- PXL065 is a new chemical entity derived from pioglitazone,
which has shown to retain NASH efficacy without triggering
peroxisome proliferator-activated receptor (PPAR)-g-related side
effects in preclinical studies
- Phase 2 trial of 123 noncirrhotic biopsy-proven NASH
patients expected to report topline results in Q3 2022; trial
designed to identify optimal dose or doses for Phase 3 registration
trial
- Streamlined development with a single Phase 2 trial given
knowledge of pioglitazone, including data in NASH, and 505(b)(2)
regulatory pathway, which offers the opportunity for an efficient
and lower risk development program
POXEL SA (Euronext – POXEL - FR0012432516), a clinical stage
biopharmaceutical company developing innovative treatments for
chronic diseases with metabolic pathophysiology, including
non-alcoholic steatohepatitis (NASH) and rare disorders, today
announced the completion of enrollment in DESTINY-1
(Deuterium-stabilized R-pioglitazone (PXL065) Efficacy and Safety
Trial In NASH), a dose-ranging Phase 2 trial evaluating PXL065 for
the treatment of NASH. PXL065 is a novel, proprietary
deuterium-stabilized R-stereoisomer of pioglitazone. DESTINY-1
enrolled 123 noncirrhotic biopsy-proven NASH patients across
multiple clinical sites in the US in a 36-week, randomized,
dose-ranging, double-blind, placebo-controlled, parallel group
study designed to assess the efficacy and safety of PXL065. 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 Q3 2022.
“Pioglitazone – and other thiazolidinedione drugs - exert both
genomic (PPARγ) and non-genomic actions. PXL065, the
deuterium-stabilized single R-stereoisomer of pioglitazone, has
been shown to selectively mediate non-genomic effects of
pioglitazone that can ameliorate key components of NASH
pathophysiology including steatosis, inflammation and fibrosis.
This preclinical profile provides for potential benefits in NASH
but with an improved side effect profile with respect to PPARγ -
mediated body weight gain and edema,” said David E. Moller, MD, EVP
and CSO of Poxel.
"In our Phase 1 development program, we first confirmed that
PXL065 was safe and well-tolerated, and that substantially greater
relative exposure to the preferred (low PPARγ) – R-stereoisomer was
achieved. By leveraging the 505(b)(2) regulatory path and with
input from several top NASH advisors, DESTINY-1 was designed as a
streamlined approach to validate that the efficacy of PXL065 in
NASH is aligned with that established with pioglitazone. Results
from this trial should allow us to select one (or potentially two)
doses that could then be studied in a confirmatory pivotal trial,"
said Pascale Fouqueray, MD, PhD, Executive Vice President, Clinical
Development and Regulatory Affairs at Poxel.
Stephen Harrison, MD, President, Summit Clinical Research,
further commented: "Pioglitazone has a strong track record of
efficacy in NASH with more than 5 trials showing substantial
benefits on liver histology that match or exceed most contemporary
efficacy results obtained with other oral molecules. Thus, testing
the hypothesis behind DESTINY-1 is a worthy objective. As the
principal investigator of this important trial, I am very excited
to see that we will be positioned to receive results next
year."
PXL065 DESTINY-1 Trial Design
The single Phase 2 36-week trial in 123 noncirrhotic
biopsy-proven NASH patients will assess three doses of PXL065 (7.5,
15, 22.5 mg) compared to placebo. The primary endpoint of this
trial will be the relative change in the percentage of liver fat
content measured by MRI-PDFF at 36 weeks. The Phase 2 trial will
also evaluate the efficacy on histological endpoints assessed by
liver biopsy, assessment of other non-invasive tests and assessment
of body weight changes. The goal of this trial is to identify the
optimal dose or doses of PXL065 to advance into a Phase 3
registration trial for the treatment of noncirrhotic biopsy-proven
NASH patients.
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 or can even result in liver failure or liver cancer.
Typical risk factors for NASH include obesity, elevated levels of
blood lipids (such as cholesterol and triglycerides) and type 2
diabetes. Currently no curative or specific therapies are
available.
About PXL065
PXL065 is a novel, proprietary deuterium-stabilized
R-pioglitazone. Although pioglitazone is not approved by the FDA
for the treatment of NASH, it is the most extensively studied drug
for NASH and has demonstrated “resolution of NASH without worsening
of fibrosis” in a Phase 4 trial1. Pioglitazone is the only drug
recommended for biopsy-proven NASH patients by the Practice
Guidelines published by the American Association for the Study of
Liver Diseases (AASLD) and the European Association for the Study
of the Liver (EASL)2. Pioglitazone’s off-label use for NASH,
however, has been limited due to the PPARγ-related side effects,
which include weight gain, bone fractures and fluid retention.
Pioglitazone is a 1:1 mixture of two mirror-image compounds (R-
and S-stereoisomers) that interconvert in vivo. Using deuterium, we
stabilized each stereoisomer and characterized their different
pharmacological properties. In in vitro studies, PXL065 has been
shown to target non-genomic pathways including mitochondrial
pyruvate carrier (MPC). In preclinical animal models, PXL065
exhibits the anti-inflammatory and NASH activity associated with
pioglitazone with little or no weight gain or fluid retention, side
effects which are associated with the S-stereoisomer3. Based upon
preclinical and Phase 1 results to date, Poxel believes that PXL065
may have a better therapeutic profile than pioglitazone for
NASH.
About Poxel SA
Poxel is a clinical stage biopharmaceutical company developing
innovative treatments for chronic serious diseases with metabolic
pathophysiology, including non-alcoholic steatohepatitis (NASH) and
rare disorders. Poxel has clinical and earlier-stage programs from
its adenosine monophosphate-activated protein kinase (AMPK)
activator and deuterated TZD platforms targeting chronic and rare
metabolic diseases. For the treatment of NASH, PXL065
(deuterium-stabilized R-pioglitazone) is in a streamlined Phase 2
trial (DESTINY1). PXL770, a first-in-class direct AMPK activator,
has successfully completed a Phase 2a proof-of-concept trial for
the treatment of NASH, which met its objectives. For the rare
inherited metabolic disorder, adrenoleukodystrophy (ALD), the
company intends to initiate Phase 2a proof of concept studies with
PXL065 and PXL770 in patients with adrenomyeloneuropathy (AMN).
TWYMEEG® (Imeglimin), Poxel’s first-in-class lead product that
targets mitochondrial dysfunction, has been approved and launched
for the treatment of type 2 diabetes in Japan. Poxel expects to
receive sales-based payments and royalties from Sumitomo Dainippon
Pharma. Poxel has a strategic partnership with Sumitomo Dainippon
Pharma for Imeglimin in Japan, China, South Korea, Taiwan and nine
other Southeast Asian countries. 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
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 Cusi, et al., Ann Intern Med. 2016, 165(5), 305-315). 2 J
Hepatol. 2016, 64(6),1388-402; Hepatology 2018, 67, 328-357. 3
Jacques et al. Deuterium‐Stabilized (R)‐Pioglitazone (PXL065) is
responsible for pioglitazone efficacy in NASH yet exhibits little
to no PPARγ activity
Hepatol Comm 2021; 5:1412-25.
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Poxel SA Catherine David Investor Relations &
Communication Manager catherine.david@poxelpharma.com +33 7 64 57
61 78
Aurélie Bozza Investor Relations & Communication Director
aurelie.bozza@poxelpharma.com +33 6 99 81 08 36
Elizabeth Woo Senior Vice President, Investor Relations &
Communication elizabeth.woo@poxelpharma.com
Investor relations / Media - EU/US Trophic Communications
Stephanie May or Valeria Fisher poxel@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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