The New England Journal of Medicine publishes the results of the
NATIVE Phase IIb clinical trial with lanifibranor in NASH
- In the Phase IIb NATIVE, lanifibranor met both the primary and
key secondary endpoints, including NASH resolution with no
worsening of fibrosis and improvement of liver fibrosis with no
worsening of NASH
- NATIVE was the first clinical trial demonstrating an effect on
the composite histology endpoint of NASH resolution and improvement
of fibrosis
- NATiV31, a pivotal phase III trial of lanifibranor in NASH is
currently ongoing with first clinical trial sites initiated and
patients screened in the United States and if topline results,
expected H2 2024, are positive, intent is to seek U.S. accelerated
approval and EU conditional approval
Daix (France), Long Island City (New
York, United States), October 20, 2021 – Inventiva
(Euronext Paris and Nasdaq: IVA), a clinical-stage
biopharmaceutical company focused on the development of oral small
molecule therapies for the treatment of non-alcoholic
steatohepatitis (NASH), mucopolysaccharidoses (MPS) and other
diseases with significant unmet medical needs, today announced the
publication of the results from its NATIVE (NAsh Trial to Validate
IVA337 Efficacy) Phase IIb clinical trial evaluating lanifibranor
for the treatment of NASH in the prestigious, peer-reviewed medical
journal The New England Journal of Medicine (NEJM).
In the 24-week clinical trial, lanifibranor, an
orally-available small molecule and the only pan-PPAR agonist
currently in clinical development for the treatment of NASH, at
1200mg/day met the primary endpoint with a statistically
significant reduction of the Steatosis Activity Fibrosis score
(SAF), which combines assessments of hepatocellular inflammation
and ballooning, with no worsening of fibrosis in the Intention To
Treat (ITT2) and the Per Protocol populations (PP3).
Lanifibranor also met key secondary endpoints,
including NASH resolution with no worsening of fibrosis4 and
improvement of liver fibrosis with no worsening of NASH5 in both
ITT and PP populations, as well as the composite endpoint of NASH
resolution and improvement of liver fibrosis. With these latter
results, lanifibranor is the first orally available drug candidate
to achieve statistically significant results on the two U.S. Food
and Drug Administration (FDA) and European Medicine Agency (EMA)
primary endpoints relevant for seeking U.S. accelerated approval
and EU conditional approval during Phase III clinical
development.
The results of NATIVE were reported in June 2020
in accordance with the study protocol and Statistical Analysis Plan
design using a single imputation method of missing data, a
conservative method that consider missing end-of-study biopsy data
as non-responders. The data presented in The New England Journal of
Medicine showed additional analyses presented in accordance with
the journal requirements using a multiple imputation method of
missing end-of-study biopsy data.
The different statistical methods lead to
similar results as shown in the table below, confirming the
robustness of NATIVE results.
|
Primary and main secondary
endpointsIntention to Treat Population
(ITT) |
Single Imputation Method |
Multiple Imputation Method |
Placebo(N = 81) |
Lanifibranor |
Placebo(N = 81) |
Lanifibranor |
800mg(N = 83) |
1200mg(N = 83) |
800mg(N = 83) |
1200mg(N = 83) |
Primaryendpoint |
Decrease of ≥2 points of SAF activity score(1) |
27% |
41% |
49% |
33% |
48% |
55% |
Risk Ratio [95%Cl](5) |
|
1.52[0.98-2.12] P=0.061 |
1.82[1.24-2.40]P=0.004 |
|
1.45[1.00-2.10] P=0.073 |
1.69[1.22-2.34] P=0.007 |
Secondary endpoints |
Resolution of NASH and no worsening of fibrosis (2) |
19% |
33% |
45% |
22% |
39% |
49% |
Risk Ratio [95%Cl] (5)(6) |
|
1.75[1.02-2.68]P=0.043 |
2.41[1.53-3.35]P<0.001 |
|
1.70[1.07-2.71]P=0.039 |
2.20[1.49-3.26]P<0.001 |
Improvement of fibrosis by at least one stage and no worsening of
NASH (3) |
24% |
28% |
42% |
29% |
34% |
48% |
Risk Ratio [95%Cl] (5)(6) |
|
1.18[0.68-1.86]P=0.530 |
1.80[1.16-2.51]P=0.011 |
|
1.15[0.72-1.85] P=0.561 |
1.68[1.15-2.46]P=0.017 |
Resolution of NASH and improvement of fibrosis (4) |
7% |
21% |
31% |
9% |
25% |
35% |
|
Risk Ratio [95%Cl] (5)(6) |
|
2.71[1.16-5.40]P=0.017 |
4.25[2.02-7.37]P<0.001 |
|
2.57[1.2-5.51] P=0.018 |
3.95[2.03-7.66]P<0.001 |
(1). Response is defined as a decrease from
baseline to week 24 of at least 2 points of the SAF Activity score
(SAF-A) with no worsening of the CRN Fibrosis score (CRN-F). No
worsening means that score remains stable or decreases.(2).
