ARIAD Announces Updated Data From Pivotal PACE Trial of Ponatinib, its Investigational Pan-BCR-ABL Inhibitor
AMSTERDAM and CAMBRIDGE, Massachusetts, June 18, 2012 /PRNewswire/ –
~ Robust anti-leukemic activity in CML patients who have become resistant or
intolerant to available tyrosine kinase inhibitors
~ 54% major cytogenetic response and 30% major molecular response reported
in heavily pre-treated chronic-phase CML patients
~ Data supports ARIAD filing for EMA approval of ponatinib in Europe
ARIAD Pharmaceuticals, Inc. [http://www.ariad.com ] (NASDAQ: ARIA) today announced
updated clinical data from the pivotal PACE trial of its investigational pan-BCR-ABL
inhibitor, ponatinib [http://www.ariad.com/wt/tertiarypage/AP24534 ], in patients with
chronic myeloid leukaemia (CML) or Philadelphia-positive acute lymphoblastic leukaemia
(Ph+ ALL), who are resistant or intolerant to dasatinib or nilotinib or who have the T315I
mutation. These data show that 54 percent of chronic-phase CML patients in the trial,
including 70 percent of patients who have a T315I mutation, achieved a major cytogenetic
The PACE trial data were featured on Sunday at 8:30 a.m. (CET) in an oral presentation
at the 2012 European Hematology Association (EHA) annual congress taking place in
Amsterdam, The Netherlands. ARIAD expects to file for regulatory approval of ponatinib in
the EU and in the U.S. in the third quarter of 2012 based on these clinical data.
“The pivotal PACE trial data show robust anti-leukaemic activity of ponatinib in
patients with CML at all stages, who are resistant or intolerant to dasatinib or
nilotinib, or who have the T315I mutation, a rare form of CML which has no available
treatment options,” said Jane F. Apperley, professor and chair, Department of Haematology
at the Imperial College, and the chief of service, Clinical Haematology, at the Imperial
College Healthcare NHS Trust, London, England. “Clinical responses to ponatinib were
observed in patients regardless of their mutation status or disease stage, and the
responses appear to be durable, with 93 percent of chronic-phase CML patients projected to
remain in major cytogenetic response at one year. This clearly highlights the potency of
CML [http://www.ariad.com/wt/tertiarypage/AP24534_CML ] is a cancer of the white blood
cells that is diagnosed in approximately 7,000 patients each year in Europe. CML is a
type of leukaemia characterized by the increased and unregulated growth of predominantly
myeloid cells in the bone marrow and the accumulation of these cells in the blood. The
genetic hallmark of CML is the Philadelphia chromosome, an abnormality resulting in a
fusion of the BCR and ABL genes. This is known as Philadelphia chromosome positive CML, or
Treatment of CML usually includes a targeted therapy, a tyrosine kinase inhibitor
(TKI), (e.g. imatinib, dasatinib or nilotinib) followed by chemotherapy if the disease
progresses. Ph+ALL is a subtype of acute lymphoblastic leukaemia that carries the Ph+
chromosome that produces the fused BCR-ABL gene. It is known to have a more aggressive
course than CML and is often treated with a combination of chemotherapy and TKIs. Because
both of these diseases express the BCR-ABL protein, this would render them potentially
susceptible to treatment with ponatinib.
For both diseases, the aim of treatment is to achieve remission of the disease by
reducing the number of Ph+ leukaemia cells and achieving a major cytogenetic response
(MCyR) (less than 35 percent Ph+ cells) or complete cytogenetic response (CCyR) (no Ph+
cells). A molecular response is the next aim of treatment as, even after someone has a
cytogenetic response, there can still be small numbers of leukaemia cells in their blood
which are undetectable by cytogenetic methods. Over time, patients may develop
resistance or insensitivity to currently available targeted therapies (TKIs), impacting
remission of the disease.
“New and effective treatment options are needed to help all CML patients achieve and
maintain an optimal response to therapy. Over time, resistance and/or intolerance to
available TKI therapies continue to be an issue for a significant group of patients,” said
Sandy Craine, founder and director of The CML Support Group. “Data from the PACE trial
show that ponatinib continues to hold real promise as a potential therapy for more
challenging cases, including patients with the multi-drug resistant T315I mutation. In our
view this is very positive news for this more difficult-to-treat population.”
Updated Results Presented at EHA
- Trial Design - Efficacy data were reported at EHA on 444 treated patients in six pre-specified cohorts receiving 45 mg of ponatinib administered orally once daily. - Patients were assigned to a cohort based on their phase of disease (chronic-phase, accelerated-phase or blast-phase CML/Ph+ALL) and T315I mutation status (with or without the mutation). - Ninety-three percent of the patients in the trial had received at least two tyrosine kinase inhibitors prior to enrollment. Fifty-eight percent of the patients had received three or more tyrosine kinase inhibitors prior to enrollment. - Chronic-phase patients had bone marrow assessments approximately every three months for determination of cytogenetic response. Findings on each of the 444 patients treated in the study were based on at least six months of available response data. - The T315I mutation status was determined using a standardized Sanger sequencing test by MolecularMD in Portland, OR.
