– Single Agent Ivosidenib Demonstrated CR+CRh
Rate of 42.4% and Overall Response Rate (ORR) of 57.6% in Newly
Diagnosed AML Patients Ineligible for Standard Treatment –
Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today presented updated efficacy and safety data from the untreated
acute myeloid leukemia (AML) arm from the ongoing Phase 1
dose-escalation and expansion study evaluating single agent
ivosidenib in patients with hematologic malignancies and an
isocitrate dehydrogenase-1 (IDH1) mutation. The data were featured
in an oral presentation at the 60th American Society of Hematology
Annual Meeting in San Diego.
“Ivosidenib induced deep, durable remissions in newly diagnosed
AML patients who are older, have high rates of secondary AML and
prior hypomethylating agent exposure,” said Gail Roboz, M.D., Weill
Cornell Medical College and an investigator in the study.
“Ivosidenib had a favorable safety profile characterized by a low
rate of febrile neutropenia and infections. In addition,
transfusion independence was observed across response categories,
including in patients who did not achieve complete remission.”
“We believe these data are encouraging and represent compelling
evidence for the potential of single agent ivosidenib as a new
treatment option for newly diagnosed AML patients who are
ineligible for standard therapies,” said Chris Bowden, M.D., chief
medical officer at Agios. “There is tremendous need for targeted
treatment options for these patients who are typically older and
have comorbid conditions, and we are on track to submit a
supplemental new drug application for ivosidenib for this patient
population under the FDA Real Time Oncology Review pilot program by
the end of January 2019.”
Untreated AML Data PresentationAs of the May
11, 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
ivosidenib daily. Enrollment to the study is closed.
- Among the untreated AML patients, 20.6% had de novo AML and
79.4% had secondary AML (sAML).
- The median age for these patients was 76.5 years (64-87) and
41.2% had received a prior hypomethylating agent.
- The median treatment duration for the untreated AML patients
was 4.3 months (0.3-35.1).
Safety DataAs of the data cut-off, a safety analysis conducted
for the 34 untreated AML patients showed that ivosidenib
demonstrates a safety profile that is consistent with previously
reported data for all 258 patients. The most common adverse events
(AEs) of any grade >25% regardless of causality were diarrhea
(52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite
(32.4%), leukocytosis (26.5%), anemia (26.5%) and edema peripheral
(26.5%). Adverse events of interest were the following:
- 8.8% reported Grade ≥3 ECG QT prolongation. Ivosidenib was dose
reduced in two patients and held in four patients (for any grade of
ECG QT prolongation).
- 17.6% reported IDH-differentiation syndrome (IDH-DS) of any
grade, which was managed with corticosteroids and diuretics. Three
patients had their dose temporarily held, and no patients required
dose reductions.
- 3% reported Grade ≥3 leukocytosis.
- No AEs of interest lead to any permanent treatment
discontinuations or deaths.
Efficacy DataData from 33 untreated AML patients with an IDH1
mutation confirmed by the Abbott RealTime IDH1 assay demonstrated
an overall response rate (ORR) of 57.6% (19 of 33 patients) [95% CI
39.2, 74.5] and a combined complete remission (CR) and CR with
partial hematologic recovery (CRh) rate of 42.4% [95% CI 25.5,
60.8] which is the primary endpoint of the study.
- The CR rate was 30.3% (10 of 33 patients) [95% CI 15.6, 48.7]
and the CRh rate was 12.1% (4 of 33 patients) [95% CI 3.4, 28.2].
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).
- Median time to first response was 1.9 months (range 0.9, 3.6)
for all patients who responded and median time to CR/CRh was 2.8
months (range 1.9, 12.9).
- Median durations of CR, CR+CRh, and ORR were not estimable
(lower bound of 95% CI 4.2, 6.5 and 6.5 months, respectively); the
estimated 12-month durations of response were 77.8%, 66.7% and
59.5%, respectively.
- Transfusion independence, defined as an absence of transfusions
for at least 56 consecutive days on treatment, was observed across
all response categories.
- Of the patients who achieved a CR or CRh and were transfusion
dependent at baseline, all became independent of platelet and RBC
transfusions during any 56-day post baseline period.
- Achievement of transfusion independence was also seen among
some non-CR/CRh responders and non-responders.
- IDH1 mutation clearance, defined as a reduction in mIDH1
variant allele frequency to below the limit of detection of
0.02–0.04% (2-4 x10-4), was observed in 64% (9/14) of patients with
untreated AML who achieved CR or CRh, including 50% (5/10) of
patients with CR and 100% (4/4) of patients with CRh.
MDS Data PresentationUpdated safety and
efficacy data based on May 11, 2018 data cutoff were also presented
on December 1, 2018 for 12 myelodysplastic syndrome (MDS) patients
from the dose-escalation (n=3) and expansion (n=9) portions of the
Phase 1 study whose starting dose was 500 mg daily. The median age
was 72.5 years (52-78).
- The most common AEs of any grade occurring in ≥20% of patients
were back pain and fatigue (n=4, 33.3% each) and anemia, decreased
appetite, diarrhea, dyspnea, hypokalemia, pruritus, and rash (n=3,
25% each). Most AEs were grade 1–2 and reported as unrelated to
treatment. No AEs led to permanent discontinuation of
treatment.
- Grade 2 IDH differentiation syndrome (IDH-DS) was observed in 1
of 12 patients.
- Of the 12 patients with MDS, five achieved CR (41.7%) [95% CI
(15.2%, 72.3%)], one achieved a partial response (PR) (8.3%) and
five achieved marrow CR (mCR) (41.7%), resulting in an ORR of 91.7%
[95% CI (61.5%, 99.8%)].
- The median durations of CR was not estimable at the time of the
data cutoff; the median duration of response was 21.4 months with
95% CI [2.3, NE]. The percentages of patients who remained in CR
and response at 12 months were 60.0% and 61.4%, respectively.
- Among the five patients who were transfusion dependent at
baseline, four became transfusion independent for at least 56 days
on treatment.
TIBSOVO® (ivosidenib) is not approved for the treatment of
patients with newly diagnosed AML or MDS by any regulatory
authority.
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 Acute Myelogenous Leukemia (AML)AML, a
cancer of blood and bone marrow characterized by rapid disease
progression, is the most common acute leukemia affecting adults.
Undifferentiated blast cells proliferate in the bone marrow rather
than mature into normal blood cells. AML incidence significantly
increases with age, and the median age of diagnosis is 68. The vast
majority of patients do not respond to chemotherapy and progress to
relapsed/refractory AML. The five-year survival rate for AML is
approximately 27 percent. IDH1 mutations are present in about 6 to
10 percent of AML cases.
About Myelodysplastic Syndrome (MDS)MDS
comprises a diverse group of bone marrow disorders in which
immature blood cells in the bone marrow do not mature or become
healthy blood cells. The National Cancer Institute estimates that
more than 10,000 people are diagnosed with MDS in the U.S. each
year. Failure of the bone marrow to produce mature healthy cells is
a gradual process, and reduced blood cell and/or reduced platelet
counts may be accompanied by the loss of the body's ability to
fight infections and control bleeding. For roughly 30 percent of
the patients diagnosed with MDS, this bone marrow failure will
progress to AML. Chemotherapy and supportive blood products are
used to treat MDS.
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.
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; Agios’s plans for
future clinical 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 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, 617-649-8299Senior
Manager, Investor RelationsRenee.Leck@agios.com
Media:Holly Manning, 617-844-6630Associate
Director, Corporate CommunicationsHolly.Manning@agios.com
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