When FDA first approved Xeljanz (tofacitinib), we required the manufacturer, Pfizer, to conduct a randomized safety clinical trial in patients with rheumatoid arthritis (RA) who were taking methotrexate to evaluate the risk of cardiovascular events, malignancy, and infections. It was a multicenter, randomized, open-label trial to evaluate two doses of Xeljanz (5 mg twice daily (N=1455), which is the approved dosage for RA, and a higher 10 mg twice daily dosage (N=1456)) in comparison to treatment with a tumor necrosis factor (TNF) blocker (N=1451). Patients in the trial were required to be 50 years of age or older and have at least one cardiovascular risk factor. The co-primary endpoints were major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; and malignancy, excluding nonmelanoma skin cancer (NMSC). The trial was designed to exclude a prespecified risk margin of 1.8 for the hazard ratio of combined Xeljanz regimens when compared to the TNF blocker control for each co-primary endpoint. The median on-study follow-up time was 4 years.
The mean age of the population was 61 years and the median age was 60 (range 50-88 years). Most patients were female (78 percent) and Caucasian (77 percent). The noninferiority criterion was not met for the comparison of the combined Xeljanz regimens to TNF blockers for the endpoints of MACE and malignancies since the upper limit of the 95% confidence intervals (CI) for these hazard ratios exceeded the prespecified noninferiority criterion of 1.8. For MACE, the estimated hazard ratio and 95% CI associated with the combined Xeljanz regimens relative to TNF blockers were 1.33 (0.91, 1.94). For malignancies excluding NMSC, the estimated hazard ratio and 95% CI associated with the combined Xeljanz regimens relative to TNF blockers were 1.48 (1.04, 2.09).
There was an increased risk of death, MACE, malignancies, and thrombosis associated with both regimens of Xeljanz. The data showed evidence of a dose-dependent increased risk for MACE, all-cause mortality, and thrombosis at both doses of Xeljanz when compared to treatment with TNF blockers. Additionally, the data showed evidence of a non-dose-dependent increased risk for malignancy excluding NMSC at both doses of Xeljanz when compared to TNF blockers. Lymphomas and lung cancers were observed at a higher rate in patients treated at both doses of Xeljanz compared to those treated with TNF blockers. In particular, a higher rate of lung cancers was observed in current or past smokers treated with Xeljanz. Current or past smokers had an additional increased risk of overall cancers.
Other JAK inhibitors have not been studied in similar large safety clinical trials, so the risk with these medicines has not been evaluated. However, since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the safety clinical trial with Xeljanz.
