- The Phase 2a trial for the treatment of NASH met its primary
efficacy endpoint; PXL770-treated patients achieved statistically
significant improvement in the relative decrease in liver fat mass
measured by magnetic resonance imaging-estimated proton density fat
fraction (MRI-PDFF) at 12-weeks with a greater response in patients
with type 2 diabetes1
- Key secondary measures in PXL770-treated patients included
statistically significant observed improvements in liver enzymes -
alanine transaminase (ALT) and hemoglobin A1c (HbA1c)
- PXL770 was observed to be safe and well tolerated; profile
supports further evaluation for combination use
- First human clinical assessment of a direct AMPK activator;
results support potential for development in NASH including key
high-risk subgroups (patients with type 2 diabetes) and utility of
AMPK activation in other chronic and rare metabolic
diseases
- Conference call in English scheduled today for 12:00 pm EDT
(New York time) / 6 pm CEST (Paris time)
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 positive top-line results
for STAMP-NAFLD, the PXL770 Phase 2a trial. The Phase 2a trial was
a 12-week, randomized, parallel group study, in 120 presumed NASH
patients with or without diabetes. 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 a range of other
chronic and rare metabolic diseases.
“The underlying pathophysiological drivers of nonalcoholic fatty
liver disease (NAFLD) and NASH are highly complex and support the
need for development of novel therapies acting on different targets
that can address a variety of key disease drivers,” said Vlad
Ratziu, MD, PhD, Professor of Hepatology, Sorbonne University and
Pitié-Salpêtrière Hospital. “AMPK activation is a differentiated
approach for NASH and these results demonstrate that it could have
a beneficial role in controlling key pathways that lead to liver
injury. By also directly targeting inflammation and fibrogenesis,
as demonstrated in preclinical models including human cells, PXL770
has the potential to independently impact multiple disease
components. As an oral agent, PXL770 also has the potential to be
used in combination with other agents, which could provide for
broad treatment of this disease.”
Summary of STAMP-NAFLD PXL770 Phase 2a Study Results
STAMP-NAFLD was a 12-week randomized, placebo-controlled,
parallel group trial in 120 presumed NASH patients, with or without
diabetes, which evaluated three dosing regimens of PXL770 versus
placebo. Primary enrollment criteria were evidence of hepatic
steatosis (NAFLD) based on a controlled attenuation parameter (CAP)
score of >300 db/m measured by MRI-PDFF. Patients were
randomized into four groups: PXL770 at 250 mg once-daily (QD); 250
mg twice-daily (BID); 500 mg once-daily (QD) versus patients who
received placebo.
The Phase 2a trial met its primary efficacy endpoint; PXL770 was
observed to produce a statistically significant mean relative
decrease of 18% in liver fat mass from baseline at 12-weeks in the
500 mg QD dose group as measured by MRI-PDFF (p=0.0036 vs. -0.7%
change in placebo). A greater proportion of patients who received
PXL770 also achieved a >30%
relative reduction in liver fat content compared to placebo;
greater liver fat content reduction (up to -85%) was also observed
in more responsive patients. Although mean baseline ALT values
(37-41 U/L) were near the upper range of normal, a statistically
significant reduction in mean ALT was also observed in the 500 mg
dose group.
In patients with type 2 diabetes (41-47% of each group), PXL770
treatment resulted in a greater mean relative reduction in liver
fat content (-27% at 500 mg QD; p=0.004 versus baseline). The
effects of PXL770 in this key subpopulation will be further
evaluated within each treatment group. Despite nearly normal mean
baseline HbA1c values (6.03-6.30%) across all groups (patients with
and without diabetes), a significant reduction in mean HbA1c was
also observed. A similar trend was also observed on fasting plasma
glucose.
PXL770 was observed to be generally safe and well tolerated. The
number of patients with treatment-emergent adverse events in each
group were similar to placebo and these events were mainly
mild-to-moderate. The safety results from the Phase 2a trial are
consistent with the PXL770 PK/PD trial and Phase 1 program.
