FDA Warns of Possibly Fatal Blood Clots With Ponatinib

The US Food and Drug Administration (FDA) issued a safety alert and reports it is investigating a high rate of thrombosis and other cardiovascular events in patients taking ponatinib (Iclusig, Ariad Pharmaceuticals) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Ponatinib, approved by the FDA in December 2012, already contained labeling warnings about blood clots. In trials that led to approval, the rate of serious arterial clots was 8%, venous blood clots were reported in 2.2% of patients. Now, new data from the PACE trial show that after a median follow-up of 24 months, serious arterial thrombosis occurred in 11.8% of patients receiving the drug. Cardiovascular events were most common (6.2%), followed by cerebrovascular events (4%) and peripheral vascular events (3.6%; some patients had more than one type of event). The rate of serious venous occlusion rose to 2.9% of patients.

According to the company that makes ponatinib, the increased totals of adverse events has not increased the incidence rate of arterial thrombotic events when normalized to the duration of treatment. The rate in the original analysis was 10 events per 100 patient-years, and has actually now dropped to 9.6 events per 100 patient-years. Still, non-serious plus serious arterial and venous events now have occurred in approximately 20% of patients treated with ponatinib.

The FDA says it is “actively working to further evaluate these adverse events and will notify the public when more information is available.” Ariad Pharmaceuticals, meanwhile, has outlined several steps it is taking in response to the safety alert. First, it has paused patient enrollment in all clinical trials of ponatinib; according to ClinicalTrials.gov, there are currently 10 trials actively recruiting patients that this may affect.

Patients currently enrolled in the EPIC trial comparing ponatinib and imatinib in newly diagnosed CML (ponatinib is currently approved only in CML that has proven resistant or intolerant to previous tyrosine kinase therapy) will have their dose of ponatinib reduced from 45 mg to 30 mg daily. If patients have achieved a major molecular response or achieve one in the future the dose will be further reduced to 15 mg per day. Other clinical trial patients will continue on the drug, but dose reductions will proceed on “a trial-by-trial” basis.

Finally, the eligibility criteria for future trials of ponatinib will be adjusted to exclude patients who have experienced arterial thrombosis resulting in heart attack or stroke in the past.

“We believe that the actions we are taking will help us ensure the most appropriate and safe use of Iclusig,” said Harvey J, Berger, MD, chairman and CEO of Ariad, in a press release. “With 2 years of follow-up, we have learned a great deal about both the efficacy and safety of Iclusig.” In spite of the increased thrombosis signal, the company points out the continued efficacy of ponatinib in the PACE trial; over 90% of patients who achieved a major cytogenetic response maintained that response after a median of 19 months in spite of dose reductions.