Inventiva announces the publication in Nature Communications of
additional results from NATIVE Phase IIb clinical trial
demonstrating improvement of markers of cardiometabolic health in
patients with MASH/NASH treated with lanifibranor
- Improvements were observed for insulin resistance (insulin
levels, HOMA-IR), lipid metabolism (triglycerides, HDL-cholesterol,
apolipoproteins), control of glycemia (HbA1c, fasting glucose (FG)
levels), systemic inflammation (hs-CRP, ferritin), hepatic
steatosis and diastolic blood pressure.
- Among the patients who had prediabetes at study entry and were
treated with lanifibranor, the majority had fasting glucose levels
within the normal range at the end of treatment. No patient treated
with lanifibranor with normal glucose levels at study entry
progressed to prediabetes during treatment, unlike in the placebo
arm.
- Adiponectin levels were increased by lanifibranor while they
remained low and unchanged under placebo. Adiponectin increase was
correlated with improvement of cardiometabolic health.
- A greater proportion of patients with MASH/NASH and high
cardiovascular risk treated with either dose of lanifibranor saw
their cardiovascular risk improved to intermediate or low risk
compared to patients in the placebo arm.
- Improvements in cardiometabolic health markers were similar
regardless of the patients’ diabetes and obesity status and
regardless of weight change during treatment with
lanifibranor.
Daix (France), Long Island City (New
York, United States), May 13, 2024 – Inventiva (Euronext
Paris and Nasdaq: IVA), a clinical-stage biopharmaceutical company
focused on the development of oral small molecule therapies for the
treatment of metabolic dysfunction-associated steatohepatitis
(“MASH”), also known as non-alcoholic steatohepatitis (“NASH”), and
other diseases with significant unmet medical needs, today
announced the publication in the peer-reviewed scientific journal
Nature Communications of additional results from its NATIVE Phase
IIb clinical trial demonstrating the improvement of markers of
cardiometabolic health in patients with MASH/NASH treated with
lanifibranor.
In the NATIVE Phase IIb clinical trial which
demonstrated improvement on liver histology following a 24-week
period with lanifibranor 800mg and 1200mg daily, including NASH
resolution and fibrosis improvement, a broad panel of markers of
cardiometabolic health were also measured. Following lanifibranor
treatment, the trial demonstrated significant improvement in
patients with MASH/NASH with and without Type 2 Diabetes and with
or without obesity of markers of insulin resistance (fasting
insulin level, HOMA-IR), glycemic control (fasting glucose, HbA1c),
lipid metabolism (triglycerides, HDL-C, APO-B, APO-B/APO-A1),
adiponectin, systemic inflammation (hs-CRP, ferritin), diastolic
blood pressure and hepatic steatosis (histological grading and
ultrasound-based (Fibroscan CAPTM)) (see table below).
Importantly, lanifibranor treatment also led to
lower fasting glucose to normal levels in 71% of patients with
MASH/NASH and prediabetes treated with the 1200mg dose and 67% of
patients treated with the 800mg dose versus 11% of patients on
placebo. In addition, no patients treated with either dose of
lanifibranor with MASH/NASH and normoglycemia at baseline
progressed to prediabetes at week 24, versus 26% of patients in the
placebo arm.
Furthermore, 38% and 44% of patients with
MASH/NASH and high cardiovascular risk (based on markers of lipids
and inflammation) treated with 1200mg and 800mg of lanifibranor,
respectively, improved to intermediate or low cardiovascular risk
at week 24, and 44% and 35% of patients at intermediate risk
improved to low risk when treated with 1200mg and 800mg of
lanifibranor, respectively. However, in the placebo arm, only 26%
of patients at high cardiovascular risk improved to intermediate
risk and 13% improved from intermediate to low cardiovascular
risk.
The weight gain observed in a portion of the
patient population treated with lanifibranor was shown to be
associated with improvement of all markers of cardiometabolic
health, similarly to patients treated with lanifibranor who
maintained a stable weight throughout the study. This finding is in
contrast to the weight gain observed in patients on placebo, which
was associated with a worsening of cardiometabolic markers. These
results highlight the critical difference between the weight gain
that can be observed with lanifibranor which can be defined as
metabolically healthy and is associated with an improvement in
insulin resistance, and the weight gain observed in patients under
placebo which is metabolically unhealthy and is influenced by
lifestyle.
