Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field
of cellular metabolism to treat cancer and rare genetic diseases,
today announced that The Lancet Oncology has published data from
its global Phase 3 ClarIDHy study of TIBSOVO® (ivosidenib) in
previously treated cholangiocarcinoma patients with an isocitrate
dehydrogenase 1 (IDH1) mutation. The study met its primary
endpoint, demonstrating a statistically significant improvement in
progression-free survival (PFS) in patients randomized to TIBSOVO®
compared with placebo patients. The safety profile observed in the
study was consistent with previously published data. Data from this
study were previously presented at the European Society for Medical
Oncology Congress (ESMO), held in September 2019 in Barcelona,
Spain.
The publication can be accessed at the following link:
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30157-1/fulltext
“We began researching IDH inhibition as a potential therapeutic
approach for solid tumors more than five years ago with the goal of
innovating on behalf of patients, including those with advanced
cholangiocarcinoma, who desperately need new treatment options,”
said Chris Bowden, M.D., chief medical officer at Agios. “We are
pleased that the ClarIDHy study supports the potential utility of
TIBSOVO® for this patient population and are focused on filing our
supplemental new drug application for previously treated
IDH1-mutant cholangiocarcinoma patients between the end of this
year and mid-2021.”
ClarIDHy Phase 3 TrialThe ClarIDHy trial is a
global, randomized Phase 3 trial in previously treated IDH1-mutant
cholangiocarcinoma patients who have documented disease progression
following one or two systemic therapies in the advanced setting.
Patients were randomized 2:1 to receive either single-agent
TIBSOVO® 500 mg once daily or placebo with crossover to TIBSOVO®
permitted at the time of documented radiographic progression per
RECIST 1.1. At the time of the primary analysis, a total of 185
patients were randomized, with 124 patients in the TIBSOVO® arm and
61 patients in the placebo arm. Thirty-five patients randomized to
placebo (57.4%) crossed over to open-label TIBSOVO® upon
radiographic disease progression and unblinding.
Results of the study were as follows:
- Median PFS for patients randomized to TIBSOVO® was 2.7 months
compared to 1.4 months with placebo (hazard ratio [HR]=0.37; 95% CI
[0.25, 0.54], one-sided p<0·0001) as assessed by independent
radiology review.
- The estimated PFS rate was 32% at six months and 22% at 12
months for patients randomized to TIBSOVO®, while no patients
randomized to placebo were free from progression beyond six months
as of the data cut-off.
- The most common treatment-emergent adverse events (AEs) of any
grade for the 121 patients who received TIBSOVO® were nausea
(36%), diarrhea (31%) and fatigue (26%).
- Less than third of patients experienced serious AEs in either
arm (30% of 121 who received TIBSOVO® versus 22% of 59
patients who received placebo).
- The most common Grade 3 or worse AE in both treatment groups
was ascites (nine [7%] of 121 patients who received TIBSOVO®
and four [7%] of 59 patients who received placebo).
- Patients randomized to placebo experienced a significantly
greater decline in physical functioning from baseline compared to
patients randomized to ivosidenib on the first day of their second
28-day treatment cycle based on European Organisation for Research
and Treatment of Cancer Quality of Life Questionnaire Core 30
(EORTC QLQ-C30) Physical Functioning subscale scores
(p=0.0059).
TIBSOVO® is not approved in any country for the treatment
of patients with previously treated advanced IDH1-mutant
cholangiocarcinoma.
About Cholangiocarcinoma Cholangiocarcinoma
(CC) is a rare cancer of the bile ducts within and outside of the
liver. Cases that occur within the liver are known as intrahepatic
cholangiocarcinoma (IHCC) and those that occur outside the liver
are considered extrahepatic. Mutations in IDH1 occur in up to 20%
of IHCC cases. Current treatment options for localized disease
include surgery, radiation and/or other ablative treatments. There
are no approved systemic therapies for IDH1-mutated
cholangiocarcinoma and limited chemotherapy options are available
in the advanced setting. Gemcitabine-based chemotherapy is often
recommended for newly diagnosed advanced or metastatic disease.
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 AgiosAgios is focused on discovering and
developing novel investigational medicines to treat malignant
hematology, solid tumors and rare genetic diseases through
scientific leadership in the field of cellular metabolism. In
addition to an active research and discovery pipeline across these
three therapeutic areas, Agios has two approved oncology precision
medicines and multiple first-in-class investigational therapies in
clinical and/or preclinical development. 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 TIBSOVO® (ivosidenib);
Agios’ plans to submit a supplemental new drug application for
TIBSOVO® in previously treated cholangiocarcinoma between the
end of 2020 and mid-2021; 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 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, without
limitation: risks and uncertainties related to the impact of the
COVID-19 pandemic to Agios’ business, operations,
strategy, goals and anticipated milestones,
including its ongoing and planned research activities,
ability to conduct ongoing and planned clinical trials, clinical
supply of current or future drug candidates, commercial supply of
current or future approved products, and launching, marketing and
selling current or future approved products; 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, the EMA or 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
required by law.
Contacts
Investors:Holly Manning, 617-844-6630Director,
Investor RelationsHolly.Manning@agios.com
Media:Jessica Rennekamp, 857-209-3286Associate
Director, Corporate CommunicationsJessica.Rennekamp@agios.com
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