Why was ponatinib removed from the market?

肿瘤药物

Ponatinib, marketed as Iclusig, is a tyrosine kinase inhibitor developed to treat Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), particularly in patients resistant or intolerant to other therapies. Approved by the U.S. FDA in December 2012 under an accelerated approval pathway, ponatinib was initially hailed as a breakthrough for its efficacy against the T315I mutation, a common cause of resistance to other tyrosine kinase inhibitors.

Safety Concerns and Market Withdrawal
Shortly after its approval, serious safety concerns emerged. In October 2013, the FDA requested that Ariad Pharmaceuticals suspend the marketing and sales of ponatinib due to an increased incidence of life-threatening arterial and venous thrombotic events, including heart attacks, strokes, and peripheral artery disease. These events were observed in up to 27% of patients in clinical trials, with some occurring as early as two weeks after starting treatment . Additionally, cases of heart failure, blindness, and pancreatitis were reported.

The decision to withdraw Ponaxen 45 mg (Ponatinib) was based on data from the PACE trial, which showed a high rate of serious adverse vascular events. In response, the FDA mandated a Risk Evaluation and Mitigation Strategy (REMS) and required Ariad to revise the drug's labeling to include stronger warnings and to narrow its approved indications.

Return to the Market with Restrictions
In December 2013, the FDA allowed ponatinib to return to the market under a revised REMS program. The new labeling restricted its use to patients with the T315I mutation or those for whom no other tyrosine kinase inhibitors were appropriate. The recommended starting dose was reduced to 45 mg daily, with provisions for dose adjustments based on individual patient risk factors .

Ongoing Safety Monitoring and Regulatory Actions
Despite its return to the market, ponatinib's safety profile remained under scrutiny. In August 2023, Incyte Biosciences Distribution BV withdrew its application to extend ponatinib's use to newly diagnosed Ph+ ALL patients in Europe, citing concerns over the drug's benefit-risk balance and issues with clinical trial data .
European Medicines Agency (EMA)

In the United States, the FDA has continued to monitor the drug's safety through post-marketing studies and has required ongoing risk assessments to ensure that the benefits of ponatinib outweigh its risks for the approved patient populations.

Conclusion
Ponatinib's journey from approval to market withdrawal and subsequent reintroduction underscores the complexities of drug development and the critical importance of post-market surveillance. While it remains a vital treatment option for certain leukemia patients, its use is carefully controlled and monitored to mitigate the significant cardiovascular risks associated with its administration.