In addition, the increase in adiponectin levels
following treatment with 1200mg and 800mg of lanifibranor occurred
in 95% and 86% of patients, respectively, versus only in 10% of
patients in the placebo arm. The increase in adiponectin level at
week 24 was correlated with improvement of markers of insulin
resistance, glycemic control, lipid metabolism and steatosis,
as well as hs-CRP, aminotransferases and improvement in liver
histological endpoints for disease activity and fibrosis.
Michael Cooreman, M.D., Chief Medical
Officer at Inventiva, commented:
“Patients with MASH/NASH generally present with poor metabolic
health resulting to a large extent from insulin resistance,
affecting their glucose and lipid metabolism, causing systemic
inflammation and significantly increasing their risk for
cardiovascular events. It is key for these patients to target the
hepatic manifestations of the disease and also improve their
cardiometabolic health. We believe these results from the NATIVE
trial demonstrates the potential of lanifibranor to address the
broad disease biology of MASH/NASH from insulin resistance to
fibrosis. We use this opportunity to express our appreciation and
thanks to all patients, investigators and their staff for having
made this relevant clinical study possible.”
Prof. Manal Abdelmalek, M.D., M.P.H.,
Mayo Clinic and co-principal investigator of the NATIVE Phase IIb
clinical trial, added: “This
cardiometabolic dataset from the NATIVE Phase IIb clinical
trial exemplifies the need for a comprehensive and
multidisciplinary management of patients with MASH/NASH and
increases our confidence in the potential for lanifibranor as a
treatment option for patients with MASH/NASH, who typically have a
cardiometabolic profile associated with cardiovascular
disease.”
Prof. Sven Francque, M.D., Ph.D., Antwerp University
Hospital and co-principal investigator of the Phase IIb NATIVE
clinical trial, said: “This analysis of results from the
NATIVE trial on the cardiometabolic health markers adds to the body
of evidence for lanifibranor’s potential. Furthermore, these new
data shed more light on the importance of managing the
full-spectrum of MASH/NASH disease.”
Prof. Arun Sanyal, Director of the Stratvitz-Sanyal
Institute for Liver Disease and Metabolic Health and Interim Chair
of the Division of Gastroenterology, Hepatology and Nutrition,
Virginia commonwealth University, commented: “This
publication highlights the need to treat MASH/NASH more
holistically, taking into account the competing threats to life
from mainly cardiometabolic and hepatic risks. It is exciting to
note that lanifibranor, which is now in advanced Phase III clinical
development for the treatment of NASH also significantly improved
the cardiometabolic risk profile and insulin sensitivity as central
component of the disease process. These compelling data further
support the promise of lanifibranor for this patient
population.”
Summary of lanifibranor treatment versus placebo on
cardiometabolic health markers at Week 24 (n=247
patients) |
|
Adjusted mean difference versus placebo at EOT
(SE) |
|
Lani 800mg |
Lani 1200mg |
Insulin Resistance |
Fasting insulin levels (pmol/L) |
-83 (16) *** |
-79 (17) *** |
HOMA‑IR+ |
-4.0 (0.9) *** |
-4.1 (0.9) *** |
Glycemic control |
Fasting glucose (mmol/L) |
-1.02 (0.16) *** |
-0.84 (0.16) *** |
HbA1c (%) |
-0.45 (0.07) *** |
-0.49 (0.07) *** |
Lipid metabolism and apolipoprotein levels |
Tryglycerides (mmol/L) |
-0.55 (0.13) *** |
-0.50 (0.12) *** |
HDL-C (mmol/L) |
0.16 (0.03) *** |
0.10 (0.03) ** |
APO-B (mg/dL) |
-9.7 (2.9) *** |
-9.8 (2.9) *** |
APO-B/APO-A1 |
-0.08 (0.03) ** |
-0.06 (0.02) * |
APO-C3 (ug/mL) |
-18 (6) *** |
-20 (6) *** |
Systemic inflammation |
hs-CRP (mg/L) |
-2.2 (0.7) *** |
-1.5 (0.7) * |
Ferritin (µg/L) |
-84 (21) *** |
-72 (21) *** |
Liver tests |
ALT (U/L) |
-25 (5) *** |
-23 (5) *** |
AST (U/L) |
-15 (5) *** |
-12 (5) ** |
GGT (U/L) |
-48 (8) *** |
-32 (8) *** |
Blood pressure |
Diastolic blood pressure (mmHg) |
-3.9 (1.5) * |
-2.5 (1.5) |
Steatosis |
CAP™ (dB/m) |
-16 (9) * |
-23 (9) * |
*p≤0.1
**p≤0.01 ***p≤0.001 versus placebo +Patients treated with
sulphonylureas were removed from HOMA-IR related analyses.
