Updated long-term safety data suggest that tofacitinib (Xeljanz, Pfizer) is generally safe for long-term use in the treatment of moderate to severe ulcerative colitis (UC), with adverse events (AE) consistent with previous studies and showed stability over time in the incidence of adverse events of special interest.
“Findings from these integrated safety analyses are reassuring for patients with UC. The incidence rates of most key events that led to the black box warning are lower in these cohorts, compared with results observed in the ORAL Surveillance study of older patients with RA [rheumatoid arthritis],” said Siddharth Singh, MD, who was asked to comment on the study.
The results support the current clinical approach, in which tofacitinib is typically employed following infliximab (Remicade, Janssen) failure, though the paradigm may change. “These findings on safety reassure our approach, though there will still be hesitation to use 10-mg twice-daily dosing in older patients. However, with the recent approval of upadacitinib (Rinvoq, AbbVie), a selective JAK1 inhibitor that seems to be more effective than tofacitinib, positioning of tofacitinib may evolve,” said Dr. Singh, who is an associate professor of medicine at University of California, San Diego, and director of the UCSD IBD Center.
There has been evidence to support safety concerns with tofacitinib. The prospective ORAL Surveillance study compared two doses of tofacitinib (5 or 10 mg, twice daily) to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis. The researchers selected patients aged 50 and older and with at least one additional cardiovascular risk factor. The study found higher rates of major adverse cardiovascular events and malignancies in the tofacitinib groups, as well as higher rates of mortality, serious infection, and venous thromboembolism. The findings prompted a Food and Drug Administration “black box” warning for tofacitinib in July 2019, which was extended to two other JAK inhibitors in September 2021.
However, patients in the UC clinical program are generally younger than participants in the ORAL Surveillance study and were less likely to have a smoking history.
The new study, published in the Journal of Crohn’s and Colitis, represents an update of a pooled analysis from phase 2, phase 3, and open-label extension studies with up to 4.4 years of exposure. Analysis of the earlier cohort showed that tofacitinib had a generally similar safety profile to other UC therapies, with the exception of a higher incidence of herpes zoster infection. Since that publication, the researchers have compiled additional person-years of tofacitinib exposure from the open-label extension OCTAVE Open study and the 6-month interim analysis of the phase 3b/4 RIVETING study.
The new study included 1,157 patients who received at least one dose of tofacitinib. Overall, 35.6% had received treatment for longer than 4 years. The mean age was 41.3 years, 58.7% were male, and 80.1% were White; 64.0% had never smoked, and 30.9% were ex-smokers. The mean disease duration was 8.2 years. In all, 83% of patients were on a 10 mg dose, and 17% were on 5 mg.
In the 2016 analysis, 82.1% of patients had an adverse event and 14.6% had a serious adverse event. In the overall cohort, the percentages were 85.7% and 21%, respectively.
In the updated analysis, 11.6% discontinued medication use because of an adverse event. For all doses, incidence rates (IRs) for adverse events were defined as unique patients with events per 100 person-years of exposure. The IRs for death and adverse events of special interest were similar between the original cohort and the updated cohort. For example, the IR for death was 0.24 for death in the earlier cohort (95% confidence interval, 0.07-0.61) and 0.23 in the combined cohort (95% CI, 0.09-0.46); it was 1.99 for serious infections in the earlier cohort (95% CI 1.37–2.79) and 1.69 in the combined cohort for serious infections (95% CI, 1.26-2.21); it was 4.07 for serious and nonserious herpes zoster infection in the earlier cohort (95% CI, 3.14-5.19), 3.30 for serious and nonserious herpes zoster infection in the combined cohort (95% CI, 2.67-4.04); and it was 1.28 for opportunistic infections in the earlier cohort (95% CI, 0.79-1.96) and 1.03 in the combined cohort for opportunistic infections (95% CI, 0.70-1.46).
The updated cohort included 3.4 more years of observation and an additional 1,386.9 person-years of exposure. That resulted in a final tally of up to 7.8 years of exposure and a combined 2,999.7 person-years of exposure, “thus demonstrating that the safety profile of tofacitinib remained consistent with increased extent and length of exposure,” the authors wrote.
Despite the promising findings, Dr. Singh called for more research. “We need a dedicated safety registry of tofacitinib and other JAK inhibitors in patients with IBD, who do not share the characteristics of those studied in the ORAL Surveillance study,” he said.
The authors disclose ties to various pharmaceutical companies, including Pfizer, which manufactures tofacitinib. Dr. Singh has received personal fees from Pfizer for ad hoc grant review.