After follow-up data from the phase 2 PACE trial revealed that ponatinib-treated patients experienced an increase in arterial and venous thrombotic events, the FDA decided to investigate the drug’s safety.

The agency placed current ponatinib trials on partial clinical hold and asked the drug’s makers, Ariad Pharmaceuticals, to end the phase 3 EPIC trial.

Now, the FDA has asked Ariad to temporarily suspend marketing and sales of ponatinib while the agency further evaluates the drug.

Ponatinib is approved in the US and the European Union to treat adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other tyrosine kinase inhibitors.

Recommendations for ponatinib use

Until its safety evaluation is complete, the FDA is recommending that healthcare professionals reconsider the use of ponatinib.

For patients who are taking ponatinib but not responding, immediately discontinue their treatment and discuss alternative treatment options.

For patients who are currently taking ponatinib and responding, determine whether the potential benefits of the therapy outweigh the risks. If they do, these patients should be treated under a single-patient investigational new drug (IND) application or expanded access registry program while the FDA’s safety investigation continues.

Do not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Patients who meet these criteria can be considered for treatment under an IND or expanded access registry program.

For more information on obtaining access to treatment for your patient under an IND, please refer to the following website: Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use.

Ponatinib safety data

Thus far, the FDA’s investigation of ponatinib has revealed an increased frequency of arterial and venous thrombotic events since the drug was approved in December 2012.

In clinical trials conducted before the drug’s approval, serious arterial thrombosis occurred in 8% of ponatinib-treated patients, and venous thromboembolism occurred in 3%. In the most recent clinical trial data, at least 20% of all participants treated with ponatinib have developed thrombosis or arteriosclerosis.

Serious adverse vascular events have occurred in about 24% of patients in the phase 2 trial of ponatinib (median treatment duration of 1.3 years) and about 48% of patients in the phase 1 trial (median treatment duration of 2.7 years).

These included fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively. Patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events.

Serious adverse reactions involving the eyes, which led to blindness or blurred vision, occurred in ponatinib-treated patients. High blood pressure occurred in 67% of patients treated with ponatinib in the trials. Heart failure, including fatalities, occurred in 8% of patients who received the drug.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

The phase 1 and 2 trials did not include a control group, so it is not possible to determine the relationship of these adverse events to ponatinib. However, the increasing rate and pattern of the events strongly suggests that many are drug-related, according to the FDA.

The agency said it cannot currently identify a dose level or exposure duration of ponatinib that is safe. Prior to the issues with adverse events, the recommended dose of ponatinib was a 45 mg tablet taken once daily.

The FDA said it plans to continue its investigation and will notify healthcare professionals and patients as more information becomes available.

Ponatinib sales and marketing suspended