FDA approves ponatinib for CML and Ph-positive ALL

Ponatinib, an oral tyrosine kinase inhibitor, has been approved for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults, the Food and Drug Administration announced on Dec. 14.

The expedited approval – which came 3 months ahead of the agency’s target date for action on ponatinib – gives a new option to patients who have stopped responding to other approved therapies for these fatal blood cancers. A BCR-ABL inhibitor, ponatinib is the only drug to date that has shown efficacy in chronic myeloid leukemia (CML) with the T315I mutation.

Dr. Jorge Cortes

Ponatinib will be marketed as Iclusig by Ariad Pharmaceuticals. The company said it will be available in the United States in about 2 weeks via "select specialty pharmacies." It also announced establishment of the ARIAD PASS (Patient Access and Support Services) program to help patients who are without insurance or underinsured gain access to ponatinib.

The approved indication is for "chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy."

The recommended dose is 45 mg once daily.

The prescribing information notes that the approved indication is based upon response rate, and that "there are no trials verifying an improvement in disease-related symptoms or increased survival," with treatment.

The expedited approval was based on the results of one study of 449 patients with various phases of CML and Ph+ALL, who were treated with ponatinib.

Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported 12-month outcomes of the pivotal phase II PACE trial earlier in December at the American Society of Hematology annual meeting in Atlanta.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia-positive patients with acute lymphoblastic leukemia," he said at a press briefing during the meeting.

"These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated."

In the study, 54% of all patients and 70% of those with the T315I mutation had a major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PcyR). At the time the data were analyzed, the median duration of MCyR had not been reached, according to the FDA.

In addition, 52% of those with accelerated phase CML had a major hematologic response (MaHR) that lasted for a median of 9.5 months; 31% of those with blast-phase CML had a MaHR that lasted for a median duration of 4.7 months; and 41% of those with Ph-positive ALL had a MaHR that lasted for a median of 3.2 months.

The most common side effects in the study included hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. The label includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

It is the third drug approved for CML and the second drug approved for ALL this year. The other treatments approved for various phases of CML this year are bosutinib (Bosulif) in September and omacetaxine mepesuccinate (Synribo) in October. In August, vincristine sulfate liposome injection (Marqibo) was approved to treat Philadelphia chromosome–negative ALL.

About 5,000 people a year develop CML, which has become a chronic condition for most patients since the introduction of imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) – all approved as first-line therapies. But some people cannot tolerate or become resistant to these drugs, and those with T315I did not respond.

Consequently, ponatinib was granted a priority review, which is completed in 6 months instead of the standard 12 months, and is used for drugs "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," 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," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.