Placebo
PXL770
250 mg QD
PXL770
250 mg BID
PXL770
500 mg QD
Patients
31
30
30
29
Relative % change in liver fat
content (per protocol)
-0.7
-2.3
-13.9*
-18.0*
Relative % change in liver fat
content (patients with diabetes)
-6.0
+1.2
-16.7
-27.2*
% patients with >30% relative reduction in liver fat
content
6.5
13.3
13.3
27.6∆
Absolute reduction in ALT
+1.0
0.0
+0.3
-6.3*
Absolute change in HbA1c (%)
+0.05
-0.08
-0.18
-0.24*
*statistically significant vs.
baseline (p < 0.05); ∆ p=0.051
“Along with previous data from our PK/PD trial where AMPK target
engagement (suppression of de novo lipogenesis) and insulin
sensitization were observed, the Phase 2a results are encouraging
and further characterize this novel molecule and mechanism. Looking
at the aggregate picture of preclinical and clinical results
obtained to-date as well as published literature in the field, we
believe that PXL770 has the potential to improve the underlying
root causes of the disease, such as insulin resistance,
dysregulation of lipid and glucose metabolism and inflammation,”
commented Pascale Fouqueray, MD, PhD, Executive Vice President,
Clinical Development and Regulatory Affairs at Poxel. “These
results support continued advancement of PXL770, which could
include longer-term assessment of important histological endpoints
such as inflammation and fibrosis and exploring subpopulations for
further differentiation.”
“AMPK is a compelling pharmaceutical target. In addition to the
potential to further pursue PXL770 in NASH, clinical evidence of
target engagement - including effects on glycemia - suggest that
PXL770 and AMPK activation could provide utility to treat a broader
range of other metabolic diseases, such as diabetic nephropathy and
certain rare diseases,” said David E. Moller, MD, Executive Vice
President and Chief Scientific Officer of Poxel. “We are currently
evaluating our library of AMPK targeted molecules, which could have
the potential to expand our pipeline into programs for other
chronic and rare metabolic diseases, and we look forward to
publishing additional data supporting PXL770 and our AMPK platform
later this year.”
The Phase 2a results will be submitted for presentation at an
upcoming scientific meeting.
In addition to Poxel’s development program for PXL770, the
Company announced on September 2, 2020, initiation of DESTINY 1
(Deuterium-stabilized R-pioglitazone [PXL065] Efficacy and Safety
Trial In NASH), the single dose-ranging Phase 2 trial of PXL065 for
the treatment of NASH. PXL065 is a novel, proprietary
deuterium-stabilized R-stereoisomer of pioglitazone.
DESTINY 1 is a Phase 2 36-week, randomized, dose-ranging,
double-blind, placebo-controlled, parallel group study that will
assess efficacy and safety of PXL065 in approximately 120
noncirrhotic biopsy-proven NASH patients across multiple clinical
sites in the US. The primary endpoint of the study will measure the
relative change in the percentage of liver fat content based on
magnetic resonance imaging-estimated proton density fat fraction
(MRI-PDFF). The study will also assess the effects of PXL065 on
liver histology and other metabolic and non-metabolic biomarkers.
Results from the Phase 2 study are anticipated in the first half of
2022.
Conference Call Information
Poxel will host a conference call to discuss the results later
today. To access the call, please use the dial-in numbers below or
click this link or refer to Poxel’s website.
US: +1 (646) 722-4916 UK: +44 20 7194 3759 France: +33 1 72 72
74 03 PIN: 16970470#
Replay: US: +1 (646) 722-4969 UK: +44 20 3364 5147 France: +33 1
70 71 01 60 Access code: 418952943#
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. Poxel also established a partnership with Roivant
Sciences for Imeglimin’s development and commercialization in
countries outside of the partnership with Sumitomo Dainippon
Pharma, including the U.S. and Europe. PXL770, a
first-in-class direct adenosine monophosphate-activated protein
kinase (AMPK) activator, is in a Phase 2a proof-of-concept program
for the treatment of NASH. PXL770 could also have the potential to
treat additional metabolic diseases. PXL065
(deuterium-stabilized R-pioglitazone), a MPC inhibitor, is in a
single 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% (Younossi ZM et al, Hepatology 64, 73–84, 2016)
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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
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