Resulting from Mixed Model for Repeated Measures (MMRM) models
using change from baseline as endpoint, the time, treatment, the
diabetic status, the interaction (treatment*time) and the baseline
value as fixed effects, a time repeated measure within each subject
and an unstructured variance covariance matrix; no adjustment for
multiple comparisons was performed. APO=apolipoprotein, ALT=alanine
aminotransferase, AST=aspartate aminotransferase, CAP™=controlled
attenuation parameter, EOT=end of treatment, GGT=gamma glutamyl
transferase, HbA1c=hemoglobin A1c, HDL=high density lipoprotein,
HOMA IR=homeostatic model assessment of insulin resistance, hs
CRP=high-sensitivity C-reactive protein, LDL=low density
lipoprotein, SE=standard error |
Publication details
Publication title: |
“The pan-PPAR
agonist lanifibranor improves cardiometabolic health in patients
with metabolic dysfunction-associated steatohepatitis” |
Date of
publication: |
May 10, 2024 |
Authors: |
Michael P. Cooreman, Javed Butler, Robert P. Giugliano, Faiez
Zannad, Lucile Dzen, Philippe Huot-Marchand, Martine Baudin, Daniel
R. Beard, Jean-Louis Junien, Pierre Broqua, Manal F. Abdelmalek,
Sven M. Francque. |
Online
version: |
https://www.nature.com/articles/s41467-024-47919-9 |
About lanifibranor
Lanifibranor, Inventiva’s lead product
candidate, is an orally-available small molecule that acts to
induce anti-fibrotic, anti-inflammatory and beneficial vascular and
metabolic changes in the body by activating all three peroxisome
proliferator-activated receptor (“PPAR”) isoforms, which are
well-characterized nuclear receptor proteins that regulate gene
expression. Lanifibranor is a PPAR agonist that is designed to
target all three PPAR isoforms in a moderately potent manner, with
a well-balanced activation of PPARα and PPARδ, and a partial
activation of PPARγ. While there are other PPAR agonists that
target only one or two PPAR isoforms for activation, lanifibranor
is the only pan-PPAR agonist in clinical development for the
treatment of MASH/NASH. Inventiva believes that lanifibranor’s
moderate and balanced pan-PPAR binding profile contributes to the
favorable tolerability profile that has been observed in clinical
trials and pre-clinical studies to date. The FDA has granted
Breakthrough Therapy and Fast Track designation to lanifibranor for
the treatment of MASH/NASH.
About the NATIVE Phase IIb
trial
The NATIVE Phase IIb (NAsh Trial to Validate
IVA337 Efficacy) clinical trial was a 24-week randomized,
double-blind, placebo-controlled Phase IIb clinical trial
evaluating lanifibranor for the treatment of patients with
MASH/NASH. The primary purpose of the trial was to assess the
efficacy of lanifibranor in improving liver inflammation and
ballooning, the two histological markers included in the definition
of the regulatory endpoint of MASH/NASH resolution. To be
considered for inclusion, patients were required to have: a
diagnosis of MASH/NASH confirmed by liver biopsy; a cumulative
score of inflammation and ballooning (as measured using the SAF
scoring system) of three or four out of four, indicating the
presence of moderate to severe inflammation and ballooning; a
steatosis score greater than or equal to one, indicating the
presence of moderate to severe steatosis; and a fibrosis score less
than four, indicating the absence of cirrhosis. The primary
endpoint of the trial was a reduction in the combined inflammation
and ballooning score of two points compared to baseline, with no
worsening fibrosis, as measured by the SAF score. Secondary
endpoints included MASH/NASH resolution, improvements in each of
the steatosis, inflammation, ballooning and fibrosis scores from
baseline and fibrosis stage scoring, improvements in various other
fibrosis measures, improvements in several metabolic markers, and
safety. The trial randomized 247 patients with MASH/NASH in 71
sites in Australia, Canada, Europe, Mauritius and the United
States.
