Servier Announces Positive Topline Data from the Global Phase 3 Study of TIBSOVO(R) (ivosidenib tablets) in Combination with Azacitidine
PR90964
Servier Announces Positive Topline Data from the Global Phase 3 Study of TIBSOVO(R) (ivosidenib tablets) in Combination with Azacitidine in Patients with Previously Untreated IDH1-mutated Acute Myeloid Leukemia
PARIS and BOSTON, Aug. 2, 2021 /PRNewswire=KYODO JBN/ --
- TIBSOVO is the first targeted therapy to show improved event-free survival
and overall survival in combination with azacitidine compared to azacitidine
monotherapy.
- Safety profile consistent with previously published data in patients with
IDH1-mutated acute myeloid leukemia.
- The study recently halted further enrollment due to compelling efficacy data
for TIBSOVO.
Servier, a global pharmaceutical company, today announced the global Phase 3
double blinded placebo controlled AGILE study of TIBSOVO (ivosidenib tablets)
in combination with the chemotherapy azacitidine in adults with previously
untreated IDH1-mutated acute myeloid leukemia (AML) met its primary endpoint of
event-free survival (EFS)[1,2]. Treatment with TIBSOVO in combination with
azacitidine compared to azacitidine in combination with placebo demonstrated a
statistically significant improvement in EFS. Additionally, the trial met all
of its key secondary endpoints, including complete remission rate (CR rate),
overall survival (OS), CR and complete remission with partial hematologic
recovery rate (CRh rate) and objective response rate (ORR). The safety profile
of TIBSOVO in combination with azacitidine was consistent with previously
published data. The study recently halted further enrollment based on the
recommendation of the Independent Data Monitoring Committee (IDMC), as a
difference of clinical importance was noted between the treatment groups.
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"The results of AGILE represent a major breakthrough and will be welcome news
for patients dealing with previously untreated IDH1-mutated acute myeloid
leukemia," said Claude Bertrand, Executive Vice President, R&D, Servier Group.
"We look forward to sharing the findings from this study with the medical
community and with regulatory authorities around the world."
A full analysis of the AGILE trial will be submitted for a presentation at a
future medical congress.
"Acute myeloid leukemia has a poor prognosis, especially for newly diagnosed
patients who are not eligible for intensive chemotherapy," said Susan Pandya,
M.D., Vice President Clinical Development, Servier Pharmaceuticals. "TIBSOVO
monotherapy has been instrumental in transforming outcomes for adult patients
with newly diagnosed or relapsed refractory AML harboring an IDH1 mutation.
These promising results from the AGILE study support the added benefit of
inhibiting the mutant IDH1 enzyme in combination with standard chemotherapy in
the newly diagnosed intensive chemotherapy ineligible setting. We look forward
to presenting the full results of the AGILE trial to show how TIBSOVO in
combination with azacitidine may improve outcomes in previously untreated
patients with IDH1-mutated acute myeloid leukemia."
TIBSOVO* is currently approved in the U.S. as monotherapy for the treatment of
adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML),
and for adults with newly diagnosed IDH1-mutant AML who are greater than or
equal to 75 years old or who have comorbidities that preclude the use of
intensive induction chemotherapy. Recently, the U.S. Food and Drug
Administration (FDA) accepted Servier's supplemental New Drug Application
(sNDA) for TIBSOVO as a potential treatment for patients with previously
treated IDH1-mutated cholangiocarcinoma. The sNDA was granted Priority Review
by the FDA.
About AGILE Phase 3 Trial
The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized,
placebo-controlled clinical trial designed to evaluate the efficacy and safety
of TIBSOVO in combination with azacitidine compared to placebo in combination
with azacitidine, in newly diagnosed AML patients non eligible for intensive
chemotherapy. The study's primary endpoint is event-free survival (EFS),
defined as the time from randomization until treatment failure, relapse from
remission, or death from any cause, whichever occurs first. Treatment failure
is defined as failure to achieve complete remission (CR) by Week 24.
Other key secondary endpoints included complete remission rate (CR rate),
defined as the proportion of participants who achieve a CR; overall survival
(OS), defined as the time from date of randomization to the date of death due
to any cause; CR and complete remission with partial hematologic recovery (CRh)
rate, defined as the proportion of participants who achieve a CR or CRh; and
objective response rate (ORR), defined as the rate of CR, CR with incomplete
hematologic recovery (CRi) (including CR with incomplete platelet recovery
[CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).
About Acute Myeloid Leukemia
Acute Myeloid Leukemia (AML) is a cancer of the blood and bone marrow marked by
rapid disease progression and is the most common acute leukemia affecting
adults with approximately 20,000 new cases in the U.S., and 43,000 cases in
Europe each year[3,4]. The majority of patients with AML eventually relapse.
Relapsed or refractory AML has a poor prognosis[5]. The five-year survival rate
is approximately 27%[3]. For 6 to 10 percent of AML patients, the mutated IDH1
enzyme blocks normal blood stem cell differentiation, contributing to the
genesis of acute leukemia[6].
