– TIBSOVO® is the First and Only Therapy Approved
for Newly Diagnosed AML Patients with an IDH1 Mutation who are
Ineligible for Intensive Chemotherapy –
Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today announced the U.S. Food and Drug Administration (FDA)
approved a supplemental New Drug Application (sNDA) to update the
U.S. Prescribing Information for TIBSOVO®, an isocitrate
dehydrogenase-1 (IDH1) inhibitor, to include adult patients with
newly diagnosed acute myeloid leukemia (AML) with a susceptible
IDH1 mutation as detected by an FDA-approved test who are ≥ 75
years old or who have comorbidities that preclude use of intensive
induction chemotherapy. The sNDA was granted Priority Review and
accepted under the FDA's Real-Time Oncology Review pilot program,
which aims to make the review of oncology drugs more efficient by
allowing the FDA access to clinical trial data before the
information is formally submitted to the agency.
TIBSOVO
® received initial FDA approval in July
2018 for adult patients with relapsed or refractory (R/R) AML and
an IDH1 mutation1.
“Despite several new AML medicines approved in the last two
years, many newly diagnosed patients are still not eligible for
existing therapies or combination regimens because of age and other
comorbidities,” said Chris Bowden, M.D., chief medical officer at
Agios. “With today’s additional TIBSOVO® approval, we are now able
to provide a targeted, oral therapy to patients with an IDH1
mutation who may not have other treatment options. In addition, we
are continuing our work to expand the utility of TIBSOVO® in newly
diagnosed AML patients in ongoing Phase 3 trials in combination
with both intensive chemotherapy and azacitidine. I would like to
thank the patients, nurses, physicians and caregivers who
participated in the clinical trial, as well as the tremendous
employees at Agios whose focus on patients made this possible.”
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 estimated in the U.S.
each year2,3. AML patients are typically older or have
comorbidities that preclude the use of intensive chemotherapy4.
These patients typically have a worse prognosis and poor outcomes5.
The majority of patients with AML eventually relapse6. The
five-year survival rate is approximately 28%2. For 6 to 10 percent
of AML patients, the mutated IDH1 enzyme blocks normal blood stem
cell differentiation, contributing to the genesis of acute
leukemia7. IDH1 mutations have been associated with negative
prognosis in AML8,9.
“The Phase 1 results for TIBSOVO® demonstrated that this oral,
single agent therapy can induce durable responses in newly
diagnosed AML patients with an IDH1 mutation,” said Gail J. Roboz,
M.D., Professor of Medicine, Director of the Leukemia Program and a
member of the Sandra and Edward Meyer Cancer Center at Weill
Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical
Center*. “Many patients included in the study had features
associated with particularly aggressive and challenging forms of
AML, including secondary disease, adverse risk genetics and prior
treatment with hypomethylating agents.”
TIBSOVO® Safety and Efficacy Data1
The efficacy of TIBSOVO® was evaluated in an open-label,
single-arm, multicenter clinical trial (Study AG120-C-001,
NCT02074839) that included 28 adult patients with newly diagnosed
AML with an IDH1 mutation who were assigned to receive a 500 mg
daily dose. The cohort included patients who were age 75 or older
or had comorbidities that precluded the use of intensive induction
chemotherapy (baseline Eastern Cooperative Oncology Group [ECOG]
performance status of ≥2, severe cardiac or pulmonary disease,
hepatic impairment with bilirubin >1.5 times the upper limit of
normal, or creatinine clearance <45 mL/min). Patients had a
median age of 77 years (range of 64 to 87) and 68% had AML with
myelodysplasia-related changes. The primary endpoint is the
combined complete remission (CR) and complete remission with
partial hematologic improvement (CRh) rate. CRh is defined as
<5% of blasts in the bone marrow, no evidence of disease and
partial recovery of peripheral blood counts (platelets
>50,000/microliter and ANC >500/microliter).
In this trial, TIBSOVO® demonstrated:
- CR+CRh rate of 42.9% (12 of 28 patients) (95% CI: 24.5,
62.8).
- The CR rate was 28.6% (8 of 28 patients) (95% CI 13.2, 48.7)
and the CRh rate was 14.3% (4 of 28 patients) (95% CI 4.0,
32.7).
- Median durations of CR and CR+CRh were not estimable, with 5
patients (41.7%) who achieved CR or CRh remaining on TIBSOVO®
treatment (treatment duration range: 20.3 to 40.9 months) as of the
data cutoff.
- 58.3% (7 of 12) of patients who achieved CR or CRh were in
remission at 1 year after receiving treatment.
