Interim results of a 24-month study regarding the effect of tofacitinib on radiographic progression were reported by Dr. Désirée van der Heijde of the department of rheumatology at Leiden (the Netherlands) University Medical Center (Arthritis Rheum. 2011;63[suppl.]:S1017-8; abstract 2592). The study included 797 patients with active RA who had a history of inadequate response to methotrexate and were on a stable dose of methotrexate. After 6 months of treatment, the mean change in the mTSS (modified Total Sharp Score) for tofacitinib 10 mg twice daily was 0.06, which was significantly lower (P less than .05) than placebo (mTSS, 0.47), indicating reduced progression of structural damage. The difference was not statistically significant for the 5-mg tofacitinib dose, in which the mTSS was 0.12.
In reviewing Dr. van der Heijde’s findings, Dr. Bergman questioned whether even a mean change of mTSS of 0.47 – on a scale of 0-400 – was clinically meaningful. At 12 months, the proportion of patients with no radiographic progression or no new erosions was greater in both tofacitinib groups, compared with placebo. "I don’t think we should make too much of these results, but I think the findings are reassuring that this oral medication has effects similar to the anti-TNFs," commented Dr. Bergman.
According to Dr. Bergman, more safety data are available for tofacitinib than for any other RA drug currently on the market, given its stage of development, especially as measured by patient-years. Two abstracts at the ACR annual meeting reported on long-term safety data, one summarizing pooled data from five randomized, double-blind, phase III studies, and two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 409) and the other just from the same two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S152-3; abstract 407). The former was an analysis by Dr. Stanley B. Cohen, a rheumatologist at the University of Texas, Dallas. It included 3,030 RA patients from the phase III trials and 3,227 from the long-term extensions, resulting in approximately 2,000 and 3,000 patient-years of exposure to tofacitinib. In the phase III studies, there were 12 deaths, with a death rate of 0.40% with tofacitinib (5 deaths caused by infections, and 2 with cardiovascular causes), and 8 deaths in the long-term extensions (3 from infections, and 1 with a cardiovascular cause), with a death rate of 0.62%; the rate for placebo was 0.15%. This rate was comparable with that reported for adalimumab (0.49%).
The rates of serious infections were 2% in the tofacitinib phase III studies, and 2.9% in the tofacitinib long-term extensions, compared with 1.5% for adalimumab. There was some indication in the long-term extension data that the higher dose was associated with more serious infections than was the lower dose. Whether tofacitinib was given as monotherapy or with background DMARDs did not change the infection rate. Opportunistic infections, including tuberculosis, were uncommon.
In the second analysis, based on data from the long-term extension studies and reported by Dr. Jürgen Wollenhaupt of the University of Hamburg (Germany), there were some adverse events to "keep an eye out for," commented Dr. Bergman. This report represented data on 3,227 patients who were treated for a total duration of 3,118 patient-years. Serious adverse events were reported in 10.5% of patients. Confirmed increases in creatinine (defined as greater than 33% from baseline) were found in 12.2% of patients. Decreased hemoglobin levels (greater than or equal to 2 g/dL or less than 8) were found in 2.5% of patients, and raised aminotransferase levels (defined as greater than three times the upper limit of normal) were found in 1.7% (alanine) and 1.1% (aspartate) of patients. A 15% persistent rise across all doses was seen in total cholesterol. Diarrhea may also be a problem for some patients.
Dr. Bergman serves as a consultant to Pfizer.