Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today announced the withdrawal of its European Marketing
Authorization Application (MAA) for TIBSOVO® (ivosidenib tablets)
for the treatment of adult patients with relapsed or refractory
acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1
(IDH1) mutation. The decision is based on feedback from the
European Medicine Agency’s (EMA) Committee for Medicinal Products
for Human Use (CHMP) that the available clinical data from the
company’ssingle arm, uncontrolled Phase 1 study do not sufficiently
support a positive benefit-risk balance for the proposed
indication.
“We are disappointed not to be able to bring
TIBSOVO® to AML patients in the EU based on our current data in the
relapsed/refractory setting, given the tremendous need for new
targeted treatment options for this devastating disease,” said
Chris Bowden, M.D., chief medical officer at Agios. “We continue to
believe in the benefit of TIBSOVO® for patients with AML and are
advancing our two ongoing Phase 3 randomized controlled trials
evaluating TIBSOVO® combinations in newly diagnosed AML. If these
trials are positive, we anticipate pursuing approvals in these
indications in both the U.S. and EU.”
About TIBSOVO®
Clinical Development in AMLAgios is currently
enrolling two Phase 3 combination trials in newly diagnosed
AML:
- AGILE, a Phase 3 trial of TIBSOVO® in combination with
azacitidine in newly diagnosed AML patients who are not eligible
for intensive chemotherapy
- HOVON150/AMLSG29, an intergroup-sponsored Phase 3 trial
evaluating TIBSOVO® or IDHIFA® (enasidenib) in combination with
standard induction and consolidation chemotherapy in newly
diagnosed AML patients who are eligible for intensive
chemotherapy
The majority of AML patients with an IDH1
mutation are eligible for intensive therapy or non-intensive
therapy.
About TIBSOVO®
(ivosidenib)TIBSOVO® 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 ≥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-Barré Syndrome:
Guillain-Barré syndrome occurred in <1% (2/258) of 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-Barré syndrome.
ADVERSE REACTIONS
- The most common adverse reactions including laboratory
abnormalities (≥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 ≥3 adverse reactions (≥5%) were fatigue
(14%), differentiation syndrome (11%), electrocardiogram QT
prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%).
Serious adverse reactions (≥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 ≥3 adverse reactions (≥5%) were
differentiation syndrome (13%), electrocardiogram QT prolonged
(10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome
(6%). Serious adverse reactions (≥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,
including Boxed WARNING.
About AgiosAgios is focused on
discovering and developing novel investigational medicines to treat
malignant hematology, solid tumors and rare genetic diseases
through scientific leadership in the field of cellular metabolism.
In addition to an active research and discovery pipeline across
these three therapeutic areas, Agios has two approved oncology
precision medicines and multiple first-in-class investigational
therapies in clinical and/or preclinical development. For more
information, please visit the company's website at
www.agios.com.
Cautionary Note Regarding
Forward-Looking StatementsThis press release contains
forward-looking statements within the meaning of The Private
Securities Litigation Reform Act of 1995. Such forward-looking
statements include those regarding: the potential benefits of
TIBSOVO® (ivosidenib tablets); and Agios’ strategic plans and
prospects. The words “anticipate,” “believe,” “estimate,” “expect,”
“intend,” “may,” “plan,” “predict,” “project,” “would,” “could,”
“potential,” “possible,” “hope” and similar expressions are
intended to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Such
statements are subject to numerous important factors, risks and
uncertainties that may cause actual events or results to differ
materially from Agios’ current expectations and beliefs. For
example, there can be no guarantee that any product candidate Agios
or its collaborators is developing will successfully commence or
complete necessary preclinical and clinical development phases, or
that development of any of Agios’ product candidates will
successfully continue. There can be no guarantee that any positive
developments in Agios’ business will result in stock price
appreciation. Management's expectations and, therefore, any
forward-looking statements in this press release could also be
affected by risks and uncertainties relating to a number of other
important factors, including, without limitation: risks and
uncertainties related to the impact of the COVID-19 pandemic to
Agios’ business, operations, strategy, goals and anticipated
milestones, including its ongoing and planned research activities,
ability to conduct ongoing and planned clinical trials, clinical
supply of current or future drug candidates, commercial supply of
current or future approved products, and launching, marketing and
selling current or future approved products; Agios’ results of
clinical trials and preclinical studies, including subsequent
analysis of existing data and new data received from ongoing and
future studies; the content and timing of decisions made by
the U.S. FDA, the EMA or other regulatory authorities,
investigational review boards at clinical trial sites and
publication review bodies; Agios’ ability to obtain and maintain
requisite regulatory approvals and to enroll patients in its
planned clinical trials; unplanned cash requirements and
expenditures; competitive factors; Agios' ability to obtain,
maintain and enforce patent and other intellectual property
protection for any product candidates it is developing; Agios’
ability to maintain key collaborations; and general economic and
market conditions. These and other risks are described in greater
detail under the caption "Risk Factors" included in Agios’ public
filings with the Securities and Exchange Commission. Any
forward-looking statements contained in this press release speak
only as of the date hereof, and Agios expressly disclaims any
obligation to update any forward-looking statements, whether as a
result of new information, future events or otherwise, except as
required by law.###
Contacts
Investors:Holly Manning,
617-844-6630Director, Investor
RelationsHolly.Manning@agios.com
Media:Jessica Rennekamp,
857-209-3286Associate Director, Corporate
CommunicationsJessica.Rennekamp@agios.com
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