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 years for chronic-phase CML (CP-CML)
patients in the trial, Iclusig continues to demonstrate
anti-leukemic activity in patients with limited treatment options.
Deep and durable responses have been maintained in CP-CML patients
with 83 percent of CP-CML patients who achieved a response,
estimated to remain in major cytogenetic response (MCyR) at three
years.
Additionally, the rate of maintenance of response in CP-CML
patients was high (greater than 90%) in patients who underwent
Iclusig dose reductions. Long-term safety data confirm that careful
benefit-risk evaluations should guide the decision to use and then
maintain Iclusig therapy, particularly in patients who may be at
increased risk for arterial thrombotic events.
The data were featured in a poster presentation on Sunday
December 7, at the 56th Annual Meeting of the American Society of
Hematology (ASH) taking place in San Francisco.
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 treated in the
PACE trial had failed two or more prior tyrosine kinase inhibitors
(TKI), and 58 percent had failed three or more prior TKIs.
Updated data in CP-CML patients (n=270) from the ongoing trial
indicate that with a median follow-up of 38.4 months (data as of
October 6, 2014), 121 patients (45%) continue to receive ponatinib.
Additional data in CP-CML patients include:
- 55% of CP patients met the primary
endpoint of MCyR by 12 months.
- 83% of patients who responded 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 61%.
- Overall survival at 3 years is
estimated to be 82%.
- 22% of CP patients experienced an
arterial thrombotic serious adverse event (SAE), and 27 percent of
CP-CML patients experienced any arterial thrombotic event,
independent of severity or attribution of relationship to
ponatinib. There was no increase in the exposure-adjusted incidence
of newly occurring arterial thrombotic events with longer
follow-up.
- 4% of CP patients experienced a venous
thrombotic SAE.
- The most common all-grade
treatment-emergent adverse events in CP-CML were rash (46%),
thrombocytopenia (45%), abdominal pain (45%), headache (43%),
constipation (41%) and dry skin (41%); the discontinuation rate for
adverse events was 17% in CP-CML.
“With a median follow-up of 3 years, there is no question that
these are very meaningful responses in a refractory CML patient
population. Responses such as this in a heavily pretreated patient
population are very encouraging,” stated Jorge E. Cortes, M.D.,
Professor and Department Chair, Department of Leukemia, The
University of Texas MD Anderson Cancer Center. “Careful
benefit-risk evaluation should guide the decision to initiate
ponatinib therapy, particularly in patients who may be at increased
risk for arterial thrombotic events. Ponatinib continues to be a
valuable treatment option for patients with refractory CML and Ph+
ALL for whom the need and potential benefit outweigh the risk.”
Efficacy Update Following Prospective Dose-Reduction
Recommendations(Data from October 10, 2013 to October 6,
2014)
On October 10, 2013, following a partial clinical hold placed on
new patient enrollment in ARIAD-sponsored trials of ponatinib,
dose-reduction recommendations were provided by ARIAD to
investigators for patients remaining on the 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 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.
Now, with approximately one year of follow-up after these
recommendations, the rate of maintenance of response overall in
CP-CML is high -- whether or not patients underwent prospective
dose reductions.
- Of the 64 patients who were in MCyR at
the time of dose reductions, 61 patients (95%) maintained their
response at 1 year following dose reduction to either 30 mg or 15
mg.
- Of the 47 patients who were in MMR at
the time of dose reductions, 44 patients (94%) maintained their
response at 1 year following dose reduction to either 30 mg or 15
mg.
- 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 more year of ponatinib
treatment.
Safety Update Following Prospective Dose-Reduction
Recommendations (Data from October 10, 2013 to October 6,
2014)
- Of the patients who underwent
prospective dose reduction, 5 of 70 patients (7%) without prior
events had a new arterial thrombotic event during the twelve-month
interval following prospective dose reduction.
- Of the patients who did not undergo
prospective dose reduction, 7 of 67 patients (10%) without prior
events had a new arterial thrombotic event in the same time
interval.
“These data show that the majority of patients in the PACE trial
retained response, 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 a randomized trial set to begin next
year.”
About Iclusig® (ponatinib) tablets
Iclusig is approved in the U.S., EU, Australia and
Switzerland.
In the US, 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.
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).
This press release contains “forward-looking statements”
including, but not limited to, statements relating to updated
clinical data for ponatinib. 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.
Iclusig® is a registered trademark of ARIAD Pharmaceuticals,
Inc.
ARIAD Pharmaceuticals, Inc.For InvestorsKendra
Adams, 617-503-7028Kendra.adams@ariad.comorFor MediaLiza
Heapes, 617-620-4888Liza.heapes@ariad.com
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