
first-in-class, oral direct adenosine monophosphate-activated
protein kinase (AMPK) activator. AMPK is a master regulator of
several important metabolic pathways, including lipid metabolism,
glucose control and inflammation, and is a novel target for NASH
and additional chronic and rare metabolic diseases.
Summary of New PXL770 Phase 2a Study Results
The STAMP-NAFLD study was a 12-week, randomized, controlled
trial in 120 presumed NASH patients, with or without T2DM, which
evaluated three dosing regimens of PXL770 versus placebo. Primary
enrollment criteria were hepatic steatosis (NAFLD) based on a
controlled attenuation parameter (CAP) score of >300 db/m
measured by MRI-PDFF. In patients with T2DM (41-47% of each group),
the results observed showed treatment with PXL770 resulted in a
-27% mean relative reduction in liver fat content at 500 mg QD
(p=0.004) versus baseline. In a new analysis of the T2DM
subpopulation patients, findings included: a significant increase
in the proportion of responders (>30% reduction in liver fat); dose-responsive
and significant mean decreases in alanine transaminase (ALT) and
aspartate transaminase (AST) levels were achieved despite only
slightly elevated mean baseline ALT levels (36-47 IU/L; normal
range <41 IU/L). In the T2DM
patients, baseline fasting glucose (121-144 mg/dL) and HbA1c
(6.6-7.1%) levels were well controlled, and in this context,
significant placebo-adjusted decreases were observed in both
glycemic parameters along with improvements in commonly used
fasting indexes of insulin sensitivity (HOMA-IR and QUICKI scores).
In the T2DM subpopulation, PXL770 was generally safe and well
tolerated and was similar to the whole trial population.
Selected Clinical Parameters in
Patients with Type 2 Diabetes at 12 Weeks
Placebo
PXL770 250 mg QD
PXL770 250 mg BID
PXL770 500 mg QD
Relative % change in liver fat content
-6.1
+1.2
-16.7
-27.2**
% responders (>30% relative reduction in liver fat
content)
7.1
15.4
21.4
58.3*
Absolute reduction in ALT (IU/L)
+2.1
-2.2
-3.8
-12.8*
Absolute reduction in AST (IU/L)
-0.8
-3.7
-0.9
-10.7*
Placebo adjusted change in HbA1c (%)
-
-0.24
-0.43
-0.64*
Placebo adjusted change in fasting glucose
(mg/dL)
-
-0.3
-14.9
-21.3*
Change from baseline in HOMA-IR /
QUICKI scores
+1.2 /
-0.01
+1.0 /
-0.01
0 /
-0.004
-1.7^ /
+ 0.005^
statistically significant vs. placebo* or
baseline** (p < 0.05) ^(p = 0.08; 0.052)
“There is a sizable overlap in the NASH patient population such
that approximately 50% of NASH patients also have co-existing type
2 diabetes. PXL770 is one of the only therapies in development that
has demonstrated the potential to treat NASH with specific use in
patients with coexisting type 2 diabetes that are at higher risk
for faster disease progression and for co-morbidities, including
cardiovascular complications,” commented Pascale Fouqueray, MD,
PhD, Executive Vice President, Clinical Development and Regulatory
Affairs at Poxel. “AMPK activation has the potential to improve the
underlying root causes of NASH, such as insulin resistance, the
dysregulation of lipid and glucose metabolism and inflammation. We
believe PXL770 has the potential to be a much-needed and
differentiated therapeutic option for NASH and could be
particularly important for the high-risk population with type 2
diabetes.”
The Phase 2a results will be submitted for presentation at an
upcoming scientific meeting.
Summary of New PXL770 Preclinical Results
In recent in vitro experiments with human macrophages,
incubation with PXL770 resulted in significant suppression of
cytokine (IL-6, TNFα, MCP-1) release. In collaboration with Dr.
Gregory Steinberg (McMaster University, Ontario, Canada),
activation of human stellate cells was observed to be strongly
inhibited by incubation with PXL770. These results are consistent
with the potential for PXL770 to have direct effects leading to
reduced inflammation and fibrosis in NASH.
