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 Phase 1 studies evaluating TIBSOVO®
(ivosidenib) in adult patients with newly diagnosed acute myeloid
leukemia (AML) and an isocitrate dehydrogenase-1 (IDH1) mutation
who are ineligible for intensive chemotherapy. The data were
presented as part of the scientific program at the 2019 American
Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
“Newly diagnosed AML patients who are not eligible for intensive
chemotherapy are typically older or have comorbidities that can
lead to a worse prognosis and poor outcomes,” said Courtney
DiNardo, M.D., lead investigator and associate professor,
department of leukemia at the University of Texas MD Anderson
Cancer Center. “With an additional six months of follow up since
the last data cutoff in the Phase 1 combination study of TIBSOVO®
with azacitidine, it is encouraging to see a 12-month survival rate
of 82% and a continued increase in CR+CRh rate to 70% and CR rate
to 61%. In addition, the majority of patients with CR also had IDH1
mutation clearance, suggesting direct impact on the biology of IDH1
“As the data from these frontline Phase 1 studies of TIBSOVO®
mature, the durability of response has continued to improve over
time and demonstrates that treating these patients with an IDH1
inhibitor early in the disease has the potential to provide deep,
durable responses,” said Chris Bowden, M.D., chief medical officer
at Agios. “The recent sNDA approval in newly diagnosed AML patients
with an IDH1 mutation who are ineligible for intensive chemotherapy
was the first step in our broad program to develop TIBSOVO® across
the frontline setting.”
Phase 1 Study of TIBSOVO® in Combination with
The ongoing Phase 1/2 study is evaluating an investigational use
of TIBSOVO® or IDHIFA® (enasidenib) in combination with azacitidine
in patients with newly diagnosed IDH mutant AML unable to receive
intensive chemotherapy. As of the February 19, 2019 data
cutoff, 23 patients received 500 mg of TIBSOVO® daily plus
azacitidine in the TIBSOVO® arm of the Phase 1b portion of the
study. Enrollment in the TIBSOVO® arm is complete. As of the data
cutoff, 10 (43%) patients remained on study, and the median number
of treatment cycles was 15 (range 1-30). The median age was 76
years old, and 52% of patients were age 75 or older. Sixty-five
percent of patients had de novo AML and 35% had secondary AML.
- The most common Grade 3/4 adverse events (AEs) regardless of
cause were thrombocytopenia (61%), anemia (44%), febrile
neutropenia (44%) and neutropenia (30%).
- Investigator reported IDH differentiation syndrome was reported
in four patients, of which three were serious AEs. All four cases
resolved, among whom two achieved a complete response (CR), one
stable disease and one was not evaluable for response.
- Mean neutrophil and platelet counts were maintained near or
above thresholds for CR with partial hematologic recovery (CRh)
while on study treatment with TIBSOVO® and azacitidine. CRh is
defined as <5% of blasts in the bone marrow, no evidence of
disease and partial recovery of peripheral blood counts (ANC
>500/microliter and platelets >50,000/microliter).
- Overall, 78% (18/23) of patients had a response.
- 70% (16/23) of patients had a CR or CRh.
- 61% (14/23) of patients had a CR.
- The median duration of CR (95% CI 9.3, NE) as well as CR+CRh
(95% CI 12.2, NE) had not been reached.
- The median time to response was 1.8 months (range 0.7-3.8
months) and the median time to CR was 3.7 months (range 0.8-15.7
- The 12-month survival rate was 82% (95% CI 58.8, 92.8).
- The median duration of follow-up was 16.1 months (range
- For patients who achieved a CR, IDH1 mutation clearance was
observed in 9 of 14 (64%) patients with available bone marrow
mononuclear cells (BMMCs) and 11 of 14 patients (79%) with
available peripheral blood mononuclear cells (PBMCs) as quantified
by a digital PCR assay with lower limit of sensitivity for mutant
IDH1 of 0.02-0.04% (or 10-4).
TIBSOVO® is not approved in any country for the treatment of
patients with newly diagnosed AML in combination with
Untreated AML Arm of Phase 1 Study of Single Agent
TIBSOVO® in IDH1 Mutant Hematologic Malignancies
As of the November 2, 2018 data cutoff, a total of 258 patients
with advanced hematologic malignances and an IDH1 mutation were
treated in the Phase 1 study, including 34 patients with untreated
AML (nine from dose-escalation and 25 from expansion) who received
500 mg of TIBSOVO® daily. Enrollment in the study is complete. The
median treatment duration for the untreated AML patients was 4.3
months (0.3-40.9). The median age for these patients was 76.5 years
(64-87) and 47% had received a prior hypomethylating agent. Among
the untreated AML patients, 24% had de novo AML and 76% had
- The most common AEs of any grade >25% regardless of
causality were diarrhea (53%), fatigue (47%), nausea (38%),
decreased appetite (35%), leukocytosis (26%), anemia (26%), edema
peripheral (26%) and thrombocytopenia (26%).
- Adverse events of interest were the following:
- 9% reported Grade ≥3 ECG QT prolongation. TIBSOVO® was dose
reduced in two patients and held in four patients (for any grade of
ECG QT prolongation).
- 18% reported IDH differentiation syndrome of any grade, which
was managed with corticosteroids and diuretics. Three patients had
their dose temporarily held, and no patients required dose
- 3% reported Grade ≥3 leukocytosis.
- No AEs of interest lead to any permanent treatment
discontinuations or deaths.
- Data from the 33 untreated AML patients with an IDH1 mutation
confirmed by the Abbott RealTimeTM IDH1 assay demonstrated an
overall response rate of 55% (18/33 patients).
- 42% (14/33) of patients had a CR or CRh.
- 30% (10/33) of patients had a CR.
- The median duration of CR (95% CI 4.2, NE) as well as CR+CRh
(95% CI 4.6, NE) had not been reached. The estimated 12-month
durations of response were 78% for CR and 62% for CR+CRh.
- Median overall survival was 12.6 months.
- Among patients who were transfusion dependent at baseline,
transfusion independence was observed across all response
categories, where it was defined as an absence of transfusions for
at least 56 consecutive days on treatment.
- IDH1 mutation clearance, defined as a reduction in mIDH1
variant allele frequency to below the limit of detection of
0.02–0.04% (or 10-4), was observed in 64% (9/14) of patients who
achieved CR+CRh, including 50% (5/10) of patients with CR and 100%
(4/4) of patients with CRh.
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
- Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION
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, 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
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
- 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
- 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
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.
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
About Acute Myeloid 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
year. AML patients are typically older or have comorbidities that
preclude the use of intensive chemotherapy. These patients
typically have a worse prognosis and poor outcomes. The majority of
patients with AML eventually relapse. The five-year survival rate
is approximately 28%. For 6 to 10 percent of AML patients, the
mutated IDH1 enzyme blocks normal blood stem cell differentiation,
contributing to the genesis of acute leukemia. IDH1 mutations have
been associated with negative prognosis in AML.
About Agios Agios 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
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 ivosidenib; Agios’s plans for
future development of ivosidenib; 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 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: 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; 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
Investor & Media Contact: Holly Manning,
617-844-6630 Associate Director, Investor Relations
Agios Pharmaceuticals (NASDAQ:AGIO)
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