Pharmaceuticals, Inc. (NASDAQ:ARIA) today announced preliminary
safety and efficacy data from the discontinued Phase 3 EPIC trial of
vs. imatinib in patients with newly diagnosed chronic-phase
chronic myeloid leukemia (CML). These data are being featured this
afternoon in a poster presentation and a poster discussion session at
the 2014 American Society of Clinical Oncology (ASCO) annual meeting in
EPIC Trial Design
The EPIC trial (Evaluation of Ponatinib vs. Imatinib
in CML) was a Phase 3, multicenter, international, two-arm,
open-label trial of ponatinib (administered at a starting dose of 45 mg
once daily) vs. imatinib (administered at a starting dose of 400
mg once daily) in patients with newly diagnosed chronic-phase CML.
Patients were randomized (1:1) to ponatinib or imatinib and stratified
by Sokal risk score determined at time of diagnosis.
On October 18, 2013, in consultation with the U.S. Food and Drug
Administration (FDA), ARIAD terminated the EPIC trial due to the
observation of the accumulation of arterial thrombotic events in the
ponatinib clinical program.
From August 2012 to October 2013, 307 patients were randomized (58% of
planned enrollment). None of the prospectively defined endpoints could
be analyzed due to the early termination of the trial. However, the
following endpoints were available for analysis:
Major Molecular Response (MMR) at 12 months was the primary endpoint of
the trial. MMR is defined as a less than or equal to 0.1% ratio of
BCR-ABL to ABL transcripts on the International Scale measured in
peripheral blood. MR4 and MR4.5 are 4 log and 4.5 log reductions in BCR
transcript levels, respectively.
EPIC Trial Findings
Despite the fact the primary endpoint could not be analyzed due to the
early termination of the trial, analysis of key secondary endpoints
provides preliminary evidence of efficacy of ponatinib compared to
imatinib in newly diagnosed patients with chronic-phase CML at the doses
studied and at the time points reached.
The median follow-up for both arms was 5 months at the time of
termination of the trial, and the following observations were made:
While no new safety signals were identified, there were more adverse
events (AEs) in the ponatinib arm compared with imatinib:
The starting dose of ponatinib used in the EPIC trial was the same as
the dose used in refractory CML patients. Going forward, further
evaluation in patients with newly diagnosed chronic-phase CML will
require evaluation of lower doses of ponatinib.
"The data from the EPIC trial have helped inform a planned dose-ranging
trial of ponatinib in patients with refractory CML and will help guide
potential future studies in earlier lines of CML therapy, including in
front-line patients," stated Frank G. Haluska, M.D., Ph.D., senior vice
president of clinical research and development and chief medical officer
at ARIAD. "Our continued goal is to optimize the benefit/risk of
ponatinib in each of these patient populations."
Investor and Analyst Briefing and Webcast
ARIAD will host an investor and analyst briefing from ASCO on Monday
June 2, 2014. This breakfast meeting will feature Dr. Lyudmila Bazhenova
from UC San Diego Moores Cancer Center to discuss the AP26113 clinical
data being presented at ASCO, Dr. Michael J. Mauro from Memorial Sloan
Kettering Cancer Center to discuss clinical data on ponatinib in CML,
and Dr. Michael C. Heinrich from Oregon Health & Science University to
discuss ponatinib clinical data in GIST.
The meeting will be webcast live along with slides and can be accessed
by visiting the investor relations section of the Company's website at http://investor.ariad.com.
A replay of the investor event will be available on the ARIAD website
approximately three hours after the presentation and will be archived on
the site for four weeks. To ensure a timely connection to the live
webcast, participants should log onto the webcast at least 15 minutes
prior to the scheduled start time.
About Iclusig® (ponatinib) tablets
Iclusig is approved in the U.S., EU and Switzerland. Iclusig is a kinase
inhibitor indicated in the U.S. for the:
NOTE: Iclusig is not approved for use in patients with newly
diagnosed CML in any market.
IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING
WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning
Vascular Occlusion: Arterial and venous thrombosis and
occlusions, including fatal myocardial infarction, stroke, stenosis of
large arterial vessels of the brain, severe peripheral vascular disease,
and the need for urgent revascularization procedures have occurred in at
least 27% of Iclusig-treated patients from the phase 1 and phase 2
trials. Iclusig can also cause recurrent or multi-site vascular
occlusion. Overall, 20% of Iclusig-treated patients experienced an
arterial occlusion and thrombosis event of any grade. Fatal and
life-threatening vascular occlusion has occurred within 2 weeks of
starting Iclusig treatment and in patients treated with average daily
dose intensities as low as 15 mg per day. The median time to onset of
the first vascular occlusion event was 5 months. Patients with and
without cardiovascular risk factors have experienced vascular occlusion
although these events were more frequent with increasing age and in
patients with prior history of ischemia, hypertension, diabetes, or
hyperlipidemia. Interrupt or stop Iclusig immediately in patients who
develop vascular occlusion events.
