ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced long-term follow-up data from the Phase 1 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). With a median follow-up of over four years (53.1 months), Iclusig continues to demonstrate anti-leukemic activity in chronic-phase (CP) CML patients with limited treatment options (n=43). Overall, 72 percent of CP-CML patients achieved a major cytogenetic response (MCyR) on trial, 65 percent a complete cytogenetic response (CCyR) and 56 percent a major molecular response (MMR). Long-term safety data on ponatinib indicate that benefit-risk evaluations should guide decisions to initiate and maintain therapy, particularly in patients who may be at increased risk for arterial occlusive events. These data are included in a poster presentation today at the Annual Meeting of the American Society of Clinical Oncology taking place in Chicago. "With more than half of the CP-CML patients still on study after a minimum of four years, ponatinib continues to maintain anti-leukemic responses in this heavily pre-treated patient population," stated Moshe Talpaz, M.D., The Alexander J. Trotman Professor of Leukemia Research, Associate Director of Translational Research, Co-Director of Hematologic Malignancies/BMT Program at the University of Michigan Comprehensive Cancer Center. "We are continuing to study the profile of ponatinib and the impact of dose reductions in patients with CML and Ph+ ALL for whom there are limited treatment options and the potential benefit outweighs the risk." Phase 1 Trial Long-Term Data The Phase 1 dose-escalation study of ponatinib (dose range, 2 to 60 mg once daily) enrolled 81 patients with resistant or refractory hematologic cancers, including 43 patients with CP-CML. Sixty percent of CP-CML patients in this study had failed at least three prior tyrosine kinase inhibitors (TKI), and 98 percent received at least two prior TKIs. Twenty-two CP-CML patients (51 percent) remain on study. Data presented at ASCO focus on CP-CML patients and represent follow-up through February 2, 2015.
- Median follow-up for CP-CML patients is over 4 years (53.1 months) with a maximum follow-up of six years (69.9 months).
- Of 22 ongoing CP-CML patients, 14 are receiving a dose of 15 mg/day ponatinib or less, 5 on 30 mg/day, and 3 on 45 mg/day; the mean current dose is 22.5 mg/day. The median dose intensity for these patients during the course of the study was 33.7 mg/day.
- Anti-leukemic activity continues to be observed with ponatinib treatment:
- 72 percent of CP-CML patients achieved MCyR, 65 percent CCyR and 56 percent MMR. Of note, 77 percent (17/22) of ongoing CP-CML patients are in deep molecular response of MMR or better,
- The median times to MCyR, CCyR and MMR were 2.8, 5.5 and 7.4 months, respectively.
- By Kaplan-Meier estimate, the probability of CP-CML patients maintaining MCyR at 4 years was 71 percent.
- Ten of the 15 CP-CML patients (67%) who started ponatinib at a dose of 30 mg or less achieved MCyR.
- Of the 12 CP-CML patients with the T315I mutation enrolled in the trial, 1 discontinued; 10 of the 11 CP-CML patients with the T315I mutation who remained on study achieved MCyR, with 8 of 10 in continuous MCyR.
- The most common treatment-emergent adverse events (≥ 50%) occurring in CP-CML patients were rash (65%), fatigue (63%), abdominal pain (58%), headache (58%), arthralgia (53%), and constipation (51%).
- The most common serious treatment-emergent adverse events were abdominal pain, atrial fibrillation, myocardial infarction, and pancreatitis (n=4 each).
- Thirty percent (n=13) of CP-CML patients experienced a serious arterial occlusive event (AOE); 40 percent (n=17) of CP-CML patients experienced an AOE of any severity. Two patients experienced a venous thromboembolic event (VTEs); no serious VTEs were observed. No patient death was attributed to an AOE or VTE. No new AOEs have been reported since study data were last reported in December 2014 (data as of September 26, 2014).
"The long-term follow-up results from the Phase 1 study of ponatinib in patients with chronic myeloid leukemia in the chronic phase show that responding patients can achieve lasting, deep responses," said Frank G. Haluska, M.D., Ph.D., chief medical officer and senior vice president, clinical R&D at ARIAD. "As we expect to start enrolling patients into the randomized OPTIC ( Optimizing Ponatinib in CML) dose-ranging study shortly, the observed robust response rates and response durations support exploring lower doses in refractory patients."About Iclusig ® (ponatinib) tablets Iclusig is approved in the U.S., EU, Switzerland, Australia, Canada and Israel. 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. 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.
Iclusig ® is a registered trademark of ARIAD Pharmaceuticals, Inc.