More Bad Safety News for Xeljanz

Another analysis of the mandatory postmarketing safety study for tofacitinib (Xeljanz) has confirmed what most observers expected: that rates of infection with the drug in rheumatoid arthritis are higher than with tumor necrosis factor (TNF) inhibitors.

In the closely watched ORAL Surveillance trial, patients with rheumatoid arthritis experienced infection at rates of 71.2% to 72.5% (two doses were evaluated) with tofacitinib, a JAK inhibitor, versus 64.1% with TNF inhibitors, according to Andra-Rodica Balanescu, MD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania, and colleagues.

Rates of serious infection events were also elevated with the pioneering oral medication, the researchers reported in Annals of the Rheumatic Diseases.

Initial analyses of the 4,362-patient ORAL Surveillance had shown that tofacitinib was also associated with higher risk of major cardiovascular events and malignancies, relative to TNF inhibitors. The drug’s label, as updated last December, now sports warnings about all three types of increased risk.

Overall, when taking into account all the findings from ORAL Surveillance, “these results should be carefully considered as part of shared decision-making between physicians and patients,” Balanescu and colleagues wrote.

The FDA had ordered tofacitinib’s maker, Pfizer, to conduct ORAL Surveillance following the drug’s initial approval in 2012 for rheumatoid arthritis. The FDA had already required a boxed warning based on results of the drug’s clinical trials. These suggested higher rates of infections and certain malignancies, but regulators wanted a safety-focused trial to get a better handle on the risks.

Only individuals 50 and older with rheumatoid arthritis not responding to methotrexate were eligible for the trial. Participants were also required to have at least one cardiovascular risk factor other than age, as assessment of cardiovascular events was a primary goal. Mean patient age was about 61 and, typical for rheumatoid arthritis patients, close to 80% were women.

Patients were initially randomized in equal numbers to tofacitinib at 5 or 10 mg twice daily or to placebo. However, an interim analysis in 2019 revealed increased mortality in the high-dosage arm, which was then terminated with those patients shifted to the lower dose for their remaining scheduled treatment. (However, 10 mg twice daily remains an approved dosage for certain ulcerative colitis patients.) For the control, North American participants were given adalimumab (Humira); etanercept (Enbrel) was used elsewhere.

Most of the infections seen in the trial were non-serious upper respiratory tract illnesses; 12.8% to 15.2% of those on tofacitinib and 12.7% of the placebo group experienced urinary tract infections, and herpes zoster attacks occurred in 11.5% to 12.1% with tofacitinib versus 3.8% with placebo.

Serious infections occurred in 9.7% to 11.6% of the tofacitinib group compared with 8.2% in the placebo group. Rates of fatal infections were 0.4% to 0.9% in the tofacitinib group versus 0.3% with placebo. Participants experiencing multiple serious infections were also more common with tofacitinib than placebo, as were cases of extensive herpes zoster attacks.

However, while tofacitinib’s label highlights tuberculosis as a special risk, rates of both latent and opportunistic tuberculosis were similar with the drug versus placebo.

Last September, when the FDA finished its own analysis of the ORAL Surveillance data provided by Pfizer, it not only required new warnings on the drug’s label, but also restricted eligibility criteria to include only those patients who had failed TNF inhibitors. And while the safety study only included patients with rheumatoid arthritis and cardiovascular risk factors, these restrictions apply to all of the approved indications, which also include ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, and ulcerative colitis. The boxed warnings also appear on labels for all other JAK inhibitors, such as baricitinib (Olumiant) and upadacitinib (Rinvoq).