- 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.
- Histology findings from paired liver biopsies showed strong
improvement in fibrosis without worsening of NASH, consistent with
dose-dependent reduction of all biomarkers related to fibrogenesis
and fibrosis risk scores; improvement seen in other NASH histology
components.
- Additional benefits on glucose control (HbA1c) and multiple
indices of insulin sensitivity.
- Validation of PXL065 hypothesis - combining efficacy on
liver and metabolic endpoints with reduced potential for
PPARγ side effects (weight gain and edema).
- Investor webcast today to further discuss data
The management team will host webcast conference calls on
Wednesday, September 21 at:
- 1:00 pm CEST, Paris time (7:00 am ET) in French
and
- 8:45 am ET, New York time (2:45 pm CEST) in
English.
A presentation will be available after the event on Poxel's
website in the Investor section.
To register for the webcast in French:
https://us02web.zoom.us/webinar/register/WN_z5Pgz18KRBqubDQ2QCjm7A
To register for the webcast in English:
https://us02web.zoom.us/webinar/register/WN_WC9_M_yvR_aKmJVcHJPXrg
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 positive histology results for DESTINY-1
(Deuterium-stabilized R-pioglitazone [PXL065] Efficacy and Safety
Trial In NASH), the dose-ranging Phase 2 trial of PXL065 for the
treatment of NASH. PXL065 is a novel, proprietary
deuterium-stabilized R-stereoisomer of pioglitazone which has
reduced PPARγ activity, but retains non-genomic
thiazolidinedione (TZD) actions.
“Pioglitazone’s positive effects in 6 independent prior trials
where NASH patients were assessed via liver biopsy propelled the
study of PXL065 in patients with NASH and fibrosis. PXL065 is
differentiated from pioglitazone based on its distinct pharmacology
and lower potential for PPARγ-mediated side effects,”
said Stephen Harrison, MD, President, Summit Clinical Research, and
principal investigator of this study. “The primary endpoint
findings observed on liver fat content reduction along with the
other positive findings observed in secondary analysis of key
histopathologic features of NASH and fibrosis are promising. When
coupled with the benefits seen in glycemic control and a very good
safety and tolerability profile, larger studies in NASH are
warranted.”
“In addition to our previously reported finding of clinically
meaningful improvements in liver fat content and circulating
biomarkers related to NASH and metabolic health, these results
address the high unmet need for fibrosis improvement that remains,
particularly for oral products, which we believe will be the
cornerstone to treatment,” said Thomas Kuhn, CEO of Poxel. “Based
on pioglitazone’s proven efficacy in NASH, PXL065 could become a
key product for the treatment of NASH, alone and in combination
with other treatment modalities. We will initiate discussions to
pursue a potential pivotal program in NASH – leveraging the FDA
505(b)(2) regulatory path and the extensive safety database of
pioglitazone as an approved medicine for Type 2 diabetes – which
would represent a potentially accelerated and de-risked development
with a high probability of success.”
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.
New top line results pertaining to liver histology and
additional parameters included:
Biopsy Endpoints
- 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.
- Worsening of fibrosis by >1
stage was observed in 9-12% of patients in PXL065 arms vs. 26% with
placebo.
- A >2 point improvement in the
NAFLD Activity Score (NAS) with no worsening of fibrosis was
observed in 50% of PXL065 treated patients at the 15 and 22.5 mg
dose levels vs. 30% with placebo.
- Across all PXL065 treatment arms (pooled data), 26% of patients
achieved NASH resolution with ≥1 stage fibrosis improvement vs. 13%
with placebo.
Changes in Liver Fat and Key Markers of
Fibrosis and Liver Injury
- The 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 (previously reported).
- Trend in least-square mean ALT decreases up to 18.4 IU/L vs.
baseline. Subjects experiencing a decrease in ALT by more than
-17U/L were numerically higher in the PXL065 groups (38% to 54%)
versus placebo (26%) (previously reported).
- Statistically significant dose-dependent decreases in PIIINP
(fibrogenesis biomarker, p=0.02 at 22.5 mg) and the NAFLD Fibrosis
Score (p=0.04 at 22.5 mg) along with favorable trends for
dose-dependent improvements in other markers of
fibrogenesis/fibrosis risk (ProC31, ELF, Fib4) were observed.
Metabolic Parameters
- A dose-dependent decrease in HbA1c (up to 0.41 %
placebo-adjusted; p=0.003 at 22.5 mg) was observed; in patients
with co-existing Type 2 diabetes, the placebo-adjusted change was
up to -0.56%. Given baseline HbA1c values indicating good glucose
control on existing Type 2 diabetes treatments (6.1-6.3% overall;
6.6-7.4% in T2D), these effects are potentially clinically
meaningful.
- Improvements in insulin levels and insulin sensitivity indices
(HOMA-IR, Adipo-IR, QUICKI) were also observed.
- Modest plasma adiponectin level increase of up to +5.26 ug/mL
(p<0.0001 vs. placebo at 22.5 mg); consistent with limited
degree of PPARγ activation and observed safety profile with reduced
potential for weight gain or peripheral edema.
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 (previously reported).
- Low incidence of edema without observed treatment or dose
relation when compared to placebo (previously reported).
- With respect to other safety measures, PXL065 was observed to
be generally safe and well tolerated; the number of patients
presenting with treatment-emergent serious adverse events (TESAEs)
were similar among all groups including placebo without dose
effect. None were treatment related (previously reported).
Pharmacokinetics
- As predicted, pharmacokinetic measurements showed
dose-proportional drug levels with the desired degree of higher
exposure to the pioglitazone R-stereoisomer and reduced exposure to
the (PPARγ active) S-stereoisomer (previously reported).
The full Phase 2 results will be submitted for presentation at
an upcoming scientific meeting.
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 demonstrated2,3.
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)4.
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,
Poxel 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) and acyl-CoA synthetase 4
(ACSL4). 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-stereoisomer5. 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 now 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
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. The Company does not endorse or is
not otherwise responsible for the content of external hyperlinks
referred to in this press release.
1 The dose-dependent decrease in Pro-C3 announced in the top
line press release on August 30, 2022 was actually a decrease in
the closely related PIIINP biomarker. 2 Cusi, et al., Ann Intern
Med. 2016, 165(5), 305-315. 3 Musso et al. Hepatology 2017; 65:
1058-1061. 4 J Hepatol. 2016, 64:1388-402; Hepatology 2018, 67:
328-357. 5 Jacques et al. Hepatol Comm 2021; 5:1412-1425.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20220920006288/en/
Contacts - Investor relations / Media
Aurélie Bozza Investor Relations & Communication Senior
Director aurelie.bozza@poxelpharma.com +33 6 99 81 08 36
Elizabeth Woo Senior Vice President, Investor Relations &
Communication elizabeth.woo@poxelpharma.com
NewCap Emmanuel Huynh or Arthur Rouillé poxel@newcap.eu +33 1 44
71 94 94
Grafico Azioni Poxel (EU:POXEL)
Storico
Da Mar 2024 a Apr 2024
Grafico Azioni Poxel (EU:POXEL)
Storico
Da Apr 2023 a Apr 2024