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ARIAD Pharmaceuticals, Inc.
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
56^th 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.”
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