- Pfizer is transitioning patients in a post-marketing study off a higher-dose regimen of Xeljanz, following an independent analysis that found pulmonary embolisms to be more frequent among patients treated with that regimen than those given an active comparator.
- The analysis also found overall mortality was greater in the higher dose of 10 mg twice daily compared to both the lower dose of 5 mg twice daily and the active comparator arm of an anti-TNF therapy. Pfizer said the 10 mg group would be moved onto the 5 mg dose, which is also the approved dose for adults with moderate to severe rheumatoid arthritis.
- A post-marketing requirement for Pfizer, the Phase 4 study is investigating the risk of cardiovascular events for moderate to severe rheumatoid arthritis patients taking Xeljanz. To participate, patients needed to be at least 50 years old and have at least one cardiovascular risk factor, such as high blood pressure or a history of heart attack.
Xeljanz (tofacitinib) interferes with JAKs, enzymes that play a critical role in immune cell signaling. Though JAK inhibitors are quite effective across a range of diseases, safety has been an overhang for multiple members of the class.
When the Food and Drug Administration first approved Xeljanz in 2012, for instance, the agency issued a black box warning for serious infections and malignancy on the drug's label. They also put in place a Risk Evaluation and Mitigation Strategy and tasked Pfizer with conducting post-market studies to evaluate long-term safety.
Cardiovascular signals have popped up as well.
In a long-term extension study of ulcerative colitis patients, there were four cases of pulmonary embolism reported in the group taking 10 mg of the drug twice daily. Eli Lilly's Olumiant (baricitinib), meanwhile, holds a black box warning for serious infections, malignancy and thrombosis due to blood clotting events — including deep venous thrombosis — seen in clinical testing.
Thrombosis events haven't occurred across the JAK class. Yet the ones seen in Olumiant's clinical testing did spur some clinicians and analysts to consider whether regulators would be more critical of the drugs moving forward.
The pulmonary embolism discrepancy seen in the Xeljanz post-marketing study may therefore put JAKs and their effects on cardiovascular health under an even greater magnifying glass.
Pfizer is now modifying the Phase 4 Xeljanz study based off observations from a data safety monitoring board. The big pharma has taken steps to transition patients in the 10 mg twice daily arm onto the 5 mg twice daily regimen, according to a Feb. 19 statement, and noted that the monitoring board "firmly believes that the risk-benefit profile of tofacitinib 5 mg twice daily in comparison to the TNFi group remains appropriately balanced in this study."
In 2012, Xeljanz became the first JAK inhibitor to secure U.S. approval for the treatment of moderate to severe rheumatoid arthritis. Since then, the drug's label has expanded into the areas of psoriatic arthritis and ulcerative colitis.
Xeljanz revenue totaled $1.77 billion in 2018, a 32% increase from the year prior.