– 91% CR+CRi/CRp Rate in Ivosidenib-treated
Patients with De Novo AML and 53% in Ivosidenib-treated Patients
with Secondary AML –
Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today presented data from a Phase 1 study evaluating ivosidenib or
enasidenib in combination with standard induction and consolidation
chemotherapy in patients with newly diagnosed acute myeloid
leukemia (AML) and an isocitrate dehydrogenase (IDH)1 or IDH2
mutation. The data were featured in an oral presentation at the
60th American Society of Hematology Annual Meeting in San Diego.
“These data demonstrate that combining full doses of standard
induction and consolidation chemotherapy with ivosidenib or
enasidenib is well tolerated and has the potential to provide
benefit for AML patients in the frontline setting,” said Eytan
Stein, M.D., study investigator and attending physician in the
leukemia service at Memorial Sloan Kettering Cancer Center. “The
addition of an IDH inhibitor to induction and consolidation
followed administration as single-agent maintenance therapy for
patients with newly diagnosed AML will be evaluated further in a
Phase 3 randomized study.”
“The molecular remissions observed in these newly diagnosed AML
patients is encouraging,” said Chris Bowden, M.D., chief medical
officer at Agios. “In conjunction with Celgene, we will provide
support of the Phase 3 HOVON 150 AML/AMLSG 29-18 study, which is
planned to initiate by year-end. HOVON 150 AML/AMLSG 29-18 is an
intergroup sponsored, global, registration-enabling trial combining
ivosidenib or enasidenib with standard induction and consolidation
chemotherapy followed by a maintenance therapy period in frontline
AML patients with an IDH1 or IDH2 mutation, respectively.”
About the Ongoing Phase 1 StudyAs of the August
1, 2018 data cut-off, 60 newly diagnosed AML patients with mIDH1
received 500 mg of ivosidenib and standard induction chemotherapy
(daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with
cytarabine 200 mg/m2/day x 7 days) and 93 newly diagnosed AML
patients with mIDH2 received 100 mg of enasidenib and standard
induction chemotherapy. After induction, patients received up to
four cycles of consolidation chemotherapy while continuing
ivosidenib (n=28) or enasidenib (n=45). Patients who achieved a
complete response (CR) or a complete response with incomplete
neutrophil or platelet recovery (CRi/CRp) after consolidation could
continue taking single agent ivosidenib or enasidenib daily until
the end of the study which is up to two years from the last patient
dosed.
- 70% of ivosidenib-treated patients and 63% of
enasidenib-treated patients had de novo AML, while the remaining
had secondary AML (sAML).
- In patients with sAML, 22% in the ivosidenib cohort and 50% in
the enasidenib cohort had received prior hypomethylating agent
therapy.
- The median age of patients was 62.5 years (range 24-76) in the
ivosidenib cohort and 63 years (range 27-77) in the enasidenib
cohort.
- The most commonly occurring baseline co-mutations in
ivosidenib-treated patients were DNMT3A, NPM1, ASXL1 and BCOR while
in enasidenib-treated patients, the most commonly occurring
baseline mutations were DNMT3A, SRSF2, ASXL1 and RUNX1.
Ivosidenib Results
Safety Data
- The frequency of Grade 3 or higher adverse events of interest,
regardless of attribution, during the induction period were: IDH
differentiation syndrome in 3% (2/60) of patients, QT interval
prolongation in 2% (1/60) of patients and blood bilirubin increased
in 7% (4/60) of patients.
- The 30-day mortality rate was 5% and the 60-day mortality rate
was 8%.
Efficacy Data
- An overall best response of CR+CRi/CRp was achieved in 80%
(39/49) of efficacy evaluable patients.
- The CR+CRi/CRp rate for de novo patients was 91% (31/34) and
53% (8/15) for sAML patients.
- In a subset of patients who achieved a CR or CRi/CRp,
elimination of measurable residual disease (MRD) by flow cytometry
was observed in 88% (15/17) of patients.
- In patients whose best response was CR or CRi/CRp, IDH1
mutation clearance by digital PCR was achieved in 41% (12/29) of
patients.
- At the time of the data cut-off, the probability of survival at
one-year was 79% and median overall survival (OS) was not yet
estimable.
- The median time to absolute neutrophil count (ANC) recovery
(>500/µL) from induction therapy (n=38) was 28 days (95% CI 28,
30). Median time to platelet recovery (>50,000/µL) from
induction therapy (n=38) was 28 days (95% CI 27, 30).
Enasidenib Results
Safety Data
- The frequency of Grade 3 or higher adverse events of interest,
regardless of attribution, during the induction period were: IDH
differentiation syndrome in 1% (1/93) of patients and blood
bilirubin increased in 14% (13/93) of patients.
- The 30-day mortality rate was 5% and the 60-day mortality rate
was 9%.
Efficacy Data
- An overall best response of CR+CRi/CRp was achieved in 72%
(64/89) of efficacy evaluable patients.
- The CR+CRi/CRp rate for de novo patients was 77% (43/56) and
64% (21/33) for sAML patients.
- In a subset of patients who achieved a CR or CRi/CRp,
elimination of MRD by flow cytometry was observed in 45% (9/20) of
patients.
- In patients whose best response was CR or CRi/CRp, IDH2
mutation clearance by digital PCR was achieved in 25% (15/59) of
patients.
- At the time of the data cut-off, the probability of survival at
one-year was 75% and median OS was not yet estimable.