About Inventiva
Inventiva is a clinical-stage biopharmaceutical
company focused on the research and development of oral small
molecule therapies for the treatment of patients with MASH/NASH and
other diseases with significant unmet medical need. The Company
benefits from a strong expertise and experience in the domain of
compounds targeting nuclear receptors, transcription factors and
epigenetic modulation. Inventiva is currently advancing one
clinical candidate, has a pipeline of two preclinical programs and
continues to explore other development opportunities to add to its
pipeline.
Inventiva’s lead product candidate,
lanifibranor, is currently in a pivotal Phase III clinical trial,
NATiV3, for the treatment of adult patients with MASH/NASH, a
common and progressive chronic liver disease for which there are
currently no approved therapies.
Inventiva’s pipeline also includes odiparcil, a
drug candidate for the treatment of adult MPS VI patients. As part
of Inventiva’s decision to focus clinical efforts on the
development of lanifibranor, it suspended its clinical efforts
relating to odiparcil and is reviewing available options with
respect to its potential further development. Inventiva is also in
the process of selecting a candidate for its Hippo signaling
pathway program.
The Company has a scientific team of
approximately 90 people with deep expertise in the fields of
biology, medicinal and computational chemistry, pharmacokinetics
and pharmacology, and clinical development. It owns an extensive
library of approximately 240,000 pharmacologically relevant
molecules, approximately 60% of which are proprietary, as well as a
wholly-owned research and development facility.
Inventiva is a public company listed on
compartment B of the regulated market of Euronext Paris (ticker:
IVA, ISIN: FR0013233012) and on the Nasdaq Global Market in the
United States (ticker: IVA). www.inventivapharma.com
Contacts
Inventiva Pascaline Clerc, PhDEVP, Strategy and
Corporate Affairs media@inventivapharma.com
+1 202 499 8937 |
Brunswick GroupTristan Roquet Montegon /Aude
Lepreux /Julia CailleteauMedia
relationsinventiva@brunswickgroup.com +33 1 53 96 83
83 |
Westwicke, an ICR CompanyPatricia L. BankInvestor
relationspatti.bank@westwicke.com
+1 415 513-1284 |
|
|
|
|
|
|
Important Notice
This press release contains “forward-looking
statements” within the meaning of the safe harbor provisions of the
Private Securities Litigation Reform Act of 1995. All statements,
other than statements of historical facts, included in this press
release are forward-looking statements.
These statements include, but are not limited
to, forecasts and estimates with respect to Inventiva’s
pre-clinical programs and clinical trials, including design,
duration, timing, recruitment costs, screening and enrollment for
those trials, including the ongoing NATiV3 Phase III clinical trial
with lanifibranor in MASH/NASH, clinical trial data releases and
publications, the information, insights and impacts that may be
gathered from clinical trials, the potential therapeutic benefits,
including glycemic control (HbA1c), reduction in hepatic steatosis,
lipid metabolism (triglycerides, HDL-C, APO-B, APO-B/APO-A1),
insulin resistance (HOMA-IR), adiponectin, systemic inflammation
(hs-CRP, ferritin) and diastolic blood pressure, of Inventiva’s
product candidates, including lanifibranor, the impact of
lanifibranor on markers of cardiometabolic health and
cardiovascular risk, potential regulatory submissions, approvals
and commercialization, Inventiva’s pipeline and preclinical and
clinical development plans, the expected benefit of having received
Breakthrough Therapy Designation, including its impact on the
development and review timeline of Inventiva’s product candidates,
the potential development of and regulatory pathway for odiparcil,
and future activities, expectations, plans, growth and prospects of
Inventiva and its partners. Certain of these statements, forecasts
and estimates can be recognized by the use of words such as,
without limitation, “believes”, “anticipates”, “expects”,
“intends”, “plans”, “seeks”, “estimates”, “may”, “will”, “would”,
“could”, “might”, “should”, “designed”, “hopefully”, “target”,
“potential”, “opportunity”, “possible”, “aim”, and “continue” and
similar expressions. Such statements are not historical facts but
rather are statements of future expectations and other
forward-looking statements that are based on management's beliefs.