- For patients who achieved a CR or CRh, the median time to best
response of CR or CRh was 2.8 months (range, 1.9 to 12.9
months).
- Among the 17 patients who were dependent on red blood cell
(RBC) and/or platelet transfusions at baseline, 7 (41.2%) became
independent of RBC and platelet transfusions during any 56-day
post-baseline period.
- Of the 11 patients who were independent of both RBC and
platelet transfusions at baseline, 6 (54.5%) remained transfusion
independent during any 56-day post-baseline period.
The safety profile of single-agent TIBSOVO® was evaluated in 28
patients with newly diagnosed AML with an IDH1 mutation treated
with a dose of 500 mg daily. The median duration of exposure to
TIBSOVO® was 4.3 months (range, 0.3 to 40.9 months). In the
clinical trial, 25% (7 of 28) of patients treated with TIBSOVO®
experienced differentiation syndrome, which can be fatal if not
treated. Of the 7 patients with newly diagnosed AML who experienced
differentiation syndrome, 6 (86%) patients recovered. QTc interval
prolongation occurred in patients treated with TIBSOVO®. The most
common adverse reactions (≥20%) of any grade in patients with newly
diagnosed AML were diarrhea, fatigue, decreased appetite, edema,
nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia,
constipation, differentiation syndrome, dizziness,
electrocardiogram QT prolonged, mucositis and vomiting.
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 Acute Myelogenous Leukemia (AML)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 estimated in the U.S. each
year2,3. AML patients are typically older or have comorbidities
that preclude the use of intensive chemotherapy4. These patients
typically have a worse prognosis and poor outcomes5. The majority
of patients with AML eventually relapse6. The five-year survival
rate is approximately 28%2. For 6 to 10 percent of AML patients,
the mutated IDH1 enzyme blocks normal blood stem cell
differentiation, contributing to the genesis of acute leukemia7.
IDH1 mutations have been associated with negative prognosis in
AML8,9.
About myAgios™ Patient Support ServicesmyAgios™
Patient Support Services is an expansive program that helps
patients with access, reimbursement, and financial assistance for
TIBSOVO® (ivosidenib). Healthcare providers and pharmacists can
enroll patients at myAgios.com/enroll.
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.
*Dr. Roboz has served as a consultant for Celgene, Bayer,
Otsuka, Pfizer, Astellas Pharmaceuticals, Argenx, Astex
Pharmaceuticals, Hoffman-La Roche, Janssen, Novartis, Amphivena,
AbbVie, Sandoz, Eisai, Jazz Pharmaceuticals, Celltrion, Orsenix and
Daiichi Sankyo.
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 Agios' products, including
TIBSOVO® (ivosidenib), and its strategic plans and focus. The words
“estimate,” “may,” “milestone,” “potential,” 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, or 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 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 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, except as required by
law.
References
- TIBSOVO® Prescribing Information (U.S.). Agios
Pharmaceuticals, Inc. Cambridge, MA. Revised May/2019.
- National Cancer Institute Surveillance, Epidemiology, and End
Results Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML).
https://seer.cancer.gov/statfacts/html/amyl.html. Accessed April
2019.
- American Cancer Society. Acute Myeloid Leukemia (AML).
https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html.
Accessed April 2019.
- Kantarjian H, et al. Intensive chemotherapy does not benefit
most older patients (age 70 years or older) with acute myeloid
leukemia. Blood. 2010;116(22):4422-4429.
- Dohner H., Estey E., Grimwade D., et al. Diagnosis and
management of AML in adults: 2017 ELN recommendations from an
international expert panel. Blood. 2017;129:424-447.
- Medeiros BC., et al. Big data analysis of treatment patterns
and outcomes among elderly acute myeloid leukemia patients in the
United States. Ann Hematol. 2015;94:1127-1138.
- DiNardo C. Durable Remissions from Ivosidenib in IDH1-Mutated
Relapsed or Refractory AML. New England Journal of
Medicine. June 2, 2018
- Zhou KG, Jiang LJ, Shang Z, et al. Potential application of
IDH1 and IDH2 mutations as prognostic indicators in
non-promyelocytic acute myeloid leukemia: a meta-analysis. Leuk
Lymphoma. 2012;53(12):2423-2429.
- Feng J-H, Guo X-P, Chen Y-Y, Wang Z-J, Cheng Y-P, Tang Y-M.
Prognostic significance of IDH1 mutations in acute myeloid
leukemia: a meta-analysis. Am J Blood Res. 2012;2(4):254-264.
Investor & Media ContactHolly Manning,
617-844-6630Associate Director, Investor
RelationsHolly.Manning@agios.com
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