“We are very encouraged by the consistency of PXL770’s
preclinical results, which are beginning to translate into
meaningful clinical outcomes as observed in our Phase 2a trial,”
said David E. Moller, MD, Executive Vice President and Chief
Scientific Officer. “Interestingly, the greater response rate in
NASH-related measures observed in the type 2 diabetes subpopulation
aligns with published literature, which shows low endogenous AMPK
tone in the context of hyperglycemia and greater degrees of
metabolic dysfunction. To fully understand the benefits of AMPK,
including direct effects on inflammation and fibrosis, which were
not measured in the Phase 2a trial, histology measures will be
included in the Phase 2b trial in order to further confirm the
preclinical findings.”
Summary of Plans for PXL770 Phase 2b Trial in NASH
Based on the results of the Phase 2a trial, as well as other
results and published literature, Poxel plans to initiate a 52-week
Phase 2b trial in noncirrhotic biopsy-proven NASH patients with
coexisting prediabetes or T2DM. The trial will evaluate up to two
oral daily doses of PXL770 compared to placebo in up to 120
patients per study arm in clinical sites located in the U.S. and in
Europe. The primary endpoint of the trial will be NASH resolution
with no worsening of fibrosis assessed on histology. The Phase 2b
trial will also evaluate efficacy on other histology endpoints
(fibrosis), assessment of metabolic and non-metabolic parameters,
pharmacokinetic assessment as well as safety and tolerability. The
Phase 2b trial is expected to begin during the second half of
2021.
NASH Investor Event Information
Poxel will host a virtual NASH investor event today, December
14, 2020 from 8:30-10:00 am EST / 2:30-4:00 pm CET.
The event will feature members of the Poxel management team and
NASH key opinion leaders, Kenneth Cusi, MD, Chief of the Division
of Endocrinology, Diabetes & Metabolism in the Department of
Medicine at the University of Florida and Stephen A. Harrison, MD,
Director, Summit Clinical Research. The agenda for the event will
include:
- Detailed results from the Phase 2a STAMP-NAFLD study of PXL770
for the treatment of NASH;
- The Phase 2b plan for PXL770; and
- The status of PXL065, Poxel’s deuterium-stabilized
R-pioglitazone for NASH.
A live webcast of the event will be available on Poxel’s
website at https://www.poxelpharma.com/en_us/news-media/events
under Events. To participate by phone, please use the following
dial-in number: 1 (847) 944-7134, Confirmation Number: 50030660. A
replay of the event will be available on Poxel’s website following
the presentation.
About PXL770
PXL770 is a first-in-class direct adenosine
monophosphate-activated protein kinase (AMPK) activator. AMPK is a
central regulator of multiple metabolic pathways leading to the
control of lipid metabolism, glucose homeostasis and inflammation.
Based on its central metabolic role, targeting AMPK offers the
opportunity to pursue a wide range of indications to treat chronic
metabolic diseases, including diseases that affect the liver, such
as non-alcoholic steatohepatitis (NASH).
About NASH
Non-alcoholic steatohepatitis (NASH) is a metabolic disease with
no clear disease origin that is quickly becoming a worldwide
epidemic. It is characterized by the accumulation of fat in the
liver causing inflammation and fibrosis. The disease can be silent
for a long period of time, but once it accelerates, severe damage
and liver cirrhosis can occur, which can significantly impact liver
function and can even result in liver failure or hepatocellular
cancer. Typical risk factors for NASH include obesity, elevated
levels of blood lipids (such as cholesterol and triglycerides) and
diabetes. Currently no curative or specific therapies are
available.
About Poxel SA
Poxel is a dynamic biopharmaceutical company that uses
its extensive expertise in developing innovative drugs for
metabolic diseases, with a focus on type 2 diabetes and
non-alcoholic steatohepatitis (NASH). In its
mid-to-late-stage pipeline, the Company is currently advancing
three drug candidates as well as earlier-stage opportunities.