Resolution of NASH with no worsening of fibrosis at week 24: CRN-I
= 0 or 1 (CRN-Inflammation), CRN-B = 0 (CRN-Ballooning) and no
worsening of CRN-F from baseline. (3). Improvement of liver
fibrosis ≥ 1 stage and no worsening of NASH at week 24: Improvement
of CRN-F ≥ 1 stage and no increase of CRN-S, CRN-I or CRN-B.(4).
Resolution of NASH and improvement of fibrosis at week 24: CRN-I =
0 or 1, CRN-B = 0 and an improvement of CRN-F ≥ 1 stage.(5). Risk
ratio was calculated using the Cochran–Mantel–Haenszel method
stratified by diabetic status at baseline, and can be interpreted
as the ratio of % responders in lanifibranor to % responders in
placebo.
(6). As per recommendations of the New England
Journal of Medicine, p values were not included on secondary
endpoints and will not appear in the publication.
Throughout the Company’s NATIVE Phase IIb
clinical trial, lanifibranor also showed an overall favorable
tolerability profile, consistent with observations from previous
clinical studies. The drop-out rates for adverse events were
3.6% in 1200mg, 4.8% in 800mg, and 3.7% in placebo, with the
vast majority being mild or moderate in intensity. The rate of
severe treatment-emergent adverse events (TEAE) was similar in the
three arms (<4%) and two serious TEAEs were assessed as
drug-related (mild heart failure; urticaria), both occurring in the
placebo group.
The Native phase IIb results contributed in
obtaining FDA Breakthrough Therapy designation in NASH in 2020 and
allowed Inventiva to start a pivotal phase III trial which is
currently ongoing following the activation of first clinical sites
and start of patient screening in the United States in September
2021.. Topline results of this study are expected H2 2024 and, if
positive, should allow us to seek U.S. accelerated approval and EU
conditional approval.
Pierre Broqua, Chief Scientist Officer
and cofounder of Inventiva, commented:
“We are delighted to see the results of our NATIVE Phase IIb
clinical trial in NASH published in the renowned and influential
The New England Journal of Medicine, which reflects the clinical
significance and scientific rigor of our lanifibranor development
program. Backed by these strong Phase IIb results and
following the recent initiation of the Phase III clinical trial, we
are convinced that lanifibranor, with its unique characteristics as
a pan-PPAR agonist, is ideally positioned in the NASH field and we
now look forward to advancing with its pivotal development
phase.”
Prof. Sven Francque, M.D., Ph.D., Antwerp University
Hospital and co-principal investigator of the Phase IIb NATIVE
clinical trial, said: “The publication of the results of
the Phase IIb NATIVE in The New England Journal of Medicine is an
important scientific accomplishment and represents a milestone for
the patients who have committed to this trial and those waiting for
a treatment. The Inventiva team and all the investigators,
including myself, are deeply grateful for all the patients who have
participated to NATIVE and the ones who will be participating in
NATiV3. This publication is a major contribution to the field of
NASH.”
