- Ivosidenib and Enasidenib Evaluated in Combination with
Standard Induction (7+3) Chemotherapy or Azacitadine in Newly
Diagnosed Patients From Two Phase 1 Studies -
Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today presented data from two studies evaluating ivosidenib
(AG-120) and an investigational use of IDHIFA® (enasidenib) in
patients with newly diagnosed acute myeloid leukemia (AML) and an
isocitrate dehydrogenase (IDH)1 or IDH2 mutation. The data were
presented as part of the scientific program at the 59th American
Society of Hematology Annual Meeting in Atlanta.
“The totality of the data presented at ASH demonstrate the
potential benefit of IDHm inhibitors in the frontline setting for
patients with AML,” said Eytan Stein, M.D., study investigator and
attending physician in the leukemia service at Memorial Sloan
Kettering Cancer Center. “The Phase 1 frontline combination trials
showed that ivosidenib and enasidenib are well tolerated when
combined with standard induction chemotherapy or azacitadine and
both trials demonstrated early encouraging signs of efficacy. I
look forward to evaluating both ivosidenib and enasidenib in
late-stage, placebo-controlled clinical trials to understand the
full impact of these medicines on newly diagnosed AML
patients.”
Combination with Standard Induction
ChemotherapyThe first presentation, given by Dr. Stein,
evaluated ivosidenib or enasidenib in combination with standard
induction chemotherapy in patients with newly diagnosed AML and an
IDH1 or IDH2 mutation. During induction, patients received either
500 mg of ivosidenib and 7 + 3 standard chemotherapy (daunorubicin
60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine
200 mg/m2/day x 7 days) (n=32) or 100 mg of enasidenib and 7 + 3
standard chemotherapy (n=56). Of these patients, 69% in the
ivosidenib arm and 57% in the enasidenib arm had de novo AML, while
the remaining patients had secondary AML (sAML). For patients with
sAML, 40% in the ivosidenib arm and 63% in the enasidenib arm had
received prior hypomethylating agent therapy. After induction,
patients could receive up to four cycles of consolidation
chemotherapy while continuing ivosidenib or enasidenib. Patients
who achieved a complete response (CR) or a complete response with
incomplete neutrophil or platelet recovery (CRi/CRp) after
consolidation could continue to take single agent ivosidenib or
enasidenib daily for up to two years from day one of induction.
Ivosidenib ResultsIn the ivosidenib arm, the most common Grade 3
or higher non-hematologic adverse events during the induction
period were febrile neutropenia (60%), blood bilirubin increased
(9%), hypertension (9%), colitis (9%), increased alanine
aminotransferase (9%) and increased aspartate aminotransferase
(9%). The 30 and 60-day mortality rates were both 6%, and there
were no dose-limiting toxicities. The median time to absolute
neutrophil count (ANC) recovery (>500/µL) was 28.5 days (95% CI
27,34). Median time to platelet recovery (>50,000/µL) was 28
days (95% CI 26,34).
The CR+CRi/CRp rate for de novo patients was 91% (19/21) and 44%
(4/9) for sAML patients. The overall best response of CR+ CRi/CRp
rate for all patients was 77% (23/30).
Enasidenib ResultsIn the enasidenib arm, the most common Grade 3
or higher non-hematologic adverse events during the induction
period were febrile neutropenia (63%), blood bilirubin increased
(9%), hypertension (9%) and bacteremia (9%). The 30 and 60-day
mortality rates were 5% and 7%, respectively. There was one
dose-limiting toxicity in the enasidenib combination arm consisting
of persistent Grade 4 thrombocytopenia lasting beyond 42 days from
the start of induction. The median time to ANC recovery
(>500/µL) was 34 days (95% CI 29,35). Median time to platelet
recovery (>50,000/µL) was 33 days (95% CI 29,50).
The CR+CRi/CRp rate for de novo patients was 67% (18/27) and 57%
(13/23) for sAML patients. The overall best response of CR+CRi/CRp
rate for all patients was 62% (31/50).
