June 2013

Intracellular Signal Pathways: Potential for Therapies

Current Rheumatology Reports 2009; 11:378-85

With recent progress in the development of drugs targeting signalling pathways for rheumatoid arthritis, this review article from the National Institutes of Health (NIH) provides an overview of the key intracellular pathways involved in the pathogenesis of rheumatoid arthritis. This paper also discusses some of the limitations of current drug targets including lack of clinical efficacy, potential adverse effects and cost, and highlights important issues associated with the design of target drugs...

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Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

Best Practice & Research Clinical Rheumatology 2010; 24:513-26

This article reviews data from animal and phase 2 clinical studies assessing the immunomodulatory effects and pharmacokinetics of CP-690,550 (now known as tofacitinib), as well as its efficacy and safety in patients with rheumatoid arthritis (RA). In two rodent models of arthritis, CP-690,550 produced dose-dependent decreases in signs of disease activity compared with untreated controls, reductions in histologically assessed inflammation and articular cartilage damage, and statistically signific...

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Back to the future: oral targeted therapy for RA and other autoimmune diseases

Nature Reviews Rheumatology 2013; 9(3):173-82

This review paper considers how advances in understanding of the disease process underlying rheumatoid arthritis (RA) and the development of novel techniques have transformed the management of this progressively disabling condition. Physicians are no longer limited to prescribing symptomatic treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) or choosing from a seemingly random array of drugs drawn from multiple disciplines, such as methotrexate and sulphasalazine, which are descri...

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Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...

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An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis

The New England Journal of Medicine 2010; 363(14):1303-12

This is the first phase 2 study to be published for spleen tyrosine kinase (Syk) inhibitor R788 (fostamatinib). This phase 2 study ingestigated the efficacy and safety of fostamatinib in patients with active RA despite long-term treatment with methotrexate. In this 6-month, double-blind, placebo-controlled trial, patients were randomised to receive two doses of R788 (100 mg twice daily or 150 mg once daily) or placebo once or twice daily. Significantly more patients on R788 achieved ACR 20 respo...

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An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

Arthritis & Rheumatism 2011; 63(2):337-45

This was the first phase 2 study to be published investigating the efficacy and safety of the spleen kinase (Syk) inhibitor R788 (fostamatinib) in patients with refractory rheumatoid arthritis (RA). In this multicentre, randomised, double-blind, placebo-controlled, 3-month trial, patients with active RA on stable background treatment (excluding biologics) were randomised to receive 100 mg R788 or placebo twice daily. Differences in ACR20 responses were significant at week 6 (p=0.003), but not th...

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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

Arthritis & Rheumatism 2012; 64(4):970-81

This study was one of two 24-week, phase 2b studies undertaken to characterise the efficacy and safety dose-response profile of the oral Janus kinase (JAK) inhibitor tofacitinib. Six doses of tofacitinib (20 mg daily and 1, 3, 5, 10 and 15 mg twice daily) and placebo were compared as add-on therapy in adults with active RA despite methotrexate (MTX) therapy. At week 12, ACR 20 response rates were significantly higher with all tofacitinib doses than with placebo (tofacitinib 45.7–58.1%; 33% place...

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Tofacitinib or adalimumab versus placebo in rheumatoid arthritis

The New England Journal of Medicine 2012; 367(6):508-19

The ORAL Standard trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 12-month, phase 3 study compared the efficacy of tofacitinib with the TNF inhibitor adalimumab or placebo. Patients with active RA despite background methotrexate (MTX) were randomised to 5 or 10 mg tofacitinib twice daily, 40 mg adalimumab fortnightly, or placebo, which was switched to tofacitinib at month 3 in non-responders and month 6 f...

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Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

The Lancet 2013; 381(9865):451-60

The ORAL Step trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 6-month, double-blind, parallel-group phase 3 study investigated the efficacy and safety of tofacitinib in adults with moderate to severe rheumatoid arthritis (RA) with an inadequate response to tumour necrosis factor (TNF) inhibitors. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to tofacitinib a...

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Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study

Annals of Rheumatic Diseases 2013; doi:10.1136/annrheumdis-2012-202442

This randomised, placebo-controlled, multicentre phase 2 study evaluated the efficacy and safety of atorvastatin versus placebo in modifying lipids in 111 patients with active rheumatoid arthritis (RA) receiving tofacitinib. All patients took tofacitinib 10 mg twice daily for 12 weeks, and after the first 6 weeks patients were randomised 1:1 to receive either atorvastatin 10 mg once daily (n=50) or matched placebo (n=48) in a double-blind phase for a further 6 weeks. Tofacitinib-induced elevatio...

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