Prof. Manal Abdelmalek, M.D., M.P.H.,
Duke University and co-principal investigator of the Phase IIb
NATIVE clinical trial, added: “It is
important when considering treatment strategy to have a therapeutic
available that will target not only NASH but also fibrosis, the
primary predictor of mortality in patients with NASH. NATIVE was
the first phase IIb to meet the composite histology endpoint of
NASH resolution and fibrosis improvement, achieving both FDA and
EMA regulatory endpoints. While a modest increase in body weight
was observed during the trial, patients receiving
lanifibranor were metabolically healthy and had better lipids
and glycemic profiles which are key for cardiovascular risk
reduction in patients at increased risk of cardiovascular disease .
The Phase IIb data certainly give us great optimism and enthusiasm
for NATiV3, the phase III clinical trial.”
Jean-Louis Junien, Chairman of Inventiva’s Scientific
Advisory Board, commented: “This article translates the
expertise and deep understanding of the Inventiva team of the
mechanism of actions of nuclear receptors, and more specifically of
PPARs, which associated with their strong experience in biology,
chemistry and pharmacology has allowed Inventiva to develop
lanifibranor.”
Publication details
Publication title: |
“A Randomized
Controlled Trial of the panPPAR agonist lanifibranor in NASH” |
Date of
publication: |
October 21,
2021 |
Authors: |
Sven M. Francque, Pierre Bedossa, Vlad Ratziu, Quentin M. Anstee,
Elisabetta Bugianesi, Arun J. Sanyal, Rohit Loomba, Stephen A.
Harrison, Rozalina Balabanska, Lyudmila Mateva, Nicolas Lanthier,
Naim Alkhouri, Christophe Moreno, Jörn M. Schattenberg, Diana
Stefanova-Petrova, Luisa Vonghia, Régine Rouzier, Maeva Guillaume,
Alexander Hodge, Manuel Romero-Gómez, Philippe Huot-Marchand,
Martine Baudin, Marie-Paule Richard, Jean-Louis Abitbol, Pierre
Broqua, Jean-Louis Junien, Manal F. Abdelmalek. |
Online version: |
http://www.nejm.org/doi/full/10.1056/NEJMoa2036205
|
Print edition: |
October 21, 2021
vol. 385 no. 17 |
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. 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 NASH.
About NASH
Nonalcoholic steatohepatitis (NASH) is a serious
liver disease characterized by excessive fat accumulation in the
liver, chronic inflammation and tissue injury (hepatitis),
resulting in progressive fibrosis that can lead to cirrhosis, and
subsequently portal hypertension, liver insufficiency and potential
liver cancer. The prevalence of NASH is rapidly increasing globally
in parallel with the growing epidemics of obesity and type 2
diabetes; correspondingly, the proportion and number of liver
transplants attributable to NASH has expand continuously in past
years. To date, there are still no drug therapies approved for the
treatment of NASH.
About the NATIVE Phase IIb
trial
The NATIVE (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 NASH. The main 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 NASH resolution. To
be considered for inclusion, patients were required to have: a
diagnosis of 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 NASH resolution, improvements in each of the steatosis,
inflammation, ballooning and fibrosis scores from baseline as
measured using the SAF score, improvements in various other
fibrosis measures, improvements in several metabolic markers,
improvements in steatosis, inflammation and ballooning as measured
using the NAS score (NAFLD activity score), and safety.
The trial randomized 247 patients with 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 development of oral small molecule therapies
for the treatment of NASH, MPS and other diseases with significant
unmet medical need.
Leveraging its expertise and experience in the
domain of compounds targeting nuclear receptors, transcription
factors and epigenetic modulation, Inventiva is currently advancing
two clinical candidates, as well as a deep pipeline of earlier
stage programs.