Imeglimin, Poxel’s first-in-class lead product, targets
mitochondrial dysfunction. Poxel has a strategic partnership with
Sumitomo Dainippon Pharma for Imeglimin in Japan, China, South
Korea, Taiwan and nine other Southeast Asian countries. A Japanese
new drug application (J-NDA) is under review by the Pharmaceuticals
and Medical Devices Agency (PMDA) to request approval for the
manufacturing and marketing of Imeglimin for the treatment of type
2 diabetes. PXL770, a first-in-class direct adenosine
monophosphate-activated protein kinase (AMPK) activator, has
successfully completed a Phase 2a proof-of-concept trial for the
treatment of NASH. The Phase 2a trial met its primary endpoint and
study objectives. PXL770 could also have the potential to treat
additional metabolic diseases. PXL065 (deuterium-stabilized
R-pioglitazone), a MPC inhibitor, is in a streamlined Phase 2 trial
for the treatment of NASH. Poxel also has additional earlier-stage
programs from its AMPK activator and deuterated TZD platforms
targeting chronic and rare metabolic diseases. The Company intends
to generate further growth through strategic partnerships and
pipeline development. Listed on Euronext Paris, Poxel is
headquartered in Lyon, France, and has subsidiaries in Boston, MA,
and Tokyo, Japan. For more information, please visit:
www.poxelpharma.com.
In the context of the COVID-19 outbreak, which was declared a
pandemic by the World Health Organization (WHO) on March 12, 2020,
the Company is regularly reviewing the impact of the outbreak on
its business.
As of the date of this press release, and based on publicly
available information, the Company has not identified the
occurrence of any material negative effect on its business due to
the COVID-19 pandemic that remains unresolved. However, the Company
anticipates that the COVID-19 pandemic could have further material
negative impact on its business operations. The worldwide impact of
COVID-19 may notably affect the Company’s internal organization and
efficiency, particularly in countries where it operates and where
confinement measures are implemented by the authorities. In
addition, COVID-19 may impact market conditions and the Company’s
ability to seek additional funding or enter into partnerships.
Particularly, delays in the supply of drug substance or drug
products, in the initiation or the timing of results of preclinical
and/or clinical trials, as well as delays linked to the
responsiveness of regulatory authorities could occur, which could
potentially have an impact on the Company’s development programs
and partnered programs. The Company will continue to actively
monitor the situation.
All statements other than statements of historical fact included
in this press release about future events are subject to (i) change
without notice and (ii) factors beyond the Company’s control. These
statements may include, without limitation, any statements preceded
by, followed by or including words such as “target,” “believe,”
“expect,” “aim,” “intend,” “may,” “anticipate,” “estimate,” “plan,”
“project,” “will,” “can have,” “likely,” “should,” “would,” “could”
and other words and terms of similar meaning or the negative
thereof. Forward-looking statements are subject to inherent risks
and uncertainties beyond the Company’s control that could cause the
Company’s actual results or performance to be materially different
from the expected results or performance expressed or implied by
such forward-looking statements.
________________________
1 Prevalence of type 2 diabetes in patients with NASH estimated
to be 47%; approximately 26% of T2DM patients have NASH; clinical
and economic burden of NASH in T2DM greater than with either
disease alone (Younossi ZM et al, Hepatology 2016, 64, 73–84; Cusi
K, Diabetes Care 2020, 43:275-79; Younossi ZM et al, Diabetes Care
2020, 43:283–89
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version on businesswire.com: https://www.businesswire.com/news/home/20201213005014/en/
Poxel SA Jonae R. Barnes Senior Vice President, Investor
Relations, Corporate Communications and Public Relations
jonae.barnes@poxelpharma.com +1 617 818 2985
Aurélie Bozza Investor Relations & Communication Director
aurelie.bozza@poxelpharma.com +33 6 99 81 08 36
Investor relations / Media - EU/US Trophic Communications
Stephanie May or Valeria Fisher may@trophic.eu or fisher@trophic.eu
+49 171 185 56 82 or +49 175 804 1816
Investor relations / Media - France NewCap Emmanuel Huynh
or Arthur Rouillé poxel@newcap.eu +33 1 44 71 94 94
Poxel (EU:POXEL)
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