Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today announced that the global Phase 3 ClarIDHy trial of TIBSOVO®
(ivosidenib) in previously treated cholangiocarcinoma patients with
an isocitrate dehydrogenase 1 (IDH1) mutation met its primary
endpoint. Treatment with TIBSOVO® demonstrated a statistically
significant improvement in progression-free survival (PFS) by
independent radiology review compared with patients who received
placebo. The safety profile observed in the study was consistent
with previously published data.
A full analysis of the ClarIDHy trial will be submitted for
presentation at the European Society for Medical Oncology Congress
taking place in Barcelona, Spain from September 27-October 1, 2019.
The company plans to submit a supplemental new drug application for
TIBSOVO® in previously treated IDH1 mutant cholangiocarcinoma by
the end of 2019.
“Advanced cholangiocarcinoma is a life-threatening disease with
no currently approved treatment options,” said Chris Bowden, M.D.,
chief medical officer at Agios. “The data from the ClarIDHy Phase 3
trial demonstrate the clinically significant benefit of TIBSOVO® in
patients with this challenging disease who harbor the IDH1
mutation. We are committed to working with regulators to bring this
potential treatment option to patients as quickly as possible. We
thank the patients and physicians who participated in the ClarIDHy
study, without whom this important advancement would not be
possible.”
ClarIDHy Phase 3 TrialThe ClarIDHy trial is a
global, randomized Phase 3 trial in previously treated IDH1 mutant
cholangiocarcinoma patients who have documented disease progression
following one or two systemic therapies in the advanced setting. As
of the January 31, 2019 data cutoff, 185 patients were
randomized.
- Patients were randomized 2:1 to receive either single-agent
TIBSOVO® 500 mg once daily or placebo with crossover to TIBSOVO®
permitted at the time of documented radiographic progression per
RECIST 1.1.
- The primary endpoint of the trial is PFS as evaluated by
independent radiology review with secondary endpoints including
investigator evaluated PFS, safety and tolerability, overall
response rate, overall survival, duration of response, PK/PD and
quality of life assessments.
- The study was designed with 96% power to detect a hazard ratio
of 0.5 for PFS (TIBSOVO® vs. placebo), with a one-sided alpha of
0.025.
- Thermo Fisher Scientific is providing next-generation
sequencing to detect IDH1 mutations for all tumor samples as
inclusion criteria for enrollment in the study and will develop and
commercialize the validated companion diagnostic.
TIBSOVO® is not approved in any country for the treatment of
patients with advanced cholangiocarcinoma.
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 CholangiocarcinomaCholangiocarcinoma (CC)
is a rare cancer of the bile ducts within and outside of the liver.
Cases that occur within the liver are known as intrahepatic
cholangiocarcinoma (IHCC) and those that occur outside the liver
are considered extrahepatic. Mutations in IDH1 occur in up to 20%
of IHCC cases. Current treatment options for localized disease
include surgery, radiation and/or other ablative treatments. There
are no approved systemic therapies for cholangiocarcinoma and
limited chemotherapy options are available in the advanced setting.
Gemcitabine-based chemotherapy is often recommended for newly
diagnosed metastatic disease.
About AgiosAgios is focused on discovering and
developing novel investigational medicines to treat cancer and rare
genetic diseases through scientific leadership in the field of
cellular metabolism and adjacent areas of biology. In addition to
an active research and discovery pipeline across both therapeutic
areas, Agios has two approved oncology precision medicines and
multiple first-in-class investigational therapies in clinical
and/or preclinical development. All Agios programs focus on
genetically identified patient populations, leveraging our
knowledge of metabolism, biology and genomics. For more
information, please visit the company's website at
www.agios.com.
Cautionary Note Regarding Forward-Looking
Statements This 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); Agios’
plans to submit a supplemental new drug application for TIBSOVO® in
previously treated IDH1 mutant positive cholangiocarcinoma by the
end of 2019; the expected timing for the report of full results
from the ClarIDHy trial; 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 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: Agios' results of clinical trials,
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 and 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, such as its agreements with
Celgene and CStone Pharmaceuticals; 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.
Investor & Media Contact: Holly Manning,
617-844-6630 Associate Director, Investor Relations
Holly.Manning@agios.com
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