Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field
of cellular metabolism to treat cancer and rare genetic diseases,
today presented translational data describing deep and durable
molecular responses to treatment of TIBSOVO® (ivosidenib) and
azacitidine and mechanisms of resistance and relapse to single
agent treatment with TIBSOVO® in acute myeloid leukemia (AML) with
an IDH1 mutation. The data were presented as part of the scientific
program at the 2019 American Society of Hematology (ASH) Annual
Meeting.
“For 10 years, we have pioneered the science behind the role of
IDH mutations in AML, while bringing to patients new oral therapies
for the approximately 20% of AML patients with an IDH mutation.
We’re pleased to share a robust set of translational data at ASH
that further elucidates our understanding of TIBSOVO® response and
resistance mechanisms in patients with IDH1 mutant AML,” said Chris
Bowden, M.D., chief medical officer at Agios. “These data show that
combination treatment with TIBSOVO® and azacitidine in newly
diagnosed IDH1 mutant AML can induce deep, durable remissions in
patients with a number of molecular profiles. Our translational
work has further elucidated mechanisms of relapse with IDH1
monotherapy in relapsed and refractory disease that includes both
IDH-related and non-IDH related pathways.”
Treatment with TIBSOVO® and Azacitidine Results in High
Rate of IDH1 Mutation Clearance and Measurable Residual Disease
Negativity in Newly Diagnosed AML As of the February 19,
2019 data cutoff, 23 patients have been treated in the ongoing
Phase 1/2 study of TIBSOVO® in combination with azacitidine in
patients with newly diagnosed IDH1 mutant AML ineligible for
intensive chemotherapy. Results from the study show a complete
response (CR) rate of 61% and a CR + CR with partial hematologic
recovery (CRh) rate of 70%. Responses were durable, and the median
duration of CR (95% CI 9.3 months, NE) as well as CR+CRh (95% CI
12.2 months, NE) had not been reached. In patients with CR, 10 of
14 (71%) had IDH1 mutation clearance in bone marrow mononuclear
cells measured by BEAMing digital PCR (limit of detection
0.02-0.04%). Additionally, the majority of CR patients with IDH1
mutation clearance demonstrated measurable residual disease (MRD)
negativity by flow cytometry or next-generation sequencing. Five
patients were shown to have RTK pathway mutations (KRAS, NRAS,
PTPN11), and three of these patients achieved CR/CRh with TIBSOVO®
and azacitidine combination therapy.
Mechanisms of Resistance to Single Agent IDH1 Inhibitors
in Relapsed/Refractory AMLComprehensive genomic profiling
was conducted using patient samples from the Phase 1 study of
TIBSOVO® in IDH1 mutant relapsed/refractory AML to characterize the
molecular predictors of response and mechanisms of relapse to
TIBSOVO monotherapy. The analysis found that multiple mechanisms
contribute to relapse or progression. RTK pathway mutations NRAS
and PTPN11 at baseline were associated with a lower likelihood of
clinical response to TIBSOVO® monotherapy in relapsed/refractory
AML, while patients with JAK2 mutations were more likely to achieve
a response. Acquired resistance is mediated by diverse mechanisms,
and mutations are acquired in multiple pathways, most frequently in
RTK and 2-HG–restoring pathways (IDH2 and second-site IDH1
mutations).
Single cell mutation profiling was conducted to explore the
evolution of mutant IDH2 clones under the selective pressure of
TIBSOVO® monotherapy in a subset of patients. The analysis revealed
multiple evolutionary mechanisms by which mutant IDH2 contributes
to relapse and reinforced the key role of 2-HG production in mutant
IDH AML.
Taken together, these results inform the design of combination
or sequential treatment strategies with TIBSOVO® in IDH1 mutant AML
and reinforce the importance of genomic testing for both IDH1 and
IDH2 mutations at relapse.
TIBSOVO® is not approved in any country for the treatment of
patients with newly diagnosed AML in combination with
azacitidine.
Investor Event and Webcast InformationAgios
will host an investor event today at 8:00 p.m. ET in Orlando, Fla.
to review the IDH and PKR 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.
The archived webcast will be available on the company's website
beginning approximately two hours after the event.
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 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
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 for the further clinical development of
TIBSOVO® (ivosidenib); 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; 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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