ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced
safety and efficacy follow-up data on Iclusig® (ponatinib), its
approved BCR-ABL inhibitor, in patients with a baseline T315I
mutation from its Phase 1 and Phase 2 PACE trials in heavily
pretreated patients with resistant or intolerant chronic myeloid
leukemia (CML) or Philadelphia chromosome-positive acute
lymphoblastic leukemia (Ph+ ALL).
With a median follow-up of three years for CP-CML patients and
nine months overall, Iclusig continues to exhibit responses in
patients with the T315I mutation, for whom there is no other
approved tyrosine kinase inhibitor (TKI) therapy. Among patients
with the T315I mutation, major cytogenetic response (MCyR) was
achieved by 92 percent (11/12) of chronic phase CML patients
(CP-CML) in the Phase 1 trial and 72 percent (46/64) of CP-CML
patients in the PACE trial; taken together, the combined MCyR rate
for all T315I CP-CML patients was 75 percent. Long-term safety data
show that careful benefit-risk evaluations should guide decisions
to use and maintain ponatinib therapy, particularly in patients who
may be at increased risk for arterial thrombotic events.
These data were featured on Monday December 8, at the 56th
Annual Meeting of the American Society of Hematology (ASH) taking
place in San Francisco.
“For CML patients with the T315I mutation, there were few
treatment options available prior to ponatinib, and prognosis for
these patients was poor. Now, with nearly six years of treatment
for some patients in these trials, we have longer term data
demonstrating that ponatinib continues to evoke responses in these
CP-CML patients,” stated Michael J. Mauro, M.D., Leader,
Myeloproliferative Neoplasms Programs, at the Memorial Sloan
Kettering Cancer Center. “With these follow-up data, overall
survival of 78 percent is now estimated at three years for
chronic-phase patients with the T315I mutation in these
trials.”
Phase 1 and PACE Data in Patients with T315I
The analysis describes the pooled efficacy and safety of
ponatinib in patients with a T315I mutation detected at baseline
from the ongoing Phase 1 dose-escalation study and Phase 2 PACE
trials. The analysis includes 147 patients with a T315I mutation
from the Phase 1 (n=19) and PACE (n=128) trials. Half of the 76
CP-CML patients with T315I remain on treatment and 44 (30%) total
patients (all disease phases) with T315I remain on treatment in the
respective trials. Data presented on these patients are as of
September 26, 2014 for the Phase 1 trial and October 6, 2014 for
the PACE trial.
- Median follow-up for all T315I patients
in this analysis is 8.9 months. The median follow-up for CP-CML
patients with T315I (n=76) is three years (maximum follow-up, 70
months).
- In these heavily pre-treated T315I
patients, 45 percent of the total patients had received treatment
with two prior TKIs, and 40 percent had received three or more
prior TKIs. In patients with CP-CML, 46 percent had received two
prior TKIs, and 39 percent had three or more prior TKIs.
- For CP patients, responses continue to
be observed in T315I patients treated with ponatinib at 3 years. In
the combined analysis of these patients from both trials:
- 75 percent of all CP-CML patients
achieved MCyR, 72 percent achieved a complete cytogenetic response
(CCyR), and 61 percent achieved a major molecular response
(MMR).
- By Kaplan-Meier estimate, 83 percent of
these CP patients were estimated to maintain MCyR at 3 years, and
81 percent were estimated to maintain CCyR at 3 years. The median
duration of response has not yet been reached.
- 58 percent of advanced phase (AP) CML
patients with T315I achieved major hematologic response (MaHR), the
end-point for those patients in the trials. Twenty-seven percent of
blast phase (BP) CML patients, and 38 percent of Ph+ ALL patients
achieved MaHR.
- The probability for overall survival in
CP patients with T315I at 36 months is 78 percent and 63 percent
for patients with AP-CML.
- The most common treatment-emergent
adverse events in T315I patients (all disease phases) were rash
(42%), abdominal pain (39%), headache (39%), and nausea (36%). The
most common serious treatment-emergent adverse events were neoplasm
progression (10%), pneumonia (7%), and acute myocardial infarction
(5%).
- Thirty-two percent (n=24) of CP-CML
patients with T315I experienced arterial thrombotic events, and 7
percent experienced a venous thrombotic event (VTE).
Exposure-adjusted incidences of arterial and venous thrombotic
events in patients with the T315I mutation were similar to those
observed in the overall patient population.
“Ponatinib is the only TKI approved for patients with the T315I
mutation of BCR-ABL, which is a common mutation that is associated
with resistance in Philadelphia-positive leukemias,” said Frank G.
Haluska, M.D., Ph.D., chief medical officer and senior vice
president, clinical R&D at ARIAD Pharmaceuticals. “The combined
data from the two ongoing trials of ponatinib show continued,
clinically meaningful responses in this difficult-to-treat patient
population.”
About Iclusig® (ponatinib) tablets
Iclusig is approved in the U.S., EU, Switzerland and
Australia.
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.
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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