Study Examines Tofacitinib’s Long-Term Cardiovascular Risk & More

New data from a post-marketing safety study evaluating the long-term effects of tofacitinib on heart disease, malignancies and serious infections found the treatment did not prove non-inferior to tumor necrosis factor (TNF) inhibitors. The randomized, open-label study was conducted in adults with rheumatoid arthritis (RA) taking either 5 or 10 mg doses of tofacitinib twice daily.¹

Background: In November 2012, tofacitinib was initially approved by U.S. Food & Drug Administration (FDA) to treat moderate to severe active RA in adults who are intolerant to methotrexate and for whom methotrexate proved inadequate. The treatment, a 5 mg dose taken twice daily, was approved for use as monotherapy and combination therapy with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). The FDA asked Pfizer, the manufacturer of tofacitinib, to conduct a post-marketing study examining the agent’s cardiovascular risks.²

Additional FDA approvals for tofacitinib include for the treatment of psoriatic arthritis, ulcerative colitis and polyarticular course juvenile idiopathic arthritis.³ In 2019, the FDA added new safety information to its label. This new boxed warning outlined the risk of thrombosis, pulmonary embolism and all-cause mortality associated with tofacitinib use for RA patients taking 10 mg of tofacitinib twice daily compared with those taking 5 mg of tofacitinib twice daily or TNF inhibitors.⁴

The Study
The phase 3B/4 ORAL Surveillance (A3921133; NCT02092467) study assessed the risk of cardiovascular events and malignancies when taking tofacitinib.⁵ Researchers randomized 4,362 RA patients. Each patient was older than 50, taking background methotrexate and had at least one additional cardiovascular risk factor. Adverse events were pooled for the two tofacitinib doses (5 or 10 mg taken twice daily) when evaluating the primary endpoints, which were non-inferiority compared with TNF inhibitors (etanercept or adalimumab).

Incidence rates for major adverse cardiovascular events were slightly higher with the 10 mg of tofacitinib vs. 5 mg of tofacitinib (10.5 vs. 9.1 per 1,000 person-years), while the rates of malignancies were not different between the two tofacitinib doses. The primary analysis included 135 patients with major adverse cardiovascular events and 164 patients with malignancies, excluding non-melanoma skin cancer. For tofacitinib, myocardial infarction was the most frequently reported major adverse cardiovascular event, and lung cancer was the most frequently reported malignancy.

Additionally, the results showed tofacitinib-treated patients had significantly higher rates of adjudicated malignancies than patients who took an TNF inhibitor (11.3 vs. 7.7 per 1,000 person-years of drug exposure; hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.04–2.09), as well as numerically higher rates of major adverse cardiovascular events. The rates of major adverse cardiovascular events were 9.8 vs. 7.3 per 1,000 person-years (HR 1.33, 95% CI 0.91–1.94) for tofacitinib and TNF inhibitors, respectively. For tofacitinib, major adverse cardiovascular events did not meet the trial’s criteria for non-inferiority.

Pfizer continues to examine data for the rates of pulmonary embolism and other secondary endpoints points. The company is working with the FDA to review the study’s full results as more information becomes available.

Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Pfizer Inc. News release: Pfizer shares co-primary endpoint results from post-marketing required safety study of Xeljanz (tofacitinib) in subjects with rheumatoid arthritis (RA). 2021 Jan 27.
2. U.S. Food & Drug Administration. Center for drug evaluation and research application number: 203214 (Xeljanz) Orig1s000 approval letter. 2021 Nov 6
3. U.S. Food & Drug Administration. Highlights of prescribing information: Xeljanz (tofacitinib). 2020 Nov.
4. U.S. Food & Drug Administration. Supplement approval letter Xeljanz (tofacitinib). 2019 July 25.
5. Pfizer Inc. Safety study of tofacitinib vs. tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis (NCT02092467). Clinicaltrials.gov. 2021 Jan 28.