Approval triggers $10 million milestone payment
to ARIAD
ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that
its partner Otsuka Pharmaceutical Co., Ltd. (Otsuka) has received
approval from the Japanese Pharmaceuticals and Medical Devices
Agency (PMDA) for Iclusig® (ponatinib) for the treatment of chronic
myeloid leukemia (CML) resistant or intolerant to preceding drug
treatment and relapsed or treatment resistant Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
“Our collaboration with Otsuka has resulted in today’s approval
of Iclusig in Japan, providing an important new treatment for
patients with refractory CML and Ph+ ALL,” stated Paris
Panayiotopoulos, president and chief executive officer of ARIAD.
“Japan represents a large market opportunity for Iclusig and its
first approval in Asia. We are committed to expanding patient
access and to continuing our successful partnership with Otsuka as
evidenced by recent marketing applications for Iclusig submitted in
Korea and Taiwan.”
This approval triggers a $10 million milestone payment to ARIAD
from Otsuka under the parties’ collaboration agreement entered in
December 2014.
”Treatment failure affects a substantial proportion of CML
patients treated with tyrosine kinase inhibitors due to resistance
or intolerance. For these patients living with CML in Japan, we are
grateful to have Iclusig as a new approved treatment option,” said
Arinobu Tojo, M.D., Ph.D, deputy director, Research Hospital, The
Institute of Medical Science at the University of Tokyo.
The PMDA filing was supported by a Phase 1/2 study in Japanese
patients as well as the international 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
confirmed that Iclusig demonstrated anti-leukemic activity in this
patient population. Among the 17 chronic-phase patients, 65 percent
achieved the primary efficacy endpoint of major cytogenetic
response, and 35 percent 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
occlusive events were reported in four patients, or 11 percent.
About Iclusig® (ponatinib)
tabletsIclusig 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, Canada and Japan.
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.
Limitations of use: Iclusig is not indicated and is not
recommended for the treatment of patients with newly diagnosed
chronic phase CML.
IMPORTANT U.S. SAFETY INFORMATION, INCLUDING THE BOXED
WARNINGWARNING: 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.
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.
Increased Toxicity in Newly Diagnosed Chronic Phase CML:
In a prospective randomized clinical trial in the first line
treatment of newly diagnosed patients with chronic phase (CP) CML,
single agent Iclusig 45 mg once-daily increased the risk of serious
adverse reactions 2-fold compared to singe agent imatinib 400 mg
once-daily. The median exposure to treatment was less than 6
months. The trial was halted for safety in October 2013. Arterial
and venous thrombosis and occlusions occurred at least twice as
frequently in the Iclusig arm compared to the imatinib arm.
Compared to imatinib-treated patients, Iclusig-treated patients
exhibited a greater incidence of myelosuppression, pancreatitis,
hepatotoxicity, cardiac failure, hypertension and skin and
subcutaneous tissue disorders. Iclusig is not indicated and is not
recommended for the treatment of patients with newly diagnosed CP
CML.
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.
About ARIAD
ARIAD Pharmaceuticals, Inc., headquartered in Cambridge,
Massachusetts is focused on discovering, developing and
commercializing precision therapies for patients with rare cancers.
ARIAD is working on new medicines to advance the treatment of rare
forms of chronic and acute leukemia, lung cancer and other rare
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 31,000 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; the anticipated market opportunity for Iclusig in Japan;
the receipt of a milestone payment from Otsuka; and ARIAD’s and
Otsuka’s plans to expand patient access and seek potential
approvals in other Asian countries, 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 successfully commercialize and generate profits
from sales of our products; 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; competition from alternative therapies; our reliance on
the performance of third-party manufacturers and specialty
pharmacies or our collaborators for the supply and distribution of
our products and product candidates; the occurrence of adverse
safety events with our products and product candidates; the costs
associated with our research, development, manufacturing,
commercialization 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; the ability to satisfy our contractual
obligations, including under our leases, convertible debt and
royalty financing agreements; patent protection and third-party
intellectual property claims; litigation; our operations in foreign
countries; 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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ARIAD Pharmaceuticals, Inc.For InvestorsManmeet S. Soni,
617-503-7298Manmeet.soni@ariad.comorFor MediaLiza Heapes,
617-621-2315Liza.heapes@ariad.com
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