ARIAD
Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced enrollment of
fifty percent of the patients planned in its randomized Phase 3 trial of
Iclusig
® (ponatinib) in adult patients with newly diagnosed
chronic myeloid leukemia (CML). The trial, formally known as
EPIC
(
Evaluation of
Ponatinib versus
Imatinib in
Chronic
Myeloid Leukemia), is designed to provide definitive clinical data to
support regulatory approval of ponatinib in treatment-naïve CML patients.
“Depending on the outcome of the interim analysis, we may be able to
file for regulatory approval of Iclusig in this front-line setting
approximately six months earlier than currently planned.”
An interim analysis of efficacy -- focused on the primary endpoint of
major molecular response rate (MMR) at twelve months -- will be
performed in the third quarter of 2014 based on the patients enrolled to
date.
Buy Aygestin (Norethisterone Bp) pills online without prescription Approximately 264 patients have been enrolled in the EPIC trial,
and full patient enrollment of approximately 500 patients in the trial
is anticipated by the end of 2013.
“The EPIC trial is a very important study in the ongoing global
development of Iclusig and will inform our clinical understanding of
Iclusig in patients with newly diagnosed CML,” said Harvey
J. Berger, M.D., chairman and chief executive officer of ARIAD.
“Depending on the outcome of the interim analysis, we may be able to
file for regulatory approval of Iclusig in this front-line setting
approximately six months earlier than currently planned.”
Trial Design and Statistical Analysis
The EPIC trial is a randomized, two-arm, multicenter trial that compares
the efficacy of ponatinib with that of imatinib in adult patients with
newly diagnosed CML in the chronic phase.
Buy Azelex (Azelaic Acid) tabs online without prescription The trial is currently being
conducted at approximately 150 investigational sites in more than 20
countries. Patients in the trial must be at least 18 years of age and
diagnosed with CML within six months prior to enrollment. Approximately
500 patients are randomized 1:1 to the standard dose of ponatinib (45 mg
given orally once daily) or imatinib (400 mg given orally once daily).
Increasing the imatinib dose to 600 mg or 800 mg per day is permitted.
As a primary endpoint, the trial is designed to measure the MMR of
patients at 12 months of treatment. This endpoint was chosen to support
accelerated approval for front-line treatment in the United States.
ARIAD also expects results from the EPIC trial to support regulatory
approval in the European Union and Japan. All patients are evaluated for
molecular response (MR) using quantitative reverse transcriptase
polymerase chain reaction (qRT PCR) at a single central laboratory
(Molecular MD, Portland, OR).
Buy Tenormin (Atenolol) without prescription To achieve MMR, the ratio of BCR-ABL
protein transcripts to ABL transcripts in a patients’ blood must be 0.1%
or less, using the International Scale in peripheral blood.
The EPIC trial is designed to have a 90% power to detect a 15% absolute
improvement in 12-month MMR rate by ponatinib compared to imatinib. This
was based, in part, on the results of the nilotinib (ENESTnd) and
dasatinib (DASISION) Phase 3 trials. The 12-month MMR rates for the
imatinib arms in these two trials were 22% and 28%, respectively. Using
the more conservative estimate of the 12-month MMR rate for imatinib,
the upper bound of the 95
th percentile confidence interval
for the higher of these two estimates is 34%.
Buy Vitamins online The ENESTnd trial was
designed to demonstrate a 15% absolute improvement in 12-month MMR rate
comparing nilotinib to imatinib. Thus, the EPIC trial is 90% powered to
detect a 15% absolute improvement in 12-month MMR rate by ponatinib
compared to imatinib (i.e., 49% vs. 34%).
Key secondary endpoints include: MMR at five years, MR at three months
(a reduction in the level of BCR-ABL transcripts to 10% or less),
complete cytogenetic response rate at 12 months, progression-free
survival and overall survival. Each patient will be followed for up to
eight years from the time the last patient is randomized to either
treatment arm.
About CML and Ph+ ALL
CML is characterized by an excessive and unregulated production of white
blood cells by the bone marrow due to a genetic abnormality that
produces the BCR-ABL protein. After a chronic phase of production of too
many white blood cells, CML typically evolves to the more aggressive
phases referred to as accelerated phase or blast crisis.
Cholesterol Medications Customer Reviews Ph+ ALL is a
subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome
that produces BCR-ABL. It has a more aggressive course than CML and is
often treated with a combination of chemotherapy and tyrosine kinase
inhibitors. The BCR-ABL protein is expressed in both of these diseases.
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.
All Best Rx : Buy drugs online 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 without food.
Important Safety Information
Boxed Warning
Arterial Thrombosis: Cardiovascular, cerebrovascular, and
peripheral vascular thrombosis, including fatal myocardial infarction
and stroke have occurred in Iclusig-treated patients.
FDA Approved Rx : Online Pharmacy 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 hepatotoxicity.
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.
Drugs Rx Guide : Buy drugs online 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 elevations.
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 pancreatitis.
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.
Adverse Reactions
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 U.S. Prescribing
Information for Iclusig, including the Boxed Warning.
About ARIAD
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.
This press release contains “forward-looking statements” including, but
not limited to, statements about an interim analysis of efficacy data in
the EPIC trial being expected in the third quarter of 2014, full patient
enrollment in the EPIC trial being anticipated by the end of 2013, the
potential for us to file for regulatory approval of Iclusig in the
front-line setting approximately six months earlier than currently
planned, our expectation that results from the EPIC trial will also
support regulatory approval in the European Union and Japan, and our
plans for following patients for up to eight years from the time the
last patient is randomized to either treatment arm in the EPIC trial.
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, our ability to
successfully launch, commercialize and generate profits from sales of
Iclusig; competition from alternative therapies and acceptance of
Iclusig by patients, physicians and third-party payors; our ability to
obtain approval for Iclusig outside of the Unites States and Europe and
in additional indications; difficulties in forecasting sales or
recognizing revenues for Iclusig; our reliance on third-party
manufacturers, including sole-source suppliers, and on specialty
pharmacies and specialty distributors for the distribution of Iclusig;
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; difficulty or delays in obtaining regulatory approvals to
market products; the timing of development and potential market
opportunity for our product candidates; our reliance on strategic
partners, licensees and other key parties for the successful
development, manufacturing and commercialization of our product
candidates; the adequacy of our capital resources and the availability
of additional funding; patent protection and third-party intellectual
property claims; our failure to comply with extensive regulatory
requirements; the occurrence of serious adverse events in patients being
treated with Iclusig or our product candidates; the ability to manage
our growth effectively; product liability claims; our operations in
foreign countries; future capital needs; risks related to key employees,
markets, economic conditions, health care reform, prices and
reimbursement rates; and other factors detailed under the heading “Risk
Factors” in Part I, Item 1A of our Annual Report on Form 10-K for the
year ended December 31, 2012 and any updates to those risk factors
contained in our subsequent periodic and current reports filed 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. We do 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 our expectations, except as required by law.
