Oral RA Drug Shows Enduring Safety Results

PARIS -- The pattern of serious adverse events with tofacitinib (Xeljanz) treatment for rheumatoid arthritis (RA) has remained stable over time and has not increased in patients with long exposure to the drug, an integrated safety analysis showed.

For instance, the incidence rates for serious infections -- the most common serious adverse events -- were 2.57 (95% CI 2.02-3.27) per 100 patient-years among patients receiving tofacitinib for up to 6 months and 1.89 (95% CI 1.16-3.09) per 100 for those remaining on this oral Janus kinase inhibitor for more than 42 months, reported Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham.

"As was typical in clinical trials for rheumatoid arthritis, most of those serious infections were pneumonia," he said at the annual European League Against Rheumatism meeting.

The analysis included 5,671 patients from six phase II trials, six phase III studies, and two ongoing long-term extension studies, among patients who had not responded to conventional or biologic therapies.

As of the cutoff date in April 2013, there had been a total of 12,664 patient-years of exposure to the drug. The median time of exposure was 2.4 years, but 555 had been on tofacitinib for more than 4 years, he noted.

Overall, 16.3% had discontinued treatment because of adverse events.

The incidence rates of herpes zoster were 4.22 (95% CI 3.87-4.61) per 100 patient-years overall, 4.20 (95% CI 3.47-5.07) per 100 for those with up to 6 months of exposure, and 2.11 (95% CI1.29-3.44) per 100 for those on treatment for more than 42 months. Most of the cases of zoster (93%) were not serious, and few patients experienced disseminated or multidermatomal shingles.

Other serious infections also occurred at low rates, with incidence rates of 0.25 (95% CI 0.18-0.36) per 100 for opportunistic infections and 0.21 (95% CI 0.14-0.30) per 100 for tuberculosis, although the rate in the U.S. was lower, at 0.02 per 100.

Of the 26 patients who developed tuberculosis, 15 were pulmonary and two patients had screened positive at baseline, Curtis said.

Rates of malignancy excluding nonmelanoma skin cancer also remained low, at 0.85 (95% CI 0.70-1.02) per 100 patient-years. For patients with less than 6 months exposure, malignancy rates were 0.70 (95% CI 0.44-1.11) per 100, while rates for more than 42 months of exposure were 1.04 (95% CI 0.54-2).

Lymphoma and lymphoproliferative disorders occurred in 0.06 (95% CI 0.03-0.13) per 100 overall, and in 0.04 (95% CI 0.01-0.28) and 0.12 (95% CI 0.02-0.82) among those with less than 6 months and more than 42 months exposure, respectively.

These rates were similar to those seen for the general population in the U.S. Surveillance, Epidemiology, and End Results program, where the standardized incidence ratio for malignancies other than nonmelanoma skin cancer was 1.08 (95% CI 0.89-1.31) and 2.58 (95% CI 1.24-4.74) for lymphoma, and were also similar to what has been seen for RA patients treated with tumor necrosis factor inhibitors.

The rate of major cardiovascular adverse events was 0.46 per 100 patient-years, which represented fewer than one in 100 patients, Curtis said.

There was one death from appendicitis.

No new safety signals have emerged with longer term use of tofacitinib, he noted.

"Long-term follow-up will continue, and additional observational experience and pharmacovigilance activities will further characterize the safety of tofacitinib in patients with rheumatoid arthritis," he concluded.