FDA Requests Marketing of Ponatinib Be Suspended

In the wake of reports that the drug ponatinib (Iclusig), used to treat resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), can significantly increase risk of dangerous cardiovascular events, the Food and Drug Administration (FDA) has asked the manufacturer to suspend sales and marketing of the drug in the United States.

The request by the FDA, made on October 31, follows a safety alert issued earlier in October. Ariad Pharmaceuticals issued a release on the day of the FDA request announcing it was complying and suspending marketing and commercial distribution “while [the company] continues to negotiate updates to the US prescribing information for Iclusig and implementation of a risk mitigation strategy.” The FDA is now providing specific instructions to health care providers who prescribe the drug to determine the best course of action for patients who are currently benefitting from it. Those who are not responding should “immediately discontinue” its use, according to the FDA statement.

The FDA approved ponatinib in late 2012, and the labeling included warnings about blood clots when first marketed. The most recent data shows that in a phase II trial of ponatinib, almost a quarter of patients (24%) have experienced serious vascular adverse events after a median treatment duration of 1.3 years; these events include fatal and life-threatening MI, stroke, and others. In the phase I trial with a median treatment duration of 2.7 years, nearly half of patients (48%) have experienced related adverse events.

According to the FDA statement, “the phase I and II clinical trials did not include a control group so it is not possible to determine the relationship of these adverse events to Iclusig, however the increasing rate and pattern of the events strongly suggests that many are drug-related.” It is not currently possible, the statement concluded, to determine a dose or exposure level that should be considered safe.

Ariad is complying with all FDA requests on the matter, though the company did make a case for its efficacy when the initial safety alert was issued. A press release cited the persistence of responses in the PACE trial, in which 90% of those patients who achieved a major cytogenetic response maintained the response after a median of 19 months.

Ponatinib also received approval in the European Union for the same indications in July of this year, and marketing there has not been suspended. The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC), responsible for assessing safety and risk signals in the EU, did issue a release on the new information ponatinib on November 8, however. “The PRAC advice is that patients and healthcare professionals may continue to use this medicine with increased caution in its authorized use and should monitor carefully for evidence of thromboembolism… and vascular occlusion,” it said.