ARIAD Presents Analysis of Cardiovascular Risk Profile of Patients from
Pivotal PACE Trial of Iclusig® (Ponatinib)
2013 ASCO Annual Meeting
CHICAGO & CAMBRIDGE, Mass. -- June 1, 2013
ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced results of
evaluation of the cardiovascular risk profile of Philadelphia-positive (Ph+)
leukemia patients treated with Iclusig^® (ponatinib) in the pivotal PACE
trial. Serious arterial thrombotic (AT) events can be a complication of
BCR-ABL tyrosine kinase inhibitor (TKI) therapy in Ph+ leukemias. In the
single-arm, PACE trial, serious AT events, including cardiovascular,
cerebrovascular and peripheral vascular events, occurred in 34 of 449 patients
(8%). This analysis showed that patients who experienced serious ATs while on
study more commonly had a history of pre-existing cardiac disease and a higher
prevalence of baseline cardiovascular risk factors prior to enrollment than in
those patients who did not experience these events.
The data are being featured today in a poster presentation at 8:00 a.m. (CT)
and a poster discussion at 12:00 p.m. (CT) at the 2013 American Society of
Clinical Oncology (ASCO) Annual Meeting taking place in Chicago.
Of 34 patients with serious AT events reported in the PACE trial, 21 had
cardiovascular events and 14 had cerebrovascular or peripheral vascular
events. Pre-existing cardiac disease was present in 15 of 21 patients (71%)
who had cardiovascular events and 6 of 14 patients (43%) who had
cerebrovascular or peripheral vascular events on study. Further, 30 patients
(88%) had at least one pre-existing cardiovascular risk factor, 14 patients
(41%) had pre-existing ischemic cardiac disease, and 19 patients (56%) were at
least 65 years of age.
“Although uncommon, cardiovascular events have been reported in patients with
Ph+ leukemias treated with BCR-ABL TKIs,” said H. Jean Khoury, M.D., professor
of hematology and medical oncology, and director of the Division of Hematology
of the Winship Cancer Institute at Emory University. “Patients in the PACE
trial were heavily pretreated with multiple prior TKIs. This analysis shows
that patients who experienced serious arterial thrombotic events generally
were older, had a more prolonged duration of leukemia since original
diagnosis, had one or more cardiovascular risk factors prior to entry in the
trial and had a high prevalence of pre-existing cardiac and ischemic
Methodology of PACE Trial Analysis
*This analysis focuses on the subset of 34 patients with reported AT events
considered serious adverse events. All adverse events presented are
treatment-emergent adverse events.
*Median follow-up for the total PACE trial patient population was 11 months
(minimum, 9 months). This data set is the same as that described in the
U.S. Prescribing Information for Iclusig.
*AT events were categorized into three groups: cardiovascular,
cerebrovascular and peripheral vascular according to the definitions of
these groups used to prepare the U.S. Prescribing Information for Iclusig.
The overall event rate was based on the summation of the individual
disease definitions. A patient was classified as having an increase in
blood pressure if a single recorded measurement of blood pressure had
changed at any time during the course of the trial.
*Analysis included assessment of the association between risk factors and
occurrence of AT events. Cardiovascular risk factors included
hypertension, elevated cholesterol, diabetes, and obesity. Additional
demographic factors of age, gender (male), time since leukemia diagnosis,
exposure to prior TKI therapy and history of cardiac disease were also
assessed. Smoking was not included in the analysis, as data were not
Summary of Characteristics and Clinical Profile of Patients with Serious AT
*Patients with serious AT events had significantly higher incidences of
pre-existing diabetes (44% vs. 14%) and hypertension (82% vs. 51%) than
patients who did not experience these events. Almost all patients who had
cerebrovascular or peripheral vascular events while on study had
hypertension at baseline.
