Tofacitinib Approved: Now How Do We Use It?

Jonathan Kay, MD


November 28, 2012

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Hello. I am Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at the University of Massachusetts Medical School and UMass Memorial Medical Center, both in Worcester.

Today I would like to talk about a new era in the treatment of rheumatoid arthritis. On November 7, 2012, the US Food and Drug Administration (FDA) approved the first oral kinase inhibitor for the treatment of rheumatoid arthritis. Tofacitinib citrate was approved at a dose of 5 mg taken by mouth twice daily for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

This is the first approval of a rheumatoid arthritis treatment in a new class of medications known as Janus kinase (JAK) inhibitors. This medication blocks a signaling molecule that transmits the signal from when a cytokine binds to the surface of a cell, inhibiting the activity of the cytokine. The clinical features of this medication are very similar to those of the interleukin-6 receptor antagonists.

This medication was approved as a second-line agent for rheumatoid arthritis, which means that treatment with a biologic agent is not required before prescribing tofacitinib. Tofacitinib can be used either as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). This drug was studied in a development program that involved approximately 5000 patients worldwide. It was studied at both the approved 5-mg dose and a 10-mg twice-daily dosing regimen in patients who had an inadequate response to non-biologic DMARDs or to anti-tumor necrosis factor (TNF) agents.

The FDA has approved the lower dose but not the higher dose at the present time. The safety findings observed in clinical trials include those characteristic of most biologic agents, including infections (such as tuberculosis and herpes zoster), malignancies (including lymphoma), gastrointestinal perforation (similar to what was observed with interleukin-6 receptor inhibitors), low neutrophil and lymphocyte counts, reduced hemoglobin, liver enzyme elevations, and lipid elevations. This safety profile is very similar to those of tocilizumab and interleukin-6 receptor antagonists.

At the American College of Rheumatology (ACR) meeting in Washington, a very interesting and important study, the ORAL Start study,[1] is being presented. This is a phase 3 study comparing the effectiveness and safety of tofacitinib with methotrexate in methotrexate-naive patients with active rheumatoid arthritis. Although this is a 24-month study, the results presented at this meeting are the 12-month interim analysis.

The study included 952 patients in 3 groups, whose demographic characteristics, including radiographic scores, were similar across groups. Patients were randomly assigned 2:2:1 to tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or methotrexate at doses up to 20 mg weekly. The predetermined primary endpoints of safety and efficacy included mean change from baseline in radiographic scoring, the van der Heijde-modified total Sharp score, and the ACR70 response, which is the most rigorous hurdle to achieve in terms of clinical response.

The most impressive finding was that the ACR70 response was 36%-38% for the 2 doses of tofacitinib, compared with only 12% for the patients treated with methotrexate. Similarly, the radiographic change in this study showed significant improvement with tofacitinib at both doses, compared with methotrexate.

Serious adverse events occurred in 6%-7% for both tofacitinib and methotrexate. Infections were slightly more common with tofacitinib, 32%-39%, compared with 27% in those treated with methotrexate, but gastrointestinal symptoms were more common with methotrexate (34% vs 21%-25% with tofacitinib). The incidence of herpes zoster was about 2% in the patients treated with tofacitinib and 1% in the patients treated with methotrexate.

In this phase 3 study, tofacitinib monotherapy was shown to be superior to methotrexate in improving signs and symptoms of rheumatoid arthritis and in inhibiting progression of structural damage. This oral medication taken twice daily has very similar efficacy to the parenteral medications that we now use for the treatment of rheumatoid arthritis.

What will be patients' preferences? Will patients prefer to take oral medication twice daily or continue with the injectable medications that are administered less frequently but require them to use a needle or to come to an infusion center periodically? The kinase inhibitors are a new class of medication, and many others are being developed. Tofacitinib is the first to be approved. We should be seeing more from this class in the near future.