Alice Goodman

May 31, 2011

May 31, 2011 (London, United Kingdom) — Tofacitinib, an oral Janus-associated kinase (JAK) inhibitor, was highly effective in patients with moderate to severe rheumatoid arthritis (RA) who failed to respond to treatment with other disease-modifying antirheumatic drugs (DMARDs), according to the first presentation of phase 3 data on this novel agent.

The findings were presented here at the European League Against Rheumatism Congress 2011. Moreover, the data suggest that the drug is safe — at least as safe as biological DMARDs, despite the recent report of 4 deaths, 3 of which have been determined to be unrelated to the drug.

"In a phase 3 trial of adults with RA and an inadequate response to at least 1 DMARD, tofacitinib achieved significant and clinically meaningful reductions in the signs and symptoms of RA and improvements in physical function throughout 6 months of therapy," stated lead author Joel Kremer, MD, from Albany Medical College in New York. He noted that tofacitinib appears to achieve its beneficial effects rapidly — within 2 weeks of treatment — and expressed hope that the compound will be an additional treatment option for patients who do not have a good response to currently available RA therapies.

In all, 792 patients were randomized to receive tofacitinib 5 mg or 10 mg twice daily or placebo added to background treatment with traditional DMARDs, including methotrexate. At month 3, all nonresponder placebo patients were blindly advanced to tofacitinib 5 or 10 mg twice daily. At month 6, the remaining placebo patients were blindly advanced to tofacitinib 5 or 10 mg. Patients were treated for a total of 12 months.

At 6 months, 58.3% of patients in the 10 mg group, 52.7% in the 5 mg group, and 31.2% in the placebo group achieved at least a 20% improvement on American College of Rheumatology criteria (ACR20). The difference between the treated groups and the placebo group was highly significant (P < .0001 for 5 and 10 mg vs placebo).

In addition, 36.6% in the 10 mg group, 33.8% in the 5 mg group, and 12.7% in the placebo group achieved at least ACR50, which was also a highly significant difference, compared with placebo (P < .0001 for 5 and 10 mg).

Physical function improved significantly in both tofacitinib groups at 6 months, according to changes from baseline on the Health Assessment Questionnaire–Disease Index.

The rates of adverse events and serious adverse events reported at 3 and 6 months were comparable across treatment groups. The majority of adverse events were mild, and the most frequently reported events were infections. Serious infections occurred in 2 patients in the 5 mg group, 4 patients in the 10 mg group, and 2 patients initially in the placebo group who advanced to the 5 or 10 mg group. Elevations in liver enzymes were reported at 3 months in 29% of patients treated with tofacitinib, although there was no further increase over the rest of the study.

"These patients [with elevated liver enzymes] did not deteriorate with further treatment," Dr. Kremer said.

Four deaths were reported, 3 of which were deemed unrelated to study drug. The fourth death, in a 58-year-old male, was due to respiratory failure and was considered drug-related. Dr. Kremer said the patient's family refused to have an autopsy, so the cause of death was made by clinical judgement.

Regarding the deaths, Paul Emery, MD, from Leeds Teaching Hospital in the United Kingdom, said that the number of deaths with traditional DMARDS is an estimated to be 22 per 1000 patient-years. He found the safety data for tofacitinib reassuring, noting that "quite a few deaths might be expected in a group of patients with moderate to severe RA switched from DMARD therapy to tofacitinib."

If tofacitinib is approved for patients who fail other therapies, cost will be a big issue, Dr. Emery noted. "Tofacitinib now has a profile in all stages of RA, and it is the most impressive profile we have seen. The cost will depend on the environment in which the drug is launched. If the cost is prohibitive, that will affect its use. I thought that biologics would never sell at the price set when they were launched. Never underestimate the power of marketing," Dr. Emery said.

Dr. Kremer reports receiving grant/research support from and serving as a consultant for Pfizer. Dr. Emery reports receiving grant/research support from and serving as a consultant for Abbott, Merck, Pfizer, Roche, and BMS.

European League Against Rheumatism (EULAR) Congress 2011: Late breaker abstract 0005. Presented May 27, 2011.

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