Pfizer announced Wednesday that Xeljanz (tofacitinib) failed to show non-inferiority versus a TNF inhibitor in the ORAL Surveillance post-marketing study of patients with rheumatoid arthritis. Results of the trial showed that rates of major adverse cardiovascular events (MACE) and malignancies were higher in participants given the oral JAK inhibitor.
Xeljanz gained FDA approval in 2012 for the treatment of patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. However, the agency only authorised the lower 5-mg, twice-daily dose of the drug in this indication and ordered Pfizer to conduct a post-marketing study to evaluate Xeljanz's long-term effects on heart disease, cancer and serious infections.
In 2019, Pfizer disclosed that in the ORAL Surveillance study, the 10-mg dose of Xeljanz taken twice a day was linked with a "statistically and clinically important difference" in the occurrence of pulmonary embolism versus subjects treated with a TNF inhibitor. At the time, the trial's data safety monitoring board also "noted an increase" in overall mortality in the 10-mg treatment arm compared to the 5-mg and TNF inhibitor groups. The results prompted the company to move all patients receiving the higher dose of Xeljanz to the lower-dose arm.
The study randomised 4362 patients with rheumatoid arthritis who were 50 years of age or older and had at least one additional cardiovascular risk factor to receive Xeljanz at a dose of 5 mg or 10 mg, or a TNF inhibitor as a control. The trial's co-primary endpoints were non-inferiority of Xeljanz compared to a TNF inhibitor in regard to MACE and malignancies, excluding non-melanoma skin cancer, while secondary goals include opportunistic infections, hepatic events, cardiovascular events other than MACE and all-cause mortality.
The latest results, which are based on primary analyses that included 135 subjects with MACE and 164 subjects with malignancies, showed that rates of MACE were 3.37% for Xeljanz, compared to 2.55% for a TNF inhibitor, while malignancies occurred in the two groups at rates of 4.19% and 2.89%, respectively. Pfizer noted that the most frequently reported MACE for Xeljanz was myocardial infarction, while the most frequently reported malignancy was lung cancer.
More detailed results showed that rates of MACE were 3.23% in the Xeljanz 5-mg dose group and 3.5% in the 10-mg dose group. Meanwhile, malignancies occurred at rates of 4.26% and 4.12%, respectively, in the Xeljanz 5-mg and 10-mg dose groups. Pfizer said that "based on the prespecified secondary comparisons, there was no evidence of a difference in the primary endpoints between the two [Xeljanz] treatment groups."
The company indicated that results for secondary endpoints, such as pulmonary embolism and mortality, are not yet available. Pfizer added that it is working with the FDA and other regulatory agencies to review the full results and analyses as they become available.
Xeljanz, which is also approved to treat certain patients with psoriatic arthritis, ulcerative colitis and juvenile idiopathic arthritis, generated sales of $654 million in the third quarter of 2020, representing year-over-year growth of 9%.
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