Because of concerns about serious cardiovascular side effects, the U.S. Food and Drug Administration asked Ariad Pharmaceuticals to temporarily suspend sales and marketing of ponatinib to treat chronic myeloid leukemia in patients resistant to first-line therapy.

Citing serious cardiovascular side effects, the U.S. Food and Drug Administration (FDA) asked Ariad Pharmaceuticals of Cambridge, MA, to temporarily suspend sales and marketing of ponatinib (Iclusig) to treat chronic myeloid leukemia (CML) in patients resistant to first-line therapy.

The FDA's October 31 request to suspend sales of ponatinib—which received accelerated approval in December 2012—followed an ongoing FDA investigation into serious arterial thrombotic events reported during the single-arm phase II PACE trial, which enrolled CML patients who failed to respond to imatinib (Gleevec; Genentech) or carried the T315I mutation.

At the time of the request, FDA investigators reported an increased frequency of serious adverse vascular events since the drug was approved, with 24% of patients enrolled in the phase II PACE trial (median treatment 1.3 years) and 48% of patients in the phase I PACE trial (median treatment 2.7 years) experiencing such events.

In an analysis of the phase II study, performed in November 2012 with a median follow-up of 15 months and published in the New England Journal of Medicine, researchers initially reported a 7.6% rate of patients with serious adverse arterial thrombosis events [N Engl J Med 2013;369:1783–96]. That rate prompted a boxed warning for these side effects when the drug was approved. After the overall rate of serious adverse vascular events rose in subsequent months, Ariad suspended the PACE trial and terminated the phase III EPIC trial, a first-line randomized trial of ponatinib versus imatinib.

The FDA says it will continue to evaluate ponatinib in order to determine whether the benefits may outweigh the risks for some patient populations. Patients enrolled in the trial who benefited from ponatinib may continue treatment under an emergency Investigational New Drug application filed by their physician.

“We know that cardiovascular risk is an evolving problem with cancer patients as you deal with problematic populations who have been previously treated,” says Christopher-Paul Milne, DVM, MPH, JD, director of research at the Tufts Center for the Study of Drug Development in Boston, MA. “Whatever underlying cardiovascular risk there was may be increased with second- and third-line agents.”

Despite the significant risk of adverse events with ponatinib, suspension might have been avoided under a better system for monitoring and reporting adverse events, says Javid Moslehi, MD, codirector of the cardiooncology program at Dana-Farber Cancer Institute in Boston.

“Currently, National Cancer Institute criteria for reporting adverse events with cancer drugs are different than ones used for other classes of drugs such as cardiovascular drugs, compromising the detection of cardiotoxicity,” says Moslehi, who coauthored a perspective on the PACE study findings [N Engl J Med 2013;369:1779–81].

“If we know the root of the problem we can address it,” he says. “It could be because of rapidly progressing atherosclerosis, and it could be very helpful if you treat those patients with a statin.” Similarly, patients with arterial clots might be pretreated with aspirin or the blood clot preventer Plavix (clopidogrel; Bristol-Myers Squibb and Sanofi), and those with vasospasm could be started on nitrates to open up the artery.

The suspension of ponatinib also raises questions about whether the accelerated approval process exposes patients to excessive risk. However, it appears as if the process worked well in this case, says Milne.

“This issue only came to the FDA's attention a few weeks ago, and they acted on it quickly,” he says. “It shows that they are increasing the ways they can make decisions in the post-marketing scenario.”

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