*Differences in demographics, medical history and previous therapy also
distinguished the population experiencing serious AT events. History of
ischemic cardiac disease (41% vs. 10%) and age of at least 65 years (56%
vs. 33%) were significantly greater in those with serious AT events than
in those without. The population also had a significantly longer duration
of prior TKI therapy (6.3 vs. 4.9 years) and significantly longer duration
of prior nilotinib therapy (1.8 vs. 1.2 years).
*Patients from the serious AT group were exposed to comparable dose
intensity of ponatinib when compared to those without serious AT events.
The median time to onset of serious AT events was approximately six
months. Blood pressure increased by one or two grades during the trial in
59% of patients who experienced serious AT events.
*Patients were managed with dose interruption and dose modification
comparably in patients with and without serious AT events. In more than
one-third of patients with serious ATs, there was no modification to
ponatinib dosing. Discontinuation rates among patients with serious AT
events were comparable to the overall discontinuation rates for the study.
*Anti-leukemic response to Iclusig was similar in patients with serious AT
events as compared to those without (chronic-phase CML, 73% vs. 52%).
Sixteen of 22 patients with serious AT events (73 %) achieved major
cytogenetic response, and nine of 22 (41 %) had a major molecular
“This analysis is important as we consider the patient population now
receiving Iclusig after becoming resistant or intolerant to prior TKI therapy
and determine how to best treat patients with prior cardiovascular history or
risk factors,” said Frank G. Haluska, M.D., Ph.D., senior vice president,
clinical research and development and chief medical officer of ARIAD. “This
analysis also showed that these patients can be managed with standard dose
adjustments while maintaining clinical benefit from treatment. In
Philadelphia-positive leukemia patients with predisposing factors or
co-morbidities, physicians should pay close attention to management of
hypertension and diabetes.”
About the PACE Trial
The FDA approval of Iclusig was based on results from the pivotal Phase 2 PACE
(Ponatinib Ph+ ALL and CML Evaluation) trial in patients with CML or Ph+ ALL
who were resistant or intolerant to prior TKI therapy, or who had the T315I
mutation of BCR-ABL. Iclusig had robust anti-leukemic activity, with 54
percent of chronic-phase CML patients, including 70 percent of patients with
the T315I mutation, achieving a major cytogenetic response (MCyR) – the
primary endpoint of the PACE trial for chronic-phase patients.
In patients with advanced disease, 52 percent of accelerated-phase CML
patients, 31 percent of blast-phase CML patients and 41 percent of Ph+ ALL
patients achieved a major hematologic response (MaHR) to Iclusig. MaHR was the
primary endpoint in the trial for patients with advanced disease.
About Iclusig® (ponatinib)
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an
abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML)
and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Iclusig was designed using ARIAD’s computational and structure-based drug
design platform specifically to inhibit the activity of BCR-ABL. Iclusig
targets not only native BCR-ABL but also its isoforms that carry mutations
that confer resistance to treatment, including the T315I mutation, a common
mutation which has been associated with resistance to other approved TKIs.
Indication, Usage and Dosing
Iclusig is indicated for the treatment of adult patients with chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) that is
resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that
is resistant or intolerant to prior TKI therapy.
This indication is based upon response rate. There are no trials verifying an
improvement in disease-related symptoms or increased survival with Iclusig.
The recommended dose of Iclusig is a 45 mg tablet taken once-daily with or
Important Safety Information
Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular
thrombosis, including fatal myocardial infarction and stroke have occurred in
Iclusig-treated patients. In clinical trials, serious arterial thrombosis
occurred in 8% of Iclusig-treated patients. Interrupt and consider
discontinuation of Iclusig in patients who develop arterial thrombotic events.
Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in
Iclusig-treated patients. Monitor hepatic function prior to and during
treatment. Interrupt and then reduce or discontinue Iclusig for
Warnings and Precautions
Congestive Heart Failure: Twenty patients treated with Iclusig (4%)
experienced serious congestive heart failure (CHF) or left ventricular
dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with
Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs
or symptoms consistent with CHF and treat as clinically indicated, including
interruption of Iclusig. Consider discontinuation of Iclusig in patients who
develop serious CHF.
