Marketing and commercial distribution of ponatinib has been temporarily suspended, following an ongoing FDA investigation that revealed an increased frequency of arterial thrombosis and severe narrowing of the blood vessels.
Harvey J. Berger, MD
Marketing and commercial distribution of ponatinib (Iclusig) has been temporarily suspended, following an ongoing FDA investigation that revealed an increased frequency of severe arterial thrombosis and stenosis.
The clinical development of ponatinib was placed on hold in early October, while the FDA investigated the adverse events associated with the drug. This was shortly followed by the early termination of the phase III EPIC trial, which was examining ponatinib in the frontline setting for untreated patients with chronic myeloid leukemia (CML). The suspension in distribution followed discussions between the manufacturer, Ariad Pharmaceuticals, Inc., and the FDA.
The FDA will continue to evaluate whether the benefits of treatment outweigh the risks. At this point, an effective dose and duration of treatment has yet to be identified.
"We continue to work with the FDA to negotiate updates to the US prescribing information for Iclusig and implementation of a comprehensive risk mitigation strategy," Harvey J. Berger, MD, chairman and chief executive officer of Ariad, said in a webcast. "Dialogue with the FDA will continue. We believe there are patients for whom there is a positive risk-benefit profile."
Ponatinib was granted accelerated approval in December 2012 for patients with CML or Philadelphia chromosome—positive acute lymphoblastic leukemia. This approval was based on data from the phase II PACE trial, which enrolled patients who were resistant or intolerant to dasatinib or nilotinib, or harbored a T315I mutation.
The drug was approved with a Boxed Warning noting that arterial thrombosis occurred in 8% of patients. Following its investigation, the FDA revealed that approximately 24% of patients in the phase II trial had experienced serious vascular adverse events (AEs), after median treatment duration of 1.3 years. After a follow-up of 2.7 years in the phase I development, the rate of serious vascular AEs was even higher at 48%, according to a statement from the FDA.
Despite the majority of data on AEs being from single-arm trials, the FDA believes that the increasing frequency and pattern of the events indicates they are drug-related. Moreover, they noted that serious AEs occurred within 2 weeks of receiving ponatinib, regardless of risk factors.
"Less than a year ago the drug was approved with these events. These are, by and large, not new. The question is quantification, what constitutes continued risk, and how the balance plays out for the agency," Frank G. Haluska, MD, PhD, the chief medical officer at Ariad, noted in a conference call.
Specifically, the FDA noted that the vessels in the heart were affected in 12% of patients, vessels in the brain were affected in 6% of patients, and circulatory issues were experienced by 8% of patients in their extremities. Serious and sometimes fatal heart failure occurred in 8% of patients.
To address the management of these side effects, Ariad is currently in negotiations with the FDA regarding updates to ponatinib’s label, which is expected to be much narrower than the previous indication. Prior to approval, the FDA's Division of Risk Management and Division of Hematology Products agreed that a risk evaluation and mitigation strategy (REMS) was not required for ponatinib, given evidence at the time. This decision was based on ponatinib's ability to fulfill an unmet medical need. However, given recent data, the company is currently developing a program.
"It takes time to put a risk mitigation program into place. Even if everyone agrees today to do it, it takes 60 to 90 days to have it fully implemented, fully rolled out, and everybody signed up," remarked Berger in a conference call. "We're working with the agency to ensure that all of the pieces are in place."
Until the label is updated or a REMS program is put into place, the administration of ponatinib will only be allowed under a single-patient Investigational New Drug application or through an expanded access registry program. This process is similar to the process used for investigational drugs that have not yet been approved by the FDA.