Xeljanz (tofacitinib)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved November 2012

Specific Treatments:

moderately to severely active rheumatoid arthritis

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General Information

Xeljanz (tofacitinib) is a selective, potent inhibitor of the JAK family of enzymes. Inhibiting these enzymes affects the signaling of multiple cytokines that are involved in a broad spectrum of inflammatory and autoimmune diseases.

Xeljanz is specifically indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs.

Xeljanz is supplied as a tablet for oral administration. The recommended initial dose is 5 mg twice daily, with or without food.

Clinical Results

FDA Approval
The FDA approval of Xeljanz was based on two dose-ranging trials and five confirmatory trials.
Dose-Ranging Trials:
Dose-Ranging Study 1:
This was a 6-month monotherapy trial in 384 subjects with active rheumatoid arthritis who had an inadequate response to a DMARD. Subjects who previously received adalimumab therapy were excluded. Subjects were randomized to 1 of 7 monotherapy treatments: Xeljanz 1, 3, 5, 10 or 15 mg twice daily, adalimumab (ADA)40 mg subcutaneously every other week for 10 weeks followed by Xeljanz 5 mg twice daily for 3 months, or placebo. In the 10 and 15mg Xeljanz arms, 80% of subjects reached ACR20 versus 40% in the ADA and and approximately 20% in the placebo arm.
Dose-Ranging Study 2
This was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of Xeljanz (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX. Approximately 55% to 60% of subjects in the 3 through 15mg Xeljanz and ADA treatment arms reached ACR20 versus approximately 30% in the placebo arm.
Confirmatory Trials:
Study I
This was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received Xeljanz 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of Xeljanz 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II
This was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received Xeljanz 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of Xeljanz 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III
This was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received Xeljanz 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV
This is an ongoing 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received Xeljanz 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study V
This was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received Xeljanz 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of Xeljanz 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Overview of Results
In all trials, patients treated with either 5 or 10 mg twice daily Xeljanz had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in Xeljanz-treated patients were consistent at 6 and 12 months. In Study IV, a greater proportion of patients treated with Xeljanz 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3. The mean difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg Xeljanz twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg Xeljanz twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in Xeljanz-treated patients were consistent at 6 and 12 months.

Side Effects

Adverse events associated with the use of Xeljanz may include, but are not limited to, the following:

  • upper respiratory tract infectionsl
  • headache
  • diarrhea
  • nasopharyngitis

Mechanism of Action

Xeljanz (tofacitinib) is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

Additional Information

For additional information regarding Xeljanz or rheumatoid arthritis, please visit the Xeljanz web page.