Ponatinib Withdrawn: A Pharmaceutical Tragedy

The next issue of The Medical Letter (November 25, 2013) will include an In Brief article on the suspension, at the FDA’s request, of the marketing and sales of ponatinib (Iclusig), a tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (ALL).

Ponatinib was the 5th tyrosine kinase inhibitor approved by the FDA for these indications, but it is not just another me-too drug. The prototype tyrosine kinase inhibitor, imatinib (Gleevec), achieved previously unheard-of rates of remission in patients with CML and ALL. When resistance developed to imatinib, the newer drugs dasatinib (Sprycel) and nilotinib (Tasigna) came along and produced major cytogenetic responses in a high percentage of imatinib-resistant patients, but then resistance developed to these agents as well. One thing imatinib, dasatinib, and nilotinib had in common was ineffectiveness against the T315I mutation, which could be detected in 20% of treatment-resistant CML. Ponatinib produced a major cytogenetic response in 70% of patients with the T315I mutation.

Its toxicity, unfortunately, is also impressive, apparently driven by an acceleration of atherosclerosis leading to a high incidence of arterial thrombosis and its consequences: stroke, heart failure, even blindness. But atherosclerosis, even bad atherosclerosis, is something many people live with, sometimes for decades. Patients with treatment-resistant leukemia don’t do well. Will we take away a drug that can put 70% of them into remission?

According to “The Pink Sheet” (November 4, 2013), a highly reliable trade publication, the manufacturer of Iclusig (Ariad Pharmaceuticals) and the FDA will probably work something out by creating what the government calls a Risk Evaluation and Mitigation Strategy with a restricted distribution program so that patients who don’t really need ponatinib will not be exposed to its risks. I hope they do. Everyone worries about drug safety, but let’s not forget the baby in the bath.

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