These statements reflect such views and assumptions prevailing as
of the date of the statements and involve known and unknown risks
and uncertainties that could cause future results, performance, or
future events to differ materially from those expressed or implied
in such statements. Actual events are difficult to predict and may
depend upon factors that are beyond Inventiva's control. There can
be no guarantees with respect to pipeline product candidates that
the clinical trial results will be available on their anticipated
timeline, that future clinical trials will be initiated as
anticipated, that product candidates will receive the necessary
regulatory approvals, or that any of the anticipated milestones by
Inventiva or its partners will be reached on their expected
timeline, or at all. Future results may turn out to be materially
different from the anticipated future results, performance or
achievements expressed or implied by such statements, forecasts and
estimates, due to a number of factors, including that Inventiva
cannot provide assurance on the impacts of the Suspected Unexpected
Serious Adverse Reaction (SUSAR) on enrollment or the ultimate
impact on the results or timing of the NATiV3 trial or regulatory
matters with respect thereto, that Inventiva is a clinical-stage
company with no approved products and no historical product
revenues, Inventiva has incurred significant losses since
inception, Inventiva has a limited operating history and has never
generated any revenue from product sales, Inventiva will require
additional capital to finance its operations, in the absence of
which, Inventiva may be required to significantly curtail, delay or
discontinue one or more of its research or development programs or
be unable to expand its operations or otherwise capitalize on its
business opportunities and may be unable to continue as a going
concern, Inventiva’s ability to obtain financing and to enter into
potential transactions, Inventiva's future success is dependent on
the successful clinical development, regulatory approval and
subsequent commercialization of current and any future product
candidates, preclinical studies or earlier clinical trials are not
necessarily predictive of future results and the results of
Inventiva's and its partners’ clinical trials may not support
Inventiva's and its partners’ product candidate claims, Inventiva's
expectations with respect to its clinical trials may prove to be
wrong and regulatory authorities may require holds and/or
amendments to Inventiva’s clinical trials, Inventiva’s expectations
with respect to the clinical development plan for lanifibranor for
the treatment of MASH/NASH may not be realized and may not support
the approval of a New Drug Application, Inventiva and its partners
may encounter substantial delays beyond expectations in their
clinical trials or fail to demonstrate safety and efficacy to the
satisfaction of applicable regulatory authorities, the ability of
Inventiva and its partners to recruit and retain patients in
clinical studies, enrollment and retention of patients in clinical
trials is an expensive and time-consuming process and could be made
more difficult or rendered impossible by multiple factors outside
Inventiva's and its partners’ control, Inventiva's product
candidates may cause adverse drug reactions or have other
properties that could delay or prevent their regulatory approval,
or limit their commercial potential, Inventiva faces substantial
competition and Inventiva’s and its partners' business, and
preclinical studies and clinical development programs and
timelines, its financial condition and results of operations could
be materially and adversely affected by geopolitical events, such
as the conflict between Russia and Ukraine and related sanctions,
impacts and potential impacts on the initiation, enrollment and
completion of Inventiva’s and its partners’ clinical trials on
anticipated timelines and the state of war between Israel and Hamas
and the related risk of a larger conflict, health epidemics, and
macroeconomic conditions, including global inflation, rising
interest rates, uncertain financial markets and disruptions in
banking systems. Given these risks and uncertainties, no
representations are made as to the accuracy or fairness of such
forward-looking statements, forecasts, and estimates. Furthermore,
forward-looking statements, forecasts and estimates only speak as
of the date of this press release. Readers are cautioned not to
place undue reliance on any of these forward-looking
statements.
Please refer to the Universal Registration
Document for the year ended December 31, 2023, filed with the
Autorité des Marchés Financiers on April 3, 2024, and the Annual
Report on Form 20-F for the year ended December 31, 2023, filed
with the Securities and Exchange Commission on April 3, 2024. Other
risks and uncertainties of which Inventiva is not currently aware
may also affect its forward-looking statements and may cause actual
results and the timing of events to differ materially from those
anticipated. All information in this press release is as of the
date of the release. Except as required by law, Inventiva has no
intention and is under no obligation to update or review the
forward-looking statements referred to above. Consequently,
Inventiva accepts no liability for any consequences arising from
the use of any of the above statements.
- Inventiva - PR - Nature Communications Cardiometabolic paper -
EN - 05 13 2024
Inventiva (TG:6IV)
過去 株価チャート
から 5 2024 まで 6 2024
Inventiva (TG:6IV)
過去 株価チャート
から 6 2023 まで 6 2024