The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Kremer, Joel M.; Bloom, Bradley J.; Breedveld, Ferdinand C.; Coombs, John; Fletcher, Mark P.; Gruben, David; Krishnaswami, Sriram; Burgos‐Vargas, Rubén; Wilkinson, Bethanie; Zerbini, Cristiano A. F.; Zwillich, Samuel H.

doi:10.1002/art.34506

Cited by 100 publications

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“…Efficacy was established as early as week 2 and was sustained to week 24. These results confirm the earlier findings from a phase IIa study (5), which indicated that tofacitinib dosages of 5, 15, and 30 mg twice daily were efficacious as monotherapy over 6 weeks.…”

Section: Discussionsupporting

confidence: 90%

“…In a 6-week phase IIa monotherapy trial in patients with active RA and an inadequate response or unacceptable toxicity to methotrexate (MTX) or tumor necrosis factor inhibitors, tofacitinib at dosages of 5 mg twice daily, 15 mg twice daily, and 30 mg twice daily was efficacious in treating the signs and symptoms of RA (5). Tofacitinib at a dosage of 30 mg twice daily appeared to offer no increase in efficacy over a dosage of 15 mg twice daily.…”

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confidence: 99%

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A phase IIb dose‐ranging study of the oral JAK inhibitor tofacitinib (CP‐690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Kremer

Cohen

Wilkinson

et al. 2012

Arthritis & Rheumatism

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309

251

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Objective. To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy.Methods. In this 24-week, double-blind, phase IIb study, patients with active RA (n ‫؍‬ 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.Results. At week 12, ACR20 response rates for patients receiving all tofacitinib dosages >3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P < 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatmentemergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed.Conclusion. In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage >3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.Tofacitinib 550) is a novel, orally administered JAK inhibitor that is being investigated as a ClinicalTrials.gov identifier: NCT00413660.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

A phase IIb dose‐ranging study of the oral JAK inhibitor tofacitinib (CP‐690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Kremer

Cohen

Wilkinson

et al. 2012

Arthritis & Rheumatism

Self Cite

309

251

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“…A phase IIa, double-blind, placebo-controlled study trial evaluated the efficacy, safety, and tolerability of three different dosages of CP-690,550 in patients with active RA. The study showed a rapid, statistically significant, and clinically meaningful improvement in the signs and symptoms of RA [Kremer et al 2009]. These data suggest a specific JAK-3 inhibitor may provide a potential therapeutic option for the treatment of SLE.…”

Section: Ctla-igmentioning

confidence: 58%

Novel treatments for systemic lupus erythematosus

Xiong

Lahita

2011

Therapeutic Advances in Musculoskeletal

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There are many new therapeutic directions for the disease systemic lupus erythematosus (SLE). Despite this, the US Food and Drug Administration (FDA) has approved only one biological agent and it involves B cells, now thought to play a significant role in the pathogenesis of SLE. The name of the drug is belimumab, which is an agent that removes the B-cell cytokine called B lymphocyte stimulation factor (BLyS). Rituximab did not achieve its primary endpoints, even though the consensus is that it may be effective in some forms of SLE including renal disease. The anticytokine therapies against interleukin (IL)-6, IL-10, IL-17 and tumor necrosis factor (TNF) are effective in their own ways and phase II and III trials are in progress.Of particular interest to immunologists are the anti-interferon alpha and gamma drugs, which show promise in the animal models. Modulation of costimulatory molecules; specifically, the anti CD40, CTLA-Ig and ICOS/B7RP blockade agents offer possibilities for the future using new pathways heretofore limited to rheumatoid arthritis. Finally, the use of tyrosine kinase inhibitors is another direction that has been successful in the inhibition of SLE in the murine model; early trials in human SLE have begun.

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“…Tofacitinib selectively inhibits JAK1 and JAK3, and has been used for the prevention of organ transplant rejection [58] and the treatment of rheumatoid arthritis [59] and psoriasis [60]. The efficacy of tofacitinib in IBD was recently evaluated in a double-blind placebo-controlled phase 2 trial, in which 194 patients with moderate to severe active UC failing conventional therapy were randomized to receive tofacitinib at a dose of 0.5, 3, 10, or 15 mg or placebo twice daily for 8 weeks.…”

Section: Oral Janus Kinase (Jak) Inhibitor Tofacitinibmentioning

confidence: 99%

Emerging biologics in inflammatory bowel disease

Chan

2016

J Gastroenterol

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Early biologic therapy is recommended in patients with inflammatory bowel disease and poor prognostic factors and in those refractory to conventional medications. Anti-tumor necrosis factor (anti-TNF) agents are the most commonly used biologic agents. However, some patients may not have an initial response to anti-TNF therapy, and one-third will develop loss of response over time. Anti-TNF drugs can also be associated with side effects. In addition, the use of biologics is currently limited by their cost, especially in developing countries. A number of new therapeutic targets, including novel small molecules, and cellular therapy are available or under investigation. These novel molecules include oral Janus kinase (JAK) inhibitor (tofacitinib), interleukin inhibitor (ustekinumab), oral SMAD7 antisense oligonucleotide (mongersen), and anti-integrin inhibitors (vedolizumab). Here, we review the mechanisms of action, the efficacy, and the safety data of these novel agents. Biological products that are highly similar to reference biologic products whose patents have expired-also known as ''biosimilars''-can be produced at lower cost with similar efficacy, and are also available for the treatment of IBD. We review the efficacy data for such agents as well.

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The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind, placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Cited by 100 publications

References 0 publications

A phase IIb dose‐ranging study of the oral JAK inhibitor tofacitinib (CP‐690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

A phase IIb dose‐ranging study of the oral JAK inhibitor tofacitinib (CP‐690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Novel treatments for systemic lupus erythematosus

Emerging biologics in inflammatory bowel disease

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