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Two trials report promising results for rheumatoid arthritis drug tofacitinib

Robin Wulffson MD's picture
rheumatoid arthritis, tofacitinib, oral, methotrexate, adalimumab, FDA approval

Two phase 3 clinical trials have reported that oral tofacitinib (Pfizer, Inc., New York, NY) was more effective than a placebo for treatment of rheumatoid arthritis. The findings were published in the August 9 issue of the New England Journal of Medicine. Results from one of the trials noted that tofacitinib may be as effective as medications that are currently available only through injection.

In one trial, Roy M. Fleischmann, MD, professor, Metroplex Clinical Research Center, Dallas Texas, and colleagues reported that tofacitinib was superior to a placebo when used alone in patients with rheumatoid arthritis resistant to earlier therapies, including methotrexate or biological therapies such as tumor-necrosis factor (TNF) inhibitors. In the other trial, tofacitinib was paired with methotrexate. Ronald F. van Vollenhoven, MD, chief of the Clinical Trials Unit, Karolinska University, Stockholm, Sweden, and colleagues reported that tofacitinib proved superior to a placebo and was similar in effectiveness to adalimumab, a TNF blocker.

In the study by Dr. Fleischmann and colleagues, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for three months followed by 5 mg of tofacitinib twice daily, or placebo for three months followed by 10 mg of tofacitinib twice daily. The primary endpoints, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire–Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).

The investigators found that at month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups. The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (−0.50 and −0.57 points, respectively, vs. −0.19 points). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil (white blood cell) counts.

The authors concluded that in patients with active rheumatoid arthritis, tofacitinib was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function.

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In the Swedish study, Dr. van Vollenhoven and colleagues reported the results of a year-long double-blind trial comparing tofacitinib and adalimumab to a placebo; 717 patients receiving methotrexate were randomly assigned to one of four groups: twice-daily doses of 5 mg or 10 mg tofacitinib, 40 mg adalimumab once everytwo2 weeks, or a placebo. After three months, participants in the placebo group who did not experience a 20% reduction in the number of swollen and tender joints were randomly assigned to receive one of the two tofacitinib doses.

ACR 20 rates, HAQ-DI scores, and DAS28-4(ESR) scores were again used as the primary endpoints. At six months, both tofacitinib groups had a higher ACR 20 response rate than the placebo group; 51.5% of the 5-mg group and 52.6% of the 10-mg group achieve an ACR score of 20. Participants receiving adalimumab had a similar response, with 47.2% achieving an ACR score of 20; in addition, 28.3% of the placebo group met ACR 20 criteria for each of the three treatments compared with placebo.)

The authors concluded that, compared to the placebo, treatment groups also had “significantly greater responses” than the placebo group in ACR 50 and ACR 70, as well as HAQ-DI and DAS28-4(ESR) scores compared with baseline scores; furthermore, the responses were stable during the 12-month study period.

Last week, Pfizer Inc. noted that the US Food and Drug Administration (FDA) may not meet the August 23 date targeted for a decision on the therapy. Pfizer Chief Executive Ian Read reportedly told analysts that the FDA’s request for more information could slow approval. Last May, a FDA advisory committee recommended approval of tofacitinib. On the negative side, the panel noted that the medication was associated with dose- and/or treatment duration-dependent increases in malignancy rates, lipid and cholesterol levels, and serious infection rates. The abstaining panel member, James Ware, PhD, from the Harvard School of Public Health in Boston, Massachusetts, noted that he understood the value of the drug; however, he was concerned about its safety profile. The majority of the panel members who voted yes expressed a preference for the 5 mg dose because it appeared to be comparable in effectiveness to the 10 mg dose. Furthermore, several committee members expressed concern that the indication for the drug was too broad. Lenore Buckley, MD, MPH, from the Virginia Commonwealth University School of Medicine in Richmond, voted no. She noted that she would have voted yes for this question if the indications were limited to high-risk patients.

Reference: The New England Journal of Medicine

See also:
New arthritis drug tofacitinib may be available soon