“The early results from these studies of ivosidenib and
enasidenib in combination with traditional frontline AML treatment
are highly encouraging and support the strategy to advance IDHm
inhibitors into the newly diagnosed setting,” said Chris Bowden,
M.D., chief medical officer of Agios. “We are focused on evaluating
the IDHm inhibitors in late-stage studies that span the entire
frontline setting with our ongoing Phase 3 AGILE study of
ivosidenib in combination with azacitidine versus azacitidine and a
planned Phase 3 study of ivosidenib and enasidenib in combination
with 7+3 intensive chemotherapy.”
Combination with AzacitidineThe second
presentation, given by Courtney DiNardo, M.D., evaluated an
investigational use of enasidenib or ivosidenib in combination with
azacitidine in patients with newly diagnosed AML unable to receive
intensive chemotherapy. In the study, patients received 100mg (n=3)
or 200mg (n=3) of enasidenib daily plus azacitidine or 500 mg of
ivosidenib (n=11) plus azacitidine. At the data cutoff, 11 patients
remained on the study (3 enasidenib, 8 ivosidenib).
Enasidenib Results
For patients receiving the enasidenib combination, the most
common Grade 3-4 hematologic adverse event was neutropenia (33%,
2/6). The most common Grade 3-4 non-hematologic adverse events were
pneumonia (33%, 2/6) and hyperbilirubinemia (33%, 2/6). IDH
differentiation syndrome was reported in one patient.
Four of six patients had a response, including two CRs, one
partial response (PR) and one morphologic leukemia-free state
(MLFS).
Ivosidenib ResultsFor patients receiving the ivosidenib
combination, the most common Grade 3-4 hematologic adverse events
were anemia (18%, 2/11) and febrile neutropenia (18%, 2/11) with
neutropenia and thrombocytopenia each with one event (9% each). The
most common Grade 3-4 non-hematologic adverse event was pneumonia
(18%, 2/11). IDH differentiation syndrome was reported in one
patient.
Eight of 11 patients had a response, including four CRs, one
CRi, one PR and two MLFS.
Neither IDHIFA nor ivosidenib are approved for the treatment of
patients with newly diagnosed AML or approved in combination with
azacitidine.
About IDHIFA
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 SYNDROMEPatients
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, which may be
life-threatening or fatal if not treated. Differentiation syndrome
has been observed with and without concomitant hyperleukocytosis,
as early as 10 days and at up to 5 months after IDHIFA initiation.
Symptoms in patients treated with IDHIFA included acute respiratory
distress represented by dyspnea and/or hypoxia and need for
supplemental oxygen; pulmonary infiltrates and pleural effusion;
renal impairment; fever; lymphadenopathy; bone pain; peripheral
edema with rapid weight gain; and pericardial effusion. Hepatic,
renal, and multi-organ dysfunction have also been observed. 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.
Investor Event and Webcast InformationAgios
will host an investor event on Monday, December 11, 2017 beginning
at 8:00 p.m. ET in Atlanta to review data presented at ASH. The
event will be webcast live and can be accessed under "Events &
Presentations" in the Investors section of the company's website at
www.agios.com.
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 an
approved oncology precision medicine 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' global strategic collaboration with
Celgene Corporation focused on cancer metabolism. Under the terms
of the 2010 collaboration agreement, 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
$95 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 IDHIFA®
(enasidenib); Agios’ plans for the further clinical development of
ivosidenib and IDHIFA®; 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 is developing will
successfully commence or complete necessary preclinical and
clinical development phases; that positive safety and efficacy
findings observed in early stage clinical trials will be replicated
in later stage trials; 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 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.
Contacts
Investors:Renee Leck, 617-649-8299Senior
Manager, Investor & Public RelationsRenee.Leck@agios.com
Media:Holly Manning, 617-844-6630Associate
Director, Corporate CommunicationsHolly.Manning@agios.com
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