Lanifibranor, its lead product candidate, is
being developed for the treatment of patients with NASH, a common
and progressive chronic liver disease for which there are currently
no approved therapies. Inventiva recently announced positive
topline data from its Phase IIb clinical trial evaluating
lanifibranor for the treatment of patients with NASH and obtained
Breakthrough Therapy and Fast Track designation for lanifibranor in
the treatment of NASH.
Inventiva is also developing odiparcil, a second
clinical stage asset, for the treatment of patients with subtypes
of MPS, a group of rare genetic disorders. Inventiva announced
positive topline data from its Phase IIa clinical trial evaluating
odiparcil for the treatment of adult MPS VI patients at the end of
2019 and received FDA Fast Track designation in MPS VI for
odiparcil in October 2020.
In parallel, Inventiva is in the process of
selecting an oncology development candidate for its Hippo
signalling pathway program. Furthermore, the Company has
established a strategic collaboration with AbbVie in the area of
autoimmune diseases. AbbVie has started the clinical development of
ABBV‑157, a drug candidate for the treatment of moderate to severe
psoriasis resulting from its collaboration with Inventiva. This
collaboration enables Inventiva to receive milestone payments upon
the achievement of pre-clinical, clinical, regulatory and
commercial milestones, in addition to royalties on any approved
products resulting from the collaboration.
The Company has a scientific team of
approximately 70 people with deep expertise in the fields of
biology, medicinal and computational chemistry, pharmacokinetics
and pharmacology, as well as in clinical development. It also 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 C 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
InventivaPascaline ClercVP of Global External
Affairs media@inventivapharma.com+1 240 620 9175 |
Brunswick GroupYannick Tetzlaff / Tristan Roquet
Montegon / Aude LepreuxMedia
relationsinventiva@brunswickgroup.com+33 1 53 96 83 83 |
Westwicke,
an ICR CompanyPatricia L. Bank Investor
relationspatti.bank@westwicke.com+1 415 513 1284 |
|
|
|
Important Notice
This press release contains forward-looking
statements, forecasts and estimates with respect to Inventiva’s
clinical trials, clinical trial data releases, clinical development
plans and anticipated future activities of Inventiva. Certain of
these statements, forecasts and estimates can be recognized by the
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“may”, “will” 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, with respect to the
anticipated timeline for seeking of regulatory approvals for
candidates, or that candidates will receive the necessary
regulatory approvals. Actual 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 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,
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 clinical trials may not
support Inventiva's product candidate claims, Inventiva may
encounter substantial delays in its clinical trials or Inventiva
may fail to demonstrate safety and efficacy to the satisfaction of
applicable regulatory authorities, 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 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 business, and preclinical studies and
clinical development programs and timelines, its financial
condition and results of operations could be materially and
adversely affected by the current COVID-19 pandemic. 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, 2020 filed with the
Autorité des Marchés Financiers on March 15, 2021, the Annual
Report on Form 20-F for the year ended December 31, 2020 filed with
the Securities and Exchange Commission on March 15, 202, Amendment
No. 1 to our Annual Report on Form 20-F for the year ended December
31, 2020 filed with the Securities and Exchange Commission on March
24, 2021, as well as the full-year financial report for the year
ended December 31, 2020 for additional information in relation to
such factors, risks and uncertainties.
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.
1 For more details, please refer to:
clinicaltrial.gov/NCT048497282 ITT: includes all patients
randomized in the trial.3 PP: includes all patients with paired
biopsies and without deviation impacting efficacy assessment.4 NASH
resolution and no worsening of fibrosis defined as CRN Lobular
inflammation score equal to 0 or 1 and CRN Hepatocyte ballooning
score equal to 0 and no worsening of the CRN-Fibrosis score.5
Improvement of liver fibrosis with no worsening of NASH defined as
improvement of CRN-Fibrosis score ≥ 1 stage and no increase of
CRN-Steatosis score and no increase of CRN-Inflammation score and
no increase of CRN-Ballooning score.
- Inventiva - PR - The New England Journal of Medicine -EN-
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