Ponatinib Safety Profile: An Analysis of 10 Years of Real-World Experience

Introduction: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. When ponatinib first became commercially available in the United States on December 14, 2012, the clinical benefits needed to be balanced with several safety concerns, notably vascular occlusive events (VOEs). Therefore, various postapproval risk management measures were implemented to improve safety associated with ponatinib. These included the circulation of direct health care professional communications, an update to the Product Information, and the distribution of educational materials for health care professionals to improve the prevention and management of these safety concerns. In addition, a dose-optimization trial was initiated, and a retrospective analysis of the arterial occlusive events (AOEs) reported in the PACE phase 2 trial was performed to better characterize the safety profile of ponatinib. This retrospective study aimed to evaluate the impact of these postapproval risk management measures on the safety profile of ponatinib by analyzing real-world safety data collated globally over the 10-year period following its commercialization.

Methods: A search of the Incyte Global Safety Database was performed to identify adverse events (AEs) reported worldwide between December 14, 2012, and December 13, 2022, pertaining to important identified risks (IIRs) of ponatinib. These included VOEs, infections, hepatotoxicity, cardiac failure/left ventricular dysfunction, pancreatitis, myelosuppression, hemorrhage, hypertension, skin reactions, and edema/fluid retention. A MedDRA search strategy for each IIR was used to extract AEs from postmarketing sources, including spontaneous, noninterventional study, and nonstudy literature reports. The reporting rate for each IIR was then determined using the ratio between the total number of AEs reported and the estimated postmarketing exposure during the same period.

Results: The most frequently reported AEs for ponatinib during the first year of commercialization pertained to the IIRs of myelosuppression, skin reactions, infections, and AOEs, with reporting rates of 0.505, 0.362, 0.330, and 0.291, respectively. The reporting rates of these IIRs decreased considerably during the first 2 years of commercialization, following the implementation of postapproval risk management measures in December 2013. By the end of the 10-year period, the reporting rates of these IIRs further decreased to 0.043, 0.030, 0.045, and 0.038, respectively. Smaller decreases in the reporting rates of the remaining IIRs were observed over the 10-year period. The total reporting rate of all IIRs decreased from 2.369 to 0.219 between December 13, 2013, and December 13, 2022. Most notably, the reporting rate of each IIR over the entire 10-year period was considerably lower than the reporting rate observed during the first year of ponatinib commercialization before the implementation of risk management measures and was comparable with the reporting rate of the final 12 months of the reporting period (December 2021 to December 2022).

Conclusion: Our study findings suggest the safety profile of ponatinib has improved since it first became commercially available, with improvements likely attributable to the implementation of risk management measures and increasing knowledge of ponatinib among clinicians. Despite the potential limitations of this analysis, such as underreporting of AEs, the Weber effect (ie, reporting bias associated with increased reporting of AEs during the initial period following a drug’s regulatory approval), and the use of estimated patient exposure, our results show that the introduction of measures designed to minimize the risks related to ponatinib use was associated with improved safety among patients receiving ponatinib.