Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and genetically defined
diseases, today reported a full analysis of the final data,
including mature overall survival (OS) results, from its global
Phase 3 ClarIDHy trial of TIBSOVO® (ivosidenib tablets) in patients
with previously treated isocitrate dehydrogenase 1 (IDH1) mutated
cholangiocarcinoma. Data from the study were featured in an oral
presentation at the American Society of Clinical Oncology
Gastrointestinal Cancers Symposium (ASCO-GI), which is being held
virtually January 15-17, 2021.
The final analysis showed an improvement in the secondary
endpoint of OS favoring patients randomized to TIBSOVO® compared to
those randomized to placebo; however, statistical significance was
not reached. The median OS for patients randomized to TIBSOVO® was
10.3 months compared to 7.5 months for patients randomized to
placebo (hazard ratio [HR]=0.79; 95% CI [0.56–1.12], 1-sided
p=0.093). The protocol specified that patients randomized to
placebo could cross over to TIBSOVO® at the time of disease
progression, and a high proportion of patients in the placebo arm
(70.5%) crossed over to TIBSOVO®. The results of a pre-specified
analysis to adjust for crossover, based on the rank-preserving
structural failure time (RPSFT) model, showed a median OS for
patients in the placebo arm of 5.1 months (HR=0.49, 95% CI
0.34–0.70, 1-sided p<0.0001). The safety profile observed in the
study was consistent with previously published data. As previously
announced, the study demonstrated a statistically significant
improvement in the primary endpoint of progression-free survival
(PFS) by independent radiology review.
“The progression-free survival and overall survival data from
the ClarIDHy Phase 3 study, coupled with a tolerable safety profile
and supportive patient-reported quality-of-life data, demonstrate
that TIBSOVO® has the potential to be a clinically meaningful
treatment option for patients with previously treated IDH1-mutant
cholangiocarcinoma, an aggressive cancer with limited effective
treatment options,” said Andrew Zhu, M.D., Ph.D., director emeritus
of liver cancer research at Massachusetts General Hospital,
director of Jiahui International Cancer Center and professor of
medicine at Harvard Medical School. “Treatment with TIBSOVO®
resulted in a consistent trend in improved overall survival,
despite the high rate of crossover from the placebo arm, and this
improvement was further supported by the pre-specified statistical
analysis to adjust for the crossover effect. I look forward to the
potential of having a new treatment option for my patients with
this devastating disease.”
“We are extremely pleased with the results of the ClarIDHy Phase
3 study, the first and only randomized Phase 3 trial for
IDH1-mutant advanced cholangiocarcinoma, and believe TIBSOVO® has
demonstrated compelling results for patients facing a grim
prognosis who currently have few treatment options,” said Chris
Bowden, M.D., chief medical officer at Agios. “We will collaborate
closely with regulators to advance this potential new oral,
non-cytotoxic, targeted treatment option, and we look forward to
filing for U.S. approval later this quarter.”
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. The primary endpoint of the ClarIDHy trial is
progression-free survival (PFS) as evaluated by independent
radiology review. Secondary endpoints include
investigator-evaluated PFS, safety and tolerability, overall
response rate, OS, duration of response, pharmacokinetics,
pharmacodynamics and quality of life assessments.
As of the May 31, 2020 data cutoff, 187 patients were
randomized, with 126 patients in the TIBSOVO® arm and 61 patients
in the placebo arm. Forty-three patients randomized to placebo
(70.5%) crossed over to open-label TIBSOVO® upon radiographic
disease progression and unblinding.
Updated Efficacy DataEfficacy data as of the
data cutoff showed:
- The median OS for patients in the TIBSOVO® arm was 10.3 months
compared to 7.5 months for patients in the placebo arm (HR=0.79;
95% CI [0.56–1.12], 1-sided p=0.093).
- After adjusting for crossover from placebo to TIBSOVO® using
the pre-specified analysis of rank-preserving structural failure
time (RPSFT), the median OS for patients in the placebo arm was 5.1
months (HR=0.49; 95% CI [0.34–0.70], 1-sided p<0.0001).
