~ 82 Percent of CP-CML Patients Who Achieved
MCyR are Estimated to Remain in MCyR at Four Years
~ Overall Survival at Four Years is Estimated
to be 77 Percent
ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) today announced
long-term follow-up data from its pivotal Phase 2 PACE clinical
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). Responses have been maintained
long-term in chronic phase CML (CP-CML) patients. The study shows
that patients treated with Iclusig continued to demonstrate
anti-leukemic activity with a median follow-up of 4.0 years for
CP-CML. Additionally, 96 percent of CP-CML patients who underwent
ponatinib dose reductions while in response maintained their
responses (MCyR) at the four year timepoint.
“We remain very pleased by these continued responses in the PACE
study in such a heavily pretreated patient population, as 59
percent of patients had previously received three or more approved
tyrosine kinase inhibitors (TKIs). Altogether, 82 percent of CP-CML
patients who achieved MCyR are estimated to remain in MCyR at four
years,” stated Jorge E. Cortes, M.D., professor and deputy chair,
department of leukemia, University of Texas MD Anderson Cancer
Center. “These data showing long-term major cytogenic response
offer the optimism of favorable outcomes for many patients who
previously had no or very limited treatment options available.”
The data were featured at the 21st Conference of the European
Hematology Association (EHA) in Copenhagen, Denmark.
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 PACE trial. A total of 449
patients were treated with ponatinib at a starting dose of 45
mg/day. An estimated 93 percent of patients received two or more
approved tyrosine kinase inhibitors (TKIs), and 59 percent of all
patients received three or more approved TKIs. Enrollment in the
PACE trial was completed in October 2011.
Updated data on CP-CML patients (n=270) from the ongoing trial
indicate that with a median follow-up of 48.2 months (data as of
August 3, 2015), 110 patients (41%) continued to receive ponatinib.
Additional data for CP-CML patients include:
- 59 percent of CP-CML patients achieved
MCyR (primary endpoint) at any time.
- 82 percent of patients who achieved
MCyR are estimated to remain in MCyR at four years by Kaplan-Meier
analysis.
- 39 percent of patients achieved a major
molecular response (MMR) or better at any time.
- By Kaplan-Meier analysis,
progression-free survival at four years is estimated to be 56
percent.
- Overall survival at four years is
estimated to be 77 percent.
- 23 percent of CP-CML patients
experienced arterial occlusive events (AOE) that were designated a
serious adverse event (SAE), and 29 percent of CP-CML patients
experienced any AOE.
- 4 percent of CP-CML patients
experienced a venous thromboembolic SAE, and 5 percent of all
patients experienced a venous thromboembolic SAE.
- The most common any-grade
treatment-emergent adverse events occurring in ≥ 20 percent of
CP-CML patients included abdominal pain (46%), rash (47%),
thrombocytopenia (45%), headache (43%), constipation (41%), and dry
skin (42%).
“These data continue to show that ongoing CP-CML patients in the
PACE trial have retained long-term cytogenetic and molecular
responses at a median of four years follow-up,” stated Timothy P.
Clackson, Ph.D., president of research and development and chief
scientific officer at ARIAD. “We currently have two additional
trials underway evaluating Iclusig. Our OPTIC randomized trial
evaluating Iclusig at starting doses of 45 mg/day or lower, is
currently enrolling patients. Outside the U.S., we initiated our
randomized Phase 3 trial of Iclusig in second-line patients with
CP-CML called OPTIC-2L in December of 2015 and expect full
enrollment in the trial in 2018.”
Efficacy Update Following Dose-Reduction
Recommendations
(Data from October 10, 2013 to August 3, 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 August 3, 2015, with an additional 1.9 years (22 months)
of follow up after these recommendations, maintenance of response
(MCyR) in CP-CML patients was 95 percent (56 of 59) and 100 percent
(25 patients), respectively, for patients who were either at 15
mg/day in October 2013 or were reduced to 15 mg/day after October
2013.
- Of the 69 patients who were in MCyR as
of October 10, 2013 and had a dose reduction, 66 patients (96%)
maintained their response at 1.9 years following prospective dose
reduction.
- Of the 51 patients who were in MMR as
of October 10, 2013 and had a dose reduction, 46 patients (90%)
maintained MMR at 1.9 years following dose reduction.
- 35 patients in MCyR did not undergo any
dose reductions (the majority of which were already at a reduced
dose of 30 mg/day or 15 mg/day as of October 10, 2013); of these,
33 patients (94%) maintained MCyR after 1.9 more years of ponatinib
treatment.
Safety Update Following Dose-Reduction Recommendations (Data
from October 10, 2013 to August 3, 2015)
- Of the patients who underwent dose
reduction, six of 75 patients (8%) without prior AOEs had a new AOE
during the 1.9-year interval following dose reduction.
- 31/75 patients reduced from 45 mg to 15
mg
- 25 /75 patients reduced from 30 mg to
15 mg
- 19/75 patients reduced either other
doses (45 mg to 30 mg or not specified)
- Of the patients who did not undergo
dose reduction, 10 of 62 patients (16%) without prior AOE had a new
AOE in the same time interval.
- 36 /62 patients were at 15 mg
- 26/62 were at 45 mg or 30 mg
About Iclusig® (ponatinib) tablets
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,
which has been associated with resistance to other approved
TKIs.
Iclusig is approved in the U.S., EU, Australia, Switzerland,
Israel and Canada.
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 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. 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 an orphan 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 orphan 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 the statements made by Drs.
Cortes and Clackson, 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 ongoing
strategic review, our ability to successfully commercialize and
generate profits from sales of Iclusig and our product candidates,
if approved; competition from alternative therapies; 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; our reliance on the performance
of third-party manufacturers and specialty pharmacies 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.
Iclusig® is a registered trademark of ARIAD Pharmaceuticals,
Inc.
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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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