Median Follow-Up Now Approximately 3.5 Years
for Chronic Phase CML Patients
ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced
long-term follow up from its pivotal Phase 2 trial of Iclusig®
(ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated
patients with resistant or intolerant chronic myeloid leukemia
(CML) or Philadelphia chromosome-positive acute lymphoblastic
leukemia (Ph+ ALL). The study now shows that with a median
follow-up of approximately 3.5 years for chronic phase CML (CP-CML)
patients and a median follow-up of approximately 2.9 years in all
patients in the trial, Iclusig continues to demonstrate
anti-leukemic activity in patients with limited treatment options.
Responses have been maintained long-term in CP-CML patients.
Eighty-three percent (83%) of CP-CML patients who achieved a major
cytogenetic response (MCyR) are estimated to remain in MCyR at
three years.
Additionally, 95 percent of CP-CML patients who underwent
ponatinib dose reductions maintained their responses (MCyR).
Benefit-risk evaluations should guide the decision to initiate and
maintain Iclusig therapy, particularly in patients who may be at
increased risk for arterial occlusive events (AOE).
“These continued responses in the PACE study, with a minimum
follow-up of 3.3 years, in such a heavily pretreated patient
population are very encouraging. Eighty-three percent of CP-CML
patients who achieved the primary endpoint of major cytogenetic
response remain in MCyR at three years,” stated Jorge E. Cortes,
M.D., Professor and Deputy Chair, Department of Leukemia, The
University of Texas MD Anderson Cancer Center. “Careful assessment
of the benefit and risk of initiating ponatinib therapy,
particularly in patients who may be at increased risk for arterial
occlusive events, can help identify patients with refractory Ph+
leukemias who can benefit most from this treatment.”
The data were featured today at the 20th Conference of the
European Hematology Association (EHA) in Vienna, Austria.
PACE Trial Update
The efficacy and safety of ponatinib in CML and Ph+ ALL patients
resistant or intolerant to dasatinib or nilotinib, or with the
T315I mutation, were evaluated in the pivotal Phase 2 PACE trial. A
total of 449 patients were treated with ponatinib at a starting
dose of 45 mg/day. Ninety-three percent of patients had previously
received two or more approved tyrosine kinase inhibitors (TKI), and
55 percent had previously received three or more approved TKIs.
Updated data on CP-CML patients (n=270) from the ongoing trial
indicate that with a median follow-up of 42.3 months (data as of
February 2, 2015), 114 patients (42%) continue to receive
ponatinib. Additional data in CP-CML patients include:
- 59% of CP-CML patients achieved MCyR
(primary endpoint) at any time.
- 83% of patients who achieved MCyR are
estimated to remain in MCyR at 3 years.
- 39% of patients achieved a major
molecular response (MMR) or better.
- By Kaplan-Meier analysis,
progression-free survival at 3 years is estimated to be 60%.
- Overall survival at 3 years is
estimated to be 81%.
- 23% of CP-CML patients experienced an
AOE designated a serious adverse event (SAE), and 28 percent of
CP-CML patients experienced any AOE. The median time to onset for
AOEs in CP-CML patients was 14.1 (0.3–44.0) months.
- 4% and 5% of CP-CML patients,
respectively experienced a venous thromboembolic SAE or AE.
- The most common all-grade
treatment-emergent adverse events occurring in ≥ 40% of CP-CML
patients were abdominal pain (46%), rash (46%), thrombocytopenia
(45%), headache (43%), constipation (41%), and dry skin (41%); the
discontinuation rate due to adverse events was 18% in CP-CML.
“These data show that the majority of CP-CML patients in the
PACE trial retained their anti-leukemic responses, even when
lowering the daily dose of Iclusig,” stated Frank G. Haluska, M.D.,
Ph.D., senior vice president of clinical research and development
and chief medical officer at ARIAD. “The safety and efficacy of
Iclusig at starting doses lower than 45 mg will be studied in the
randomized OPTIC (Optimizing Ponatinib
Treatment In CML) trial set to begin
shortly.”
Efficacy Update Following Prospective Dose-Reduction
Recommendations(Data from October 10, 2013 to February 2,
2015)
On October 10, 2013, dose-reduction recommendations were
provided by ARIAD to investigators for patients remaining on the
PACE trial. The following dose reductions were recommended, unless
the benefit-risk analysis warranted treatment with a higher
dose:
- CP-CML patients who already achieved a
MCyR should have their ponatinib dose reduced to 15 mg/day,
- CP-CML patients who had not already
achieved MCyR should have their dose reduced to 30 mg/day, and
- Advanced-phase patients should have
their dose reduced to 30 mg/day.
As of February 2015, with 1.3 years (16 months) of follow-up
after these recommendations, the rate of maintenance of response in
CP-CML was 95% -- whether or not patients underwent prospective
dose reductions.
- Of the 64 patients who were in MCyR as
of October 10, 2013 and had a prospective dose reduction, 61
patients (95%) maintained their response at 1.3 years following
prospective dose reduction.
- Of the 47 patients who were in MMR as
of October 10, 2013 and had a prospective dose reduction, 44
patients (94%) maintained their response at 1.3 years following
prospective dose reduction.
- 42 patients in MCyR did not undergo any
dose reductions (the majority of which were already at a reduced
dose of 30 mg or 15 mg as of October 10, 2013); of these, 39
patients (93%) maintained MCyR after 1.3 more years of ponatinib
treatment.
Safety Update Following Prospective Dose-Reduction
Recommendations (Data from October 10, 2013 to February 2,
2015)
- Of the patients who underwent
prospective dose reduction, 5 of 71 patients (7%) without prior
AOEs had a new AOE during the 1.3 year interval following
prospective dose reduction.
- Of the patients who did not undergo
prospective dose reduction, 9 of 67 patients (13%) without prior
AOE had a new AOE in the same time interval.
About Iclusig® (ponatinib) tablets
Iclusig is approved in the U.S., EU, Australia, Israel, Canada
and Switzerland.
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.
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).
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 related to:
updated clinical data for Iclusig; the therapeutic potential of
Iclusig and the expected timing for starting to enroll patients in
our OPTIC dose-ranging study, 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: the costs
associated with our research, development, manufacturing and other
activities; the conduct, timing and results of additional clinical
studies of Iclusig and our product candidates; the adequacy of our
capital resources and the availability of additional funding;
safety issues related to Iclusig and those additional 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.
Iclusig® is a registered trademark of ARIAD Pharmaceuticals,
Inc.
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version on businesswire.com: http://www.businesswire.com/news/home/20150612005041/en/
ARIAD Pharmaceuticals, Inc.For InvestorsKendra Adams,
617-503-7028Kendra.adams@ariad.comorFor MediaLiza Heapes,
617-620-4888Liza.heapes@ariad.com
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