Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that the U.S.
Food and Drug Administration (FDA) has approved revised U.S. Prescribing
Information (USPI) and a Risk Evaluation and Mitigation Strategy (REMS)
for Iclusig® (ponatinib) that allows immediate resumption of
its marketing and commercial distribution. The USPI includes a revised
indication statement and boxed warning, updated safety information and
recommendations regarding dosing considerations for prescribers.
ARIAD Pharmaceuticals, Inc., based in Cambridge, MA
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Iclusig is now 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 (Ph+) acute lymphoblastic leukemia, and
Chronic phase, accelerated phase, or blast phase chronic myeloid
leukemia or Ph+ acute lymphoblastic leukemia for whom no other
tyrosine-kinase inhibitor therapy is indicated.
The FDA granted approval of the revised USPI based on its review of the
Iclusig clinical-trial data, including 24-month follow up of the pivotal
PACE trial. The boxed warning has been revised to alert patients and
healthcare professionals to the risk of vascular occlusive events and
includes a new warning for heart failure. The starting dose of Iclusig
remains 45 mg daily.
"In less than two months of suspending marketing and commercial
distribution of Iclusig in the U.S., we addressed the issues raised by
the FDA and now are able to market and distribute Iclusig again in the
U.S.," stated Harvey J. Berger, M.D. chairman and chief executive
officer of ARIAD. "As we look ahead to re-launching Iclusig in the U.S.
and fulfilling our post-marketing requirements, we will continue to
focus on understanding the benefits and risks of Iclusig treatment in
patients with resistant or intolerant Philadelphia-positive leukemias."
At the end of October 2013, there were approximately 640 patients
receiving Iclusig obtained through commercial channels in the U.S. Since
then, Iclusig has been made available through emergency and
single-patient investigational new drug (IND) applications, which were
reviewed and approved by the FDA on a case-by-case basis. Through today,
FDA has approved 350 INDs. This figure includes approximately 260
patients who have already received Iclusig and approximately 90
additional patients who have been approved to receive Iclusig through
"We are committed to continuing our productive collaboration with the
FDA and to helping patients and their physicians make informed decisions
about the most appropriate use of Iclusig in the context of the revised
product label," stated Frank Haluska, M.D., Ph.D., senior vice president
and chief medical officer of ARIAD.
"Commercial distribution of Iclusig will begin by mid-January at which
time we will deploy dedicated commercial and medical affairs teams in
the U.S. In the meantime, patients will continue to receive Iclusig
through the IND mechanism," stated Marty Duvall, executive vice
president and chief commercial officer. "We expect the commercialization
of Iclusig to be cash-flow positive from the onset."
REMS Program and Post-Marketing Requirements
The objective of the REMS program is to inform prescribers of the risk
of vascular occlusion associated with Iclusig and of the revised
indications. The REMS program, which will be initiated within three
weeks, includes letters to physicians and professional societies, a fact
sheet and information that will be communicated through professional
journals and displayed at scientific meetings. All of these materials
will be available on an Iclusig REMS website.
In addition, ARIAD has agreed to fulfill a series of post-marketing
requirements beginning in 2014 to better understand the risks of
vascular occlusion and to further explore various doses of Iclusig, as
Enhanced pharmacovigilance assessment of risk factors for, and the
management and consequences of, vascular occlusive events that are
serious or require medical evaluation or treatment, occurring while
patients are receiving Iclusig administered in clinical trials or
obtained through commercial channels,
Prospective observation of patients on Iclusig obtained through
commercial channels to evaluate the incidence of, and risk factors
for, vascular occlusive events when Iclusig is given with or without
anticoagulant or antiplatelet agents,
Continued follow-up of patients from the three ARIAD-sponsored trials
of Iclusig in Philadelphia-positive leukemias to assess the long-term
safety of Iclusig treatment, including the long-term risk of vascular
occlusive events, and
A randomized, multi-arm trial to characterize a range of Iclusig doses
and to inform its safe use in patients with refractory, chronic-phase
chronic myeloid leukemia.
Today's Conference Call at 11:30 a.m. ET
ARIAD management will host a conference call and webcast to discuss the
approval of a new U.S. product label for Iclusig today, December 20 at
11:30 a.m. ET. The live webcast can be accessed by visiting the investor
relations section of the Company's website at http://investor.ariad.com.
The call can be accessed by dialing 888-771-4371 (U.S.) or +1
847-585-4405 (international) and providing the participant code
36331249. A replay of the call will be available on the ARIAD website
approximately two hours after completion of the call and will be
archived for three weeks.
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.
IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING
WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY
See full U.S. 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.
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
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 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, the timing and financial success of the resumption of
commercial marketing and sales of Iclusig; the Company's ability to
fulfill the four post-marketing requirements to the satisfaction of the
FDA; the timing and results of the enhanced pharmacovigilance study, the
prospective observational study and the long-term follow-up of subjects
in Iclusig clinical studies; the timing, enrollment and results of the
randomized, multi-arm trial to characterize a range of Iclusig doses;
and the safety profile for Iclusig as it continues to be studied.
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.
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ARIAD Pharmaceuticals, Inc.
Bill Berry, 212-253-8881