- Chronic-phase CML patients evaluable for cytogenetic response (N=267) - Based on assessment of all evaluable chronic-phase patients in the trial, 54% (144 of 267) achieved a major cytogenetic response (MCyR), with 44% achieving a complete cytogenetic response (CCyR). The median follow up of the chronic-phase CML patients is 10.1 months. MCyR is the primary end-point for chronic-phase CML patients in this pivotal trial of ponatinib. - Of the 64 evaluable chronic-phase CML patients with the T315I mutation, 70% (45 of 64) of these patients achieved a MCyR, with 66% achieving a CCyR. The MCyR rate in evaluable chronic-phase patients without the T315I mutation was 49% (99 of 203). - Thirty percent (79 of 267) of chronic-phase patients achieved a major molecular response (MMR). Of 64 chronic-phase patients with the T315I mutation, 50% (32 of 64) attained a MMR. MMR is the primary end-point in ARIAD's planned Phase 3 trial of ponatinib against imatinib in newly diagnosed CML patients that is expected to begin in the 3Q of 2012.
- Responses in chronic-phase patients who had received only one prior TKI (N=19) - There were a total of 19 chronic-phase patients treated with ponatinib in the PACE trial who had previously received only one tyrosine kinase inhibitor (TKI). Thirteen of these patients had previously been treated with imatinib only and six had previously received either dasatinib or nilotinib. Of the 19 patients who received ponatinib following treatment with only one prior TKI, 84 percent (16/19) achieved a MCyR.
- Advanced phase CML patients evaluable for response (N=177) - Sixty percent (39 of 65) of accelerated-phase patients in the resistant or intolerant cohort achieved a major hematologic response (MaHR). Fifty percent (9 of 18) of accelerated-phase patients with the T315I mutation achieved a MaHR. MaHR is the primary end-point in accelerated and blast-phase CML or Ph+ALL patients in the trial. - Thirty-five percent (17 of 48) of blast-phase CML or Ph+ALL patients in the resistant or intolerant group achieved a MaHR. Similarly, 33% percent (15 of 46) of blast-phase CML or Ph+ALL patients with the T315I mutation also had a MaHR. - Thirty-four percent (22 of 65) of accelerated phase patients and 27% (13 of 48) of blast phase or Ph+ALL patients in the resistant or intolerant cohorts achieved a MCyR. Twenty percent (13 of 65) of patients in accelerated phase and 23 percent (11 of 48) of patients in blast phase or Ph+ALL in this same group achieved a CCyR.
- Safety profile (N=449) - Updated safety data show ponatinib to have a favorable profile in these heavily pretreated patients. - The most common adverse events considered related to ponatinib included thrombocytopenia (in 35% of patients), rash (32%), dry skin (30%), abdominal pain (22%), and headache (18%). Elevated serum lipase, fatigue and arthralgia were observed less frequently. - The incidence of pancreatitis across the study and including all grades was 6%. Pancreatitis was previously determined to be the dose-limiting toxicity of ponatinib in the Phase 1 trial.
“These updated findings of the PACE trial show beneficial responses and an increasing
molecular response rate to ponatinib,” said Frank G. Haluska, M.D., Ph.D., senior vice
president and chief medical officer of ARIAD. “Importantly, these data provide clear
evidence of a favourable safety and tolerability profile of ponatinib in resistant or
intolerant CML patients. The adverse event profile is similar to what was seen in the
earlier Phase 1 study of ponatinib, although the incidence of pancreatitis is less in the
PACE trial,” added Dr. Haluska.
ARIAD Pharmaceuticals, Inc. is an emerging global oncology company focused on the
discovery, development and commercialization of medicines to transform the lives of cancer
patients. ARIAD’s approach to structure-based drug design has led to several internally
discovered, molecularly targeted product candidates for drug-resistant and
difficult-to-treat cancers, including certain forms of chronic myeloid leukaemia and
non-small cell lung cancer. For additional information, visit http://www.ariad.com.
This press release contains “forward-looking statements” including, but not limited
to, statements relating to the updated clinical data for ponatinib, the positive treatment
effects of ponatinib over time and the timing of regulatory filings for marketing
approvals. 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.
1. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best
Pract Res Clin Haematol
[http://www.ncbi.nlm.nih.gov/pubmed/19959081?dopt=Abstract&reason=0 ]. 2009 Sep;22(3
):295-302. Based on current estimate of population of Europe (738,199,000 in 2010).
2. McMillian Cancer Support web site. Section: What is CML?
Accessed on: 8 June 2012
3. McMillian Cancer Support web site. Section: Treating CML
Accessed on 8 June 2012
4. McMillian Cancer Support web site. Section: Treating CML – Monitoring targeted
Accessed on 8 June 2012
5. McMillian Cancer Support web site. Section: Symptoms & diagnosis – Phases of CML
. Accessed on 8 June 2012
SOURCE ARIAD Pharmaceuticals, Inc.