About Servier Pharmaceuticals
Servier Pharmaceuticals LLC is a commercial-stage company with a passion for
innovation and improving the lives of patients, their families and caregivers.
A privately held company, Servier has the unique freedom to devote its time and
energy toward putting those who require our treatment and care first, with
future growth driven by innovation in areas of unmet medical need.
As a growing leader in oncology, Servier is committed to finding solutions that
will address today's challenges. The company's oncology portfolio of innovative
medicines is designed to bring more life-saving treatments to a greater number
of patients, across the entire spectrum of disease and in a variety of tumor
types.
Servier believes co-creation is fundamental to driving innovation and is
actively building alliances, acquisitions, licensing deals and partnerships
that bring solutions and accelerate access to therapies. With our commercial
expertise, global reach, scientific expertise and commitment to clinical
excellence, Servier Pharmaceuticals is dedicated to bringing the promise of
tomorrow to the patients that we serve.
More information: www.servier.us
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About Servier Group
Servier is a global pharmaceutical group governed by a Foundation. With a
strong international presence in 150 countries and a total revenue of 4.7
billion euros in 2020, Servier employs 22,500 people worldwide. Servier is an
independent group that invests over 20% of its brand-name revenue in Research
and Development every year. To accelerate therapeutic innovation for the
benefit of patients, the Group is committed to open and collaborative
innovation with academic partners, pharmaceutical groups, and biotech
companies. It also integrates the patient's voice at the heart of its
activities.
A leader in cardiology, the ambition of the Servier Group is to become a
renowned and innovative player in oncology. Its growth is based on a sustained
commitment to cardiovascular and metabolic diseases, oncology, neuroscience and
immuno-inflammatory diseases. To promote access to healthcare for all, the
Servier Group also offers a range of quality generic drugs covering most
pathologies.
More information: www.servier.com
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Press Contacts
Servier Group (France and worldwide)
Sonia Marques
presse@servier.com
+33 (0)1 55 72 40 21 / + 33 (0)7 84 28 76 13
Servier Pharmaceuticals (U.S.)
Megan Talon
megan.talon@servier.com
+1 857-895-4334
Disclosures
This release contains general information about the Servier Group and its
entities (hereinafter "Servier and its Affiliates") and is intended for
informational purposes only. The information is thought to be reliable;
however, Servier and its Affiliates make no representation as to the
completeness of the information contained herein or otherwise provided and
accept no responsibility or liability, in contract, in tort, in negligence, or
otherwise, should the information be found to be inaccurate or incomplete in
any respect.
Servier and its Affiliates are not acting as an advisor to the recipient of
this information, and the ultimate decision to proceed with any transaction
rests solely with the recipient of this information. Therefore, prior to
entering into any proposed transaction, the recipient of this information
should determine, without reliance upon Servier or its Affiliates, the economic
risks and merits, as well as the legal, tax, and accounting characterizations
and consequences, of the transaction and that it is able to assume these risks.
This statement also contains forward-looking statements that are subject to
varying levels of uncertainty and risk. Investigational new drugs and
indications are subject to further scientific and medical review and regulatory
approval. They are not approved for use by the FDA.
Any reliance placed on this document is done entirely at the risk of the person
placing such reliance. The information contained in this document is neither an
offer to sell nor the solicitation of an offer to enter into a transaction.
The content of this document is a summary only, is not complete, and does not
include all material information about Servier and its Affiliates, including
potential conflicts of interest.
To the maximum extent permitted by applicable laws and regulations, Servier and
its Affiliates disclaim all representations, warranties, conditions and
guarantees, whether express, implied, statutory or of other kind, nor does it
accept any duty to any person, in connection with this document. Without
prejudice to the generality of the foregoing, Servier and its Affiliates do not
warrant or represent that the information or opinions contained in this
document is accurate or complete.
To the maximum extent permitted by applicable laws and regulations, Servier and
its Affiliates shall not be liable for any loss, damage or expense whatsoever,
whether direct or indirect, howsoever arising, whether in contract, tort
(including negligence), strict liability or otherwise, for direct, indirect,
incidental, consequential, punitive or special damages arising out of or in
connection with this document, including (without limitation) any course of
action taken on the basis of the same.
The estimates, strategies, and views expressed in this document are based upon
past or current data and information and are subject to change without notice.
About TIBSOVO(R) (ivosidenib tablets)
TIBSOVO(R) is indicated for the treatment of acute myeloid leukemia (AML) with
a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an
FDA-approved test in:
-- Adult patients with newly-diagnosed AML who are greater than or equal to
75 years old or who have comorbidities that preclude use of intensive
induction chemotherapy.
-- Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Patients treated with TIBSOVO have experienced symptoms of differentiation
syndrome, which can be fatal if not treated. Symptoms may include fever,
dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions,
rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or
multi-organ dysfunction. If differentiation syndrome is suspected, initiate
corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28)
of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed
or refractory AML treated with TIBSOVO experienced differentiation syndrome.
