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 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.
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.
- 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.
- 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.
About Iclusig® (ponatinib) tabletsIclusig 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.
- 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.
Iclusig ® is a registered trademark of ARIAD Pharmaceuticals, Inc.