Ponatinib Wins Early FDA Nod

Ponatinib Wins Early FDA Nod

By John Gever, Senior Editor, MedPage Today

Published: December 14, 2012

SILVER SPRING, Md. -- The FDA has approved ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor, to treat two forms of drug-resistant leukemia, the agency said Friday.

The approved indications include chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) in adults.

The FDA noted that it was approving ponatinib 3 months before its official deadline for acting on the drug's marketing application.

Approval was based on a single phase II trial, results of which were reported last week at the American Society of Hematology's annual meeting.

In the 449-patient study, called PACE, rates of major cytogenetic and hematologic responses to daily oral treatment with ponatinib ranged from 33% to 70%, depending on the disease subtype. Toxicities were generally mild, except for a few patients who experienced serious pancreatitis.

The drug was designed to get around one of the most common mutations that confer resistance to tyrosine kinase inhibitors (TKIs), the "gatekeeper" T315I substitution that blocks binding for all three currently approved drugs: imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Ponatinib is considered a pan-BCR-ABL inhibitor because it is effective against native and all tested mutant forms of the BCR-ABL protein produced by the Philadelphia chromosome, which gives rise to CML and Ph-positive ALL.

Patients in the trial had previously failed other tyrosine kinases, with most showing resistance or intolerance to dasatinib or nilotinib.

But the FDA's announcement of the approval did not say that patients should not receive ponatinib as first-line treatment.

Response rates in the PACE trial were highest in patients with chronic- and acute-phase CML, ranging from 50% to 70%. For patients with blast-phase CML or Ph-positive ALL, response rates were in the 33% to 35% range.

Common side effects were rashes, dry skin, abdominal pain, headache, and constipation, all seen in about 40% of patients. Most cases were reported to be mild.

Nevertheless, the drug's label will include a boxed warning about blood clots and liver toxicity, the FDA said.

"The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options," said Richard Pazdur, MD, director of the FDA's Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research, in an agency statement.

Ponatinib was approved under the FDA's accelerated approval program, which requires the drug's manufacturer to perform additional studies to confirm the product's benefit and safety. The agency did not indicate what shape those studies would take.

The drug will be sold by Ariad Pharmaceuticals in Cambridge, Mass.