Differentiation syndrome is associated with rapid proliferation and
differentiation of myeloid cells and may be life-threatening or fatal if not
treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO
included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea,
pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis,
pericardial effusion, rash, fluid overload, tumor lysis syndrome, and
creatinine increased. Of the 7 patients with newly diagnosed AML who
experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34
patients with relapsed or refractory AML who experienced differentiation
syndrome, 27 (79%) patients recovered after treatment or after dose
interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day
and up to 3 months after TIBSOVO initiation and has been observed with or
without concomitant leukocytosis.
If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every
12 hours (or an equivalent dose of an alternative oral or IV corticosteroid)
and hemodynamic monitoring until improvement. If concomitant noninfectious
leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis,
as clinically indicated. Taper corticosteroids and hydroxyurea after resolution
of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of
differentiation syndrome may recur with premature discontinuation of
corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms
persist for more than 48 hours after initiation of corticosteroids, interrupt
TIBSOVO until signs and symptoms are no longer severe.
QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc)
prolongation and ventricular arrhythmias. One patient developed ventricular
fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known
to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones,
triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may
increase the risk of QTc interval prolongation. Conduct monitoring of
electrocardiograms (ECGs) and electrolytes. In patients with congenital long
QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in
those who are taking medications known to prolong the QTc interval, more
frequent monitoring may be necessary.
Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500
msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec.
Permanently discontinue TIBSOVO in patients who develop QTc interval
prolongation with signs or symptoms of life-threatening arrhythmia.
Guillain-Barre Syndrome: Guillain-Barre syndrome occurred in less than 1%
(2/258) of AML patients treated with TIBSOVO in the clinical study. Monitor
patients taking TIBSOVO for onset of new signs or symptoms of motor and/or
sensory neuropathy such as unilateral or bilateral weakness, sensory
alterations, paresthesias, or difficulty breathing. Permanently discontinue
TIBSOVO in patients who are diagnosed with Guillain-Barre syndrome.
ADVERSE REACTIONS
-- The most common adverse reactions including laboratory abnormalities
(greater than or equal to 20%) were hemoglobin decreased (60%), fatigue (43%),
arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis
(38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%),
dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline
phosphatase increased (30%), mucositis (28%), aspartate aminotransferase
increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged
(24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite
(22%), myalgia (21%), constipation (20%), and pyrexia (20%).
-- In patients with newly diagnosed AML, the most frequently reported Grade
greater than or equal to 3 adverse reactions (greater than or equal to 5%) were
fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged
(11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse
reactions (greater than or equal to 5%) were differentiation syndrome (18%),
electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of
posterior reversible encephalopathy syndrome (PRES).
-- In patients with relapsed or refractory AML, the most frequently reported
Grade greater than or equal to 3 adverse reactions (greater than or equal to
5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%),
dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse
reactions (greater than or equal to 5%) were differentiation syndrome (10%),
leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case
of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS
Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4
inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.
QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration
is unavoidable, monitor patients for increased risk of QTc interval
prolongation.
LACTATION
Because many drugs are excreted in human milk and because of the potential for
adverse reactions in breastfed children, advise women not to breastfeed during
treatment with TIBSOVO and for at least 1 month after the last dose.
Please see full Prescribing Information (https://c212.net/c/link/?t=0&l=en&o=3245194-1&h=1549900327&u=https%3A%2F%2Fc212.net%2Fc%2Flink%2F%3Ft%3D0%26l%3Den%26o%3D3185619-1%26h%3D1440211408%26u%3Dhttps%253A%252F%252Fwww.tibsovopro.com%252Fpdf%252Fprescribinginformation.pdf%26a%3DPrescribing%2BInformation&a=Prescribing+Information), including Boxed WARNING.
References
1. Data on file. Servier. July 30, 2021
2. ClinicalTrials.gov. Study of AG-120 (Ivosidenib) vs. Placebo in Combination
With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia
With an IDH1 Mutation (AGILE). Available at:
https://clinicaltrials.gov/ct2/show/NCT03173248 Last accessed: July 2021.
3. National Cancer Institute Surveillance, Epidemiology, and End Results
Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML).
https://seer.cancer.gov/statfacts/html/amyl.html Last accessed: July 2021.
4. American Cancer Society. Acute Myeloid Leukemia (AML).
https://www.cancer.org/content/dam/CRC/PDF/Public/8674.00.pdf. Accessed July
2021.
5. Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute
Myeloid Leukemia. Genes Cancer. 2011; 2:95-107.
6. DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions from Ivosidenib
in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 2018;378:2386-98.
* Servier has an exclusive collaboration and license agreement with CStone for
the development and commercialization of TIBSOVO (ivosidenib tablets) in
Mainland China, Taiwan, Hong Kong, Macau and Singapore.
SOURCE Servier Pharmaceuticals
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