In December, the FDA granted accelerated approval to ponatinib (Iclusig) for the treatment of adult patients with chronic-, accelerated-, 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 (ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. Ponatinib is an oral, third-generation, pan–BCR-ABL tyrosine kinase inhibitor that targets CML cells with the T315I mutation. The drug was approved more than 3 months ahead of the its prescription user fee goal date of March 27, 2013, the date the agency was scheduled to complete review of the drug application.
“The approval of [ponatinib] 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 Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “[Ponatinib] is the third drug approved to treat CML and the second drug approved to treat ALL this year, demonstrating FDA’s commitment to approving safe and effective drugs for patients with rare diseases.”
PACE Trial
The approval was based on the results of the PACE trial, a multicenter, international, single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy.
The drug’s effectiveness was demonstrated by a reduction in the percentage of cells expressing the Philadelphia chromosome genetic mutation to less than 35%, a major cytogenetic response. Fifty-four percent of all patients and 70% of patients with the T315I mutation achieved major cytogenetic response. The median duration of major cytogenetic response had not yet been reached at the time of analysis.
In accelerated- and blast-phase CML and Philadelphia chromosome–positive ALL, ponatinib’s effectiveness was determined by the number of patients who experienced major hematologic response. Results showed:
- 52% of patients with accelerated-phase CML experienced major hematologic response for a median duration of 9.5 months;
- 31% of patients with blast-phase CML achieved major hematologic response for a median duration of 4.7 months; and
- 41% of patients with Philadelphia chromosome–positive ALL achieved major hematologic response for a median duration of 3.2 months.
Ponatinib is being approved with a Boxed Warning alerting patients and health care professionals that the drug can cause blood clots and liver toxicity. The most common side effects reported during clinical trials include high blood pressure, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. ■