- The 6-month survival rate for patients in the TIBSOVO® arm was
69 percent compared to 57 percent of patients in the placebo arm,
not adjusted for crossover.
- The 12-month survival rate for patients in the TIBSOVO® arm was
43 percent compared to 36 percent for patients in the placebo arm,
not adjusted for crossover.
- Treatment with TIBSOVO® preserved patients’ physical
functioning from baseline, as assessed by the EORTC QLQ-C30
questionnaire, whereas patients in the placebo arm experienced
decline from baseline at cycle 2, day 1 (2-sided p=0.002) and cycle
3, day 1 (2-sided p=0.004).
- Treatment with TIBSOVO® improved patients’ pain at cycle 2, day
1 compared to placebo, as assessed by the EORTC QLQ-BIL21
questionnaire (2-sided p=0.039); no difference was observed at
cycle 3, day 1.
- Neither arm was favored on other pre-specified quality-of-life
subscales (QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and
Eating).
Updated Safety Data
- Grade 3 or above treatment-emergent adverse events (TEAE) were
reported in 53 percent of total TIBSOVO® patients, which includes
patients originally randomized to TIBSOVO® and those who crossed
over from placebo to TIBSOVO®, compared to 37.3 percent of patients
on placebo, with the most common being ascites (9.0% total TIBSOVO®
vs. 6.8% placebo), anemia (7.2% total TIBSOVO® vs. 0% placebo) and
increased blood bilirubin (5.4% total TIBSOVO® vs. 1.7%
placebo).
- TEAEs leading to discontinuation were more common with placebo
compared with total TIBSOVO® (8.5% vs. 6.6%).
- TEAEs leading to dose reductions (3.0% vs. 0%) and
interruptions (30.1% vs. 18.6%) were more common with total
TIBSOVO® compared with placebo.
- The most common TEAEs of any grade for total TIBSOVO® were
nausea (38.0%), diarrhea (33.1%) and fatigue (28.9%).
Previously Reported DataData from the study
were previously presented at the European Society for
Medical Oncology Congress (ESMO), held in September
2019 in Barcelona, Spain, and published in The Lancet
Oncology on May 13, 2020. Results from the trial demonstrated a
statistically significant improvement in the primary endpoint of
PFS among patients randomized to TIBSOVO® compared with placebo
patients (HR=0.37; 95% CI [0.25–0.54], p<0.0001), with a median
PFS of 2.7 months in the TIBSOVO® arm versus a median PFS of 1.4
months in the placebo arm. The estimated PFS rate was 32 percent at
six months and 22 percent at 12 months for patients randomized to
TIBSOVO®, while no patients randomized to placebo were free from
progression or death beyond six months as of the data cut-off.
Based on these data, the National Comprehensive Cancer Network
(NCCN) guidelines, the French National Treatment Guidelines for
Biliary Cancer and the Italian Clinical Practice Guidelines on
Cholangiocarcinoma were updated to recommend treatment with
TIBSOVO® for patients with advanced previously treated IDH1-mutant
cholangiocarcinoma.
Agios plans to submit a supplemental new drug application for
TIBSOVO® in previously treated IDH1-mutant cholangiocarcinoma in
the first quarter of 2021.
TIBSOVO® is not approved in any country for the treatment
of patients with previously treated advanced IDH1-mutant
cholangiocarcinoma.
About CholangiocarcinomaCholangiocarcinoma 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. IDH1 mutations occur in approximately
10% of cholangiocarcinoma 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 AML 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 genetically defined 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 tablets);
Agios’ plans to submit a supplemental new drug application for
TIBSOVO® in previously treated IDH1 mutant cholangiocarcinoma in
the first quarter of 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
Agios Pharmaceuticals (NASDAQ:AGIO)
Historical Stock Chart
From Mar 2024 to Apr 2024
Agios Pharmaceuticals (NASDAQ:AGIO)
Historical Stock Chart
From Apr 2023 to Apr 2024