Submission based on Phase 2 trial in Japanese
patients with refractory chronic myeloid leukemia (CML) or
Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+
ALL)
ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that
its partner Otsuka Pharmaceutical Co., Ltd. (Otsuka) has submitted
a new drug application (NDA) to the Japanese Pharmaceuticals and
Medical Devices Agency (PMDA) seeking approval for Iclusig®
(ponatinib) for the treatment of resistant or intolerant chronic
myeloid leukemia (CML) and Philadelphia-chromosome positive acute
lymphoblastic leukemia (Ph+ALL).
“The collaborative work to file this new drug application in
Japan marks a significant milestone in expanding patient access to
Iclusig in major geographies around the world,” said Timothy P.
Clackson, Ph.D., president of research and development and chief
scientific officer of ARIAD. “If approved, Iclusig will provide an
important new treatment option for Japanese patients with
refractory Philadelphia-positive leukemia.”
ARIAD expects Otsuka to receive a decision on the new drug
application in Japan in the second half of 2016.
The NDA for ponatinib is supported by the Phase 1/2 study in
Japanese patients, as well as the global pivotal PACE and Phase 1
trials of ponatinib. The Japanese study included 35 Japanese
patients with CML or Ph+ALL who experienced failure of prior
tyrosine kinase inhibitor (TKI) therapy. With a median follow-up of
14.9 months at the time of analysis, the Phase 1/2 study results
confirm that Iclusig demonstrates anti-leukemic activity in this
patient population. Among chronic-phase patients, 65% achieved the
primary efficacy endpoint of major cytogenetic response, and 35%
had a major molecular response. Thirteen patients remained on
therapy including 12 in chronic phase. The median duration of
response had not been reached. The most common treatment-emergent
adverse events in the trial of any grade were decreased platelet
and neutrophil counts, pyrexia, hypertension, dry skin, rash and
increased lipase. Treatment-emergent arterial thrombotic events
were reported in four patients, or 11%.
According to a 2011 survey by the Ministry of Health Labor and
Welfare in Japan, CML occurs in approximately 1 out of 100,000
people among all age groups and it is estimated that there are
approximately 11,000 patients living with CML in Japan.
About Iclusig® (ponatinib) tablets
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,
which has been associated with resistance to other approved
TKIs.
Iclusig is approved in the U.S., EU, Australia, Switzerland,
Israel and Canada.
In the U.S., Iclusig is a kinase inhibitor indicated for
the:
- Treatment of adult patients with
T315I-positive chronic myeloid leukemia (chronic phase, accelerated
phase, or blast phase) or T315I-positive Philadelphia chromosome
positive acute lymphoblastic leukemia (Ph+ ALL).
- Treatment of adult patients with
chronic phase, accelerated phase, or blast phase chronic myeloid
leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor
(TKI) therapy is indicated.
These indications are based upon response rate. There are no
trials verifying an improvement in disease-related symptoms or
increased survival with Iclusig.
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 have occurred in at least 27% of
Iclusig treated patients, including fatal myocardial infarction,
stroke, stenosis of large arterial vessels of the brain, severe
peripheral vascular disease, and the need for urgent
revascularization procedures. Patients with and without
cardiovascular risk factors, including patients less than 50 years
old, experienced these events. Monitor for evidence of
thromboembolism and vascular occlusion. Interrupt or stop Iclusig
immediately for vascular occlusion. A benefit risk consideration
should guide a decision to restart Iclusig therapy.
- Heart Failure, including fatalities,
occurred in 8% of Iclusig-treated patients. Monitor cardiac
function. Interrupt or stop Iclusig for new or worsening heart
failure.
- Hepatotoxicity, liver failure and
death have occurred in Iclusig-treated patients. Monitor hepatic
function. Interrupt Iclusig if hepatotoxicity is
suspected.
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. In the event of
significant worsening, labile or treatment-resistant hypertension,
interrupt treatment and consider evaluating for renal artery
stenosis. In the event of significant worsening, labile or
treatment-resistant hypertension, interrupt treatment and consider
evaluating for renal artery stenosis.
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 during
treatment.
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 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.
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, for additional
important safety information.
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. For additional information, visit
http://www.ariad.com or follow ARIAD on Twitter
(@ARIADPharm).
About Otsuka Pharmaceutical Co., Ltd.
Otsuka Pharmaceutical is a global healthcare company with the
corporate philosophy: “Otsuka-people creating new products for
better health worldwide.” Otsuka researches, develops, manufactures
and markets innovative and original products, with a focus on
pharmaceutical products for the treatment of diseases and
nutraceutical products for the maintenance of everyday health.
Otsuka Pharmaceutical is a leading firm in the challenging area
of mental health and also has products and research programs for
several under-addressed diseases including tuberculosis, a
significant global public health issue. These commitments
illustrate more powerfully than words how Otsuka is a “big venture”
company at heart, applying a youthful spirit of creativity in
everything it does. Otsuka Pharmaceutical and its affiliates employ
approximately 30,000 people globally, and the company welcomes you
to visit its global website at: http://www.otsuka.co.jp/en.
Forward-Looking Statements
This press release contains forward-looking statements, each of
which are qualified in their entirety by this cautionary statement.
Any statements contained herein which do not describe historical
facts, including, but not limited to, statements regarding: the
potential for Iclusig to provide an important new treatment option
for Japanese patients with refractory Philadelphia-positive
leukemia, if approved; the expected timing of a decision from
Japanese regulatory authorities; and the anticipated size of the
patient population in Japan, are forward-looking statements that
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 factors, risks
and uncertainties include, but are not limited to, our ability to
meet anticipated clinical trial commencement, enrollment and
completion dates and regulatory filing dates for our products and
product candidates and to move new development candidates into the
clinic; our ability to execute on our key corporate initiatives;
regulatory developments and safety issues, including difficulties
or delays in obtaining regulatory and pricing and reimbursement
approvals to market our products; our ability to successfully
commercialize and generate profits from sales of Iclusig or our
other product candidates, including brigatinib, if approved;
competition from alternative therapies; our reliance on the
performance of third-party manufacturers and specialty pharmacies
for the distribution of Iclusig; the occurrence of adverse safety
events with our products and product candidates; the costs
associated with our research, development, manufacturing and other
activities; the conduct, timing and results of preclinical and
clinical studies of our products and product candidates, including
that preclinical data and early-stage clinical data may not be
replicated in later-stage clinical studies; the adequacy of our
capital resources and the availability of additional funding;
patent protection and third-party intellectual property claims;
risks related to key employees, markets, economic conditions,
health care reform, prices and reimbursement rates; and other risk
factors detailed in our public filings with the U.S. Securities and
Exchange Commission, including our most recent Annual Report on
Form 10-K and subsequent Quarterly Reports on Form 10-Q. Except as
otherwise noted, these forward-looking statements speak only as of
the date of this press release and we undertake no obligation to
update or revise any of these statements to reflect events or
circumstances occurring after this press release. We caution
investors not to place considerable reliance on the forward-looking
statements contained in this press release.
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version on businesswire.com: http://www.businesswire.com/news/home/20160108005281/en/
ARIAD PharmaceuticalsFor InvestorsMaria Cantor,
617-621-2208Maria.cantor@ariad.comorFor MediaLiza Heapes,
617-621-2315Liza.heapes@ariad.com
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