Heart Failure: Fatal and serious heart failure or left
ventricular dysfunction occurred in 5% of Iclusig-treated patients
(22/449). Eight percent of patients (35/449) experienced any grade of
heart failure or left ventricular dysfunction. Monitor patients for
signs or symptoms consistent with heart failure and treat as clinically
indicated, including interruption of Iclusig. Consider discontinuation
of Iclusig in patients who develop serious heart failure.
Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver
failure and death. Fulminant hepatic failure leading to death occurred
in an Iclusig-treated patient within one week of starting Iclusig. Two
additional fatal cases of acute liver failure also occurred. The fatal
cases occurred in patients with blast phase CML (BP-CML) or Philadelphia
chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe
hepatotoxicity occurred in all disease cohorts. Iclusig treatment may
result in elevation in ALT, AST, or both. Monitor liver function tests
at baseline, then at least monthly or as clinically indicated.
Interrupt, reduce or discontinue Iclusig as clinically indicated.
Hypertension: 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). Eight patients treated with
Iclusig (2%) experienced treatment-emergent symptomatic hypertension as
a serious adverse reaction, including one patient (<1%) with
hypertensive crisis. Patients may require urgent clinical intervention
for hypertension associated with confusion, headache, chest pain, or
shortness of breath. In 131 patients with Stage 1 hypertension at
baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and
manage blood pressure elevations during Iclusig use and treat
hypertension to normalize blood pressure. Interrupt, dose reduce, or
stop Iclusig if hypertension is not medically controlled.
Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of
patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in
discontinuation or treatment interruption in 6% of patients (25/449).
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. Consider additional serum lipase
monitoring in patients with a history of pancreatitis or alcohol abuse.
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 pancreatitis. Do not consider
restarting Iclusig until patients have complete resolution of symptoms
and lipase levels are less than 1.5 x ULN.
Neuropathy: Peripheral and cranial neuropathy have occurred in
Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated
patients experienced a peripheral neuropathy event of any grade (2%,
grade 3/4). In clinical trials, the most common peripheral neuropathies
reported were peripheral neuropathy (4%, 18/449), paresthesia (4%,
17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449).
Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients
(<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65)
developed neuropathy during the first month of treatment. Monitor
patients for symptoms of neuropathy, such as hypoesthesia,
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic
pain or weakness. Consider interrupting Iclusig and evaluate if
neuropathy is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness
or blurred vision have occurred in Iclusig-treated patients. Retinal
toxicities including macular edema, retinal vein occlusion, and retinal
hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or
corneal irritation, dry eye, or eye pain occurred in 13% of patients.
Visual blurring occurred in 6% of the patients. Other ocular toxicities
include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative
keratitis. Conduct comprehensive eye exams at baseline and periodically
Hemorrhage: Serious bleeding events, including fatalities,
occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic
events occurred in 24% of patients. The incidence of serious bleeding
events was higher in patients with accelerated phase CML (AP-CML),
BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all, occurred in
patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or
severe hemorrhage and evaluate.
Fluid Retention: Serious fluid retention events occurred in 3%
(13/449) of patients treated with Iclusig. One instance of brain edema
was fatal. In total, fluid retention occurred in 23% of the patients.
The most common fluid retention events were peripheral edema (16%),
pleural effusion (7%), and pericardial effusion (3%). 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 1% (3/449) of
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% (25/449) 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).
Interrupt Iclusig and evaluate.
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). Due to the potential for
tumor lysis syndrome in patients with advanced disease, ensure adequate
hydration and treat high uric acid levels prior to initiating therapy
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.
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,
Please see the full U.S. Prescribing
Information for Iclusig, including the Boxed Warning, for
additional important safety information.
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.com or
follow ARIAD on Twitter (@ARIADPharm).
This press release contains "forward-looking statements" including, but
not limited to, updates on clinical data from the discontinued EPIC
trial with ponatinib and potential future development plans for our
product candidates. 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 and results of preclinical and clinical studies of our product
candidates; the adequacy of our capital resources and the availability
of additional funding; and other risk 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.
Iclusig® is a registered trademark of ARIAD Pharmaceuticals,
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