- PXL065 Phase 2 trial for the treatment of NASH met its
primary efficacy endpoint for liver fat content reduction at
36-weeks for all doses.
- Fibrosis improvement by >1
stage without worsening of NASH, an endpoint recognized by FDA for
approval, occurred in 31-50% patients in the PXL065 study arms vs.
17% with placebo.
- Validation of PXL065 hypothesis - combining efficacy on
liver and metabolic endpoints with reduced potential for PPARg side
effects (weight gain and edema).
Regulatory News:
POXEL SA (Euronext : POXEL – FR0012432516), clinical stage
biopharmaceutical company developing innovative treatments for
chronic serious diseases with metabolic pathophysiology, including
non-alcoholic steatohepatitis (NASH) and rare metabolic disorders,
today announced publication in Journal of Hepatology of positive
results for DESTINY-1 (Deuterium-stabilized R-pioglitazone [PXL065]
Efficacy and Safety Trial In NASH), a 36-week dose-ranging Phase 2
trial. PXL065 is a novel, proprietary deuterium-stabilized
R-stereoisomer of pioglitazone which has reduced PPARγ
activity, but retains non-genomic pioglitazone actions.
To access the online publication from Journal of Hepatology,
please use the following link: Evaluation of PXL065 –
Deuterium-Stabilized (R)-Pioglitazone in NASH Patients: a Phase 2
randomized placebo-controlled trial (DESTINY-1) - Journal of
Hepatology (journal-of-hepatology.eu)
Lead author, Stephen Harrison, MD, President, Summit Clinical
Research, and principal investigator of the study, commented:
“Publication of these new clinical findings in such a prestigious
journal is an important milestone in the field of new NASH
therapeutics. With PXL065, an attractive and differentiated
clinical profile has emerged, including reduced liver fat, fibrosis
improvements and metabolic benefits along with very good safety and
tolerability. PXL065 merits further study in a pivotal trial that
could yield an important new oral medicine for NASH with additional
potential for use in combination approaches.”
Summary of Phase 2 NASH (DESTINY-1) PXL065 Study
Results
DESTINY-1 is a Phase 2, 36-week, randomized, dose-ranging,
double-blind, placebo-controlled, parallel group study designed to
assess the efficacy and safety of PXL065 in patients with
noncirrhotic biopsy-proven NASH across multiple clinical sites in
the US. The primary endpoint of the study measured the relative
change in the percentage of liver fat content based on magnetic
resonance imaging-estimated proton density fat fraction (MRI-PDFF).
The study also assessed the effects of PXL065 on liver histology
and other metabolic and non-metabolic biomarkers.
117 subjects were randomized to one of 4 daily (QD) treatment
arms (7.5 mg, 15 mg, 22.5 mg, placebo). Analysis of histologic
changes was based on paired liver biopsies in PXL065 vs.
placebo-treated NASH patients before and after the 36-week
treatment period. This trial was not powered to detect
statistically significant changes in histology endpoints.
Key Findings
- Primary efficacy endpoint was achieved: a statistically
significant (p=0.024 to p=0.008) mean relative decrease vs. placebo
of 21% to 25% in liver fat content from baseline to 36 weeks was
observed at all PXL065 doses. 40% of patients who received PXL065
at the 22.5 mg dose achieved a >30% relative reduction in liver
fat content.
- Histology: Fibrosis improvement by >1 stage without worsening of NASH, an endpoint
recognized by FDA for approval, occurred in 31-50% patients in the
PXL065 study arms vs. 17% with placebo. Across all PXL065 treatment
arms (pooled data), 39% of patients had fibrosis improvement by ≥1
stage without worsening NASH (%) vs. 17% with placebo.
- Safety & tolerability: There was no dose-dependent increase
in body weight: a minimal least-square mean increase of 0.68 kg was
observed at the top dose of 22.5 mg vs. placebo. No increase in the
incidence of peripheral edema vs. placebo.
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; in multiple prior trials, improvements in liver
histology, including reductions in fibrosis, were demonstrated1,2.
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)3.
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. PXL065 is a new chemical entity
(NCE) where its further development will also be able to leverage
the FDA 505(b)(2) regulatory pathway.
Pioglitazone is a 1:1 mixture of two mirror-image compounds (R-
and S-stereoisomers) that interconvert in vivo. Using deuterium,
Poxel stabilized each stereoisomer and characterized their
different pharmacological properties. In in vitro studies, PXL065
has been shown to target non-genomic pathways –mitochondrial
pyruvate carrier (MPC) and acyl-CoA synthetase 4 (ACSL4) - each of
which are implicated as NASH targets. In preclinical animal models,
PXL065 exhibits the NASH efficacy associated with pioglitazone with
no significant weight gain or fluid retention, side effects which
are associated with the S-stereoisomer4. NASH Phase 2 (DESTINY 1
trial) results available to-date show statistically significant
effects of PXL065 on liver fat content, biomarkers related to liver
fibrogenesis-fibrosis risk, as well as positive effects on fibrosis
and other key parameters based on histology analysis. Relative to
published data for pioglitazone, reduced potential for weight gain
and edema was also evident. Based upon preclinical, Phase 1 and
Phase 2 results, Poxel believes that PXL065 may have a better
therapeutic profile than pioglitazone for NASH and may also have
suitable properties for further development in other indications
including adrenoleukodystrophy (ALD).
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 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. For the treatment of
NASH, PXL065 (deuterium-stabilized R-pioglitazone) met its
primary endpoint in a streamlined Phase 2 trial (DESTINY-1). In
rare diseases, development of PXL770, a first-in-class direct
adenosine monophosphate-activated protein kinase (AMPK) activator,
is focused on the treatment of adrenoleukodystrophy (ALD) and
autosomal dominant polycystic kidney disease (ADPKD).
TWYMEEG® (Imeglimin), Poxel’s first-in-class product that
targets mitochondrial dysfunction, is marketed for the treatment of
type 2 diabetes in Japan by Sumitomo Pharma and Poxel expects to
receive royalties and sales-based payments. Poxel has a strategic
partnership with Sumitomo Pharma for Imeglimin in Japan, China, and
eleven other Asian countries. 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
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thereof. Forward-looking statements are subject to inherent risks
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Company’s actual results or performance to be materially different
from the expected results or performance expressed or implied by
such forward-looking statements. The Company does not endorse or is
not otherwise responsible for the content of external hyperlinks
referred to in this press release.
________________________ 1 Cusi, et al., Ann Intern Med. 2016,
165(5), 305-315. 2 Musso et al. Hepatology 2017; 65: 1058-1061. 3 J
Hepatol. 2016, 64:1388-402; Hepatology 2018, 67: 328-357. 4 Jacques
et al. Hepatol Comm 2021; 5:1412-1425.
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Director aurelie.bozza@poxelpharma.com +33 6 99 81 08 36
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Communication elizabeth.woo@poxelpharma.com
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