Hypertension: Eight patients treated with Iclusig (2%) experienced
treatment-emergent symptomatic hypertension as a serious adverse reaction,
including hypertensive crisis. Treatment-emergent hypertension (defined as
systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion)
occurred in 67% of patients (300/449). Monitor and manage blood pressure
Pancreatitis: Clinical pancreatitis occurred in 6% of patients (5% Grade 3)
treated with Iclusig. The incidence of treatment emergent lipase elevation was
41%. Check serum lipase every 2 weeks for the first 2 months and then monthly
thereafter or as clinically indicated. Dose interruption or reduction may be
required. In cases where lipase elevations are accompanied by abdominal
symptoms, interrupt treatment with Iclusig and evaluate patients for
Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients
treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24%
of patients. The incidence of serious bleeding events was higher in patients
with AP-CML, BP-CML, and Ph+ ALL. Most events occurred in patients with grade
4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage.
Fluid Retention: Serious fluid retention events occurred in 3% of patients
treated with Iclusig. One instance of brain edema was fatal. Monitor patients
for fluid retention and manage patients as clinically indicated. Interrupt,
reduce, or discontinue Iclusig as clinically indicated.
Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement
for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise
patients to report signs and symptoms suggestive of slow heart rate (fainting,
dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% of
Iclusig-treated patients. Atrial fibrillation was the most common
supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients,
the event led to hospitalization. Advise patients to report signs and symptoms
of rapid heart rate (palpitations, dizziness).
Myelosuppression: Severe (Grade 3 or 4) myelosuppression occurred in 48%
(215/449) of patients treated with Iclusig. The incidence of these events was
greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with
CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and
then monthly or as clinically indicated, and adjust the dose as recommended.
Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML,
BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis
syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the
majority had CP-CML (19 patients). Ensure adequate hydration and treat high
uric acid levels prior to initiating therapy with Iclusig.
Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may
compromise wound healing, interrupt Iclusig for at least 1 week prior to major
surgery. Serious gastrointestinal perforation (fistula) occurred in one
patient 38 days post-cholecystectomy.
Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during
pregnancy, or if the patient becomes pregnant while taking Iclusig, the
patient should be apprised of the potential hazard to the fetus. Advise women
to avoid pregnancy while taking Iclusig.
The most common non-hematologic adverse reactions (≥20%) were hypertension,
rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia,
nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia,
anemia, neutropenia, lymphopenia, and leukopenia. Please see the full
Prescribing Information for Iclusig, including the Boxed Warning.
ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts and
Lausanne, Switzerland, is an integrated global oncology company focused on
transforming the lives of cancer patients with breakthrough medicines. ARIAD
is working on new medicines to advance the treatment of various forms of
chronic and acute leukemia, lung cancer and other difficult-to-treat cancers.
ARIAD utilizes computational and structural approaches to design
small-molecule drugs that overcome resistance to existing cancer medicines.
For additional information, visit http://www.ariad.comor follow ARIAD on
This press release contains “forward-looking statements” including, but not
limited to, statements relating to the analysis of safety data for
ponatinib.Forward-looking statements are based on management's expectations
and are subject to certain factors, risks and uncertainties that may cause
actual results, outcome of events, timing and performance to differ materially
from those expressed or implied by such statements. These risks and
uncertainties include, but are not limited to, preclinical data and
early-stage clinical data that may not be replicated in later-stage clinical
studies, the costs associated with our research, development, manufacturing
and other activities, the conduct, timing and results of pre-clinical and
clinical studies of our product candidates, the adequacy of our capital
resources and the availability of additional funding, and other factors
detailed in the Company's public filings with the U.S. Securities and Exchange
Commission. The information contained in this press release is believed to be
current as of the date of original issue. The Company does not intend to
update any of the forward-looking statements after the date of this document
to conform these statements to actual results or to changes in the Company's
expectations, except as required by law.
ARIAD Pharmaceuticals, Inc.
Kendra Adams, 617-503-7028
Liza Heapes, 617-621-2315
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