- The median time to ANC recovery (>500/µL) from induction
therapy (n=46) was 34 days (95% CI 31, 36). Median time to platelet
recovery (>50,000/µL) from induction therapy (n=46) was 30 days
(95% CI 29, 34).
Neither IDHIFA® nor TIBSOVO® are approved for the treatment of
patients with newly diagnosed AML or approved in combination with
induction and consolidation chemotherapy.
About TIBSOVO® (ivosidenib)
TIBSOVO® (ivosidenib) is an isocitrate
dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of
adult patients with relapsed or refractory acute myeloid leukemia
(AML) with a susceptible IDH1 mutation as detected by an
FDA-approved test. For more information, visit TIBSOVO.com.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROMEPatients
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, 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 34 patients who
experienced differentiation syndrome, 27 (79%) 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, 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 (≥20%) of any grade were
fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea
(34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%),
electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%),
cough (22%), and constipation (20%).
- The most frequently reported ≥Grade 3 adverse reactions (≥5%)
were electrocardiogram QT prolonged (10%), dyspnea (9%),
leukocytosis (8%), tumor lysis syndrome (6%), and differentiation
syndrome (5%).
- 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
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 IDHIFA® (enasidenib)
IDHIFA® (enasidenib) is indicated for the treatment of adult
patients with relapsed or refractory acute myeloid leukemia with an
isocitrate dehydrogenase-2 mutation as detected by an FDA-approved
test.
Important Safety Information
WARNING: DIFFERENTIATION
SYNDROME |
Patients treated with IDHIFA have
experienced symptoms of differentiation syndrome, which can be
fatal if not treated. Symptoms may include fever, dyspnea, acute
respiratory distress, pulmonary infiltrates, pleural or pericardial
effusions, rapid weight gain or peripheral edema, lymphadenopathy,
bone pain, 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, 14% of patients treated
with IDHIFA experienced differentiation syndrome. Differentiation
syndrome has been observed with and without concomitant
hyperleukocytosis, as early as 10 days and at up to 5 months after
IDHIFA initiation. If differentiation syndrome is suspected,
initiate systemic corticosteroids and hemodynamic monitoring until
improvement. Taper corticosteroids only after resolution of
symptoms. Differentiation syndrome symptoms may recur with
premature discontinuation of corticosteroids. If severe pulmonary
symptoms requiring intubation or ventilator support and/or renal
dysfunction persist for more than 48 hours after initiation of
corticosteroids, interrupt IDHIFA until signs and symptoms are no
longer severe. Hospitalization for close observation and monitoring
of patients with pulmonary and/or renal manifestation is
recommended.
Embryo-Fetal Toxicity: Based on animal
embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm
when administered to a pregnant woman. Advise females of
reproductive potential and males with female partners of
reproductive potential to use effective contraception during
treatment with IDHIFA and for at least 1 month after the last dose.
Pregnant women, patients becoming pregnant while receiving IDHIFA,
or male patients with pregnant female partners should be apprised
of the potential risk to the fetus.
ADVERSE REACTIONS
- The most common adverse reactions (≥20%) included total
bilirubin increased (81%), calcium decreased (74%), nausea (50%),
diarrhea (43%), potassium decreased (41%), vomiting (34%),
decreased appetite (34%), and phosphorus decreased (27%)
- The most frequently reported ≥Grade 3 adverse reactions (≥5%)
included total bilirubin increased (15%), potassium decreased
(15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea
(8%), differentiation syndrome (7%), non-infectious leukocytosis
(6%), tumor lysis syndrome (6%), and nausea (5%)
- Serious adverse reactions were reported in 77.1% of patients.
The most frequent serious adverse reactions (≥2%) were leukocytosis
(10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased
appetite (3%), tumor lysis syndrome (5%), and differentiation
syndrome (8%). Differentiation syndrome events characterized as
serious included pyrexia, renal failure acute, hypoxia, respiratory
failure, and multi-organ failure
LACTATIONMany drugs are excreted in human milk
and because of the potential for adverse reactions in breastfed
infants, advise women not to breastfeed during treatment with
IDHIFA 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 cancer and rare
genetic diseases through scientific leadership in the field of
cellular metabolism. 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.
About Agios/Celgene CollaborationIDHIFA®
(enasidenib) is part of Agios' collaboration with Celgene
Corporation. Under the terms of the 2010 collaboration agreement
focused on cancer metabolism, Celgene has worldwide development and
commercialization rights for IDHIFA® (enasidenib). Agios continues
to conduct certain clinical development activities within the
IDHIFA® (enasidenib) development program and is eligible to receive
reimbursement for those development activities and up to $80
million in remaining payments assuming achievement of certain
milestones, and royalties on any net sales. Celgene and Agios are
currently co-commercializing IDHIFA® (enasidenib) in the U.S.
Celgene will reimburse Agios for costs incurred for its
co-commercialization efforts.
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 ivosidenib and enasidenib;
Agios’s plans for future clinical development of ivosidenib and
enasidenib; and the potential benefit of Agios’s strategic plans
and focus. The words “could,” “expect,” “intend,” “may,” “path,”
“plan,” “potential,” “strategy,” “will,” 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 collaborator, Celgene, 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: 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.
Contacts
Investors:Renee Leck, 617-649-8299Associate
Director, Investor RelationsRenee.Leck@agios.com
Media:Holly Manning, 617-844-6630Associate
Director, Corporate CommunicationsHolly.Manning@agios.com
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