January 2014

Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis

J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304

Preclinical studies can provide insight into mechanisms of efficacy and optimal dosing regimens. In this study, Dowty et al. compare the pharmacokinetic / pharmacodynamic profiles of tofacitinib in a murine arthritis model and in patients with rheumatoid arthritis from tofacitinib clinical trials. The main driver of efficacy in both preclinical murine arthritis models and clinical RA was found to be inhibition of JAK1 heterodimer signalling, where total drug exposure (Cave) was a predictor of pr...

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November 2013

Therapeutic Targeting of the JAK/STAT Pathway

Basic Clin Pharmacol Toxicol. 2013 Oct 24. doi: 10.1111/bcpt.12164

The inhibition of the JAK/STAT pathway has proven to be a powerful therapeutic tool in the treatment of autoimmune diseases. The authors review the role of the JAK/STAT pathway in human disease, including the role of mutations in defective function of this pathway. They discuss the rationale behind JAK inhibition and review the two JAK inhibitors currently approved by the FDA for clinical use; tofacitinib, for the treatment of RA, and ruxolitinib, for the treatment of polycythaemia vera and myel...

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October 2013

Involvement of JAK/STAT signalling in the pathogenesis of inflammatory bowel disease

Pharmacological Research 2013; 76:1–8

The JAK/STAT signalling pathway has been implicated in the pathogenesis of several inflammatory diseases including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In this review, Coskun et al. provide an excellent background overview of the JAK/STAT cascade. They also highlight recent study findings investigating the mechanisms of the JAK/STAT pathway and the anti-inflammatory effects of novel JAK inhibitors in development and in clinical trials, particularly in IBD. In one study...

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Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases

Journal of Immunology 2013;191:3568–77

JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...

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The JAK inhibitor, tofacitinib, reduces the t cell stimulatory capacity of human monocyte-derived dendritic cells

Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203756

The role of JAKs is highly important in lymphocyte differentiation, but their function in dendritic cells in unknown. In this study, the authors used tofacitinib, a JAK inhibitor, to assess the function of these kinases in dendritic cell activity. The results show that tofacitinib reduced the expression of CD80/CD86 by suppressing the activation of interferon regulatory factor (IRF)-7 and production of type 1 interferon (IFN), and also decreased T cell stimulatory capability. This suggests a nov...

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A meta-analysis of p38 mitogen-activated protein kinase inhibitors in patients with active rheumatoid arthritis

Clinical Rheumatology 2013 doi 10.1007/s10067-013-2340-1

The role of p38-MAPK inhibitors in treating RA is the subject of some debate. Li et al. therefore performed the first meta-analysis of the current data to evaluate the efficacy and safety of these compounds. The authors identified 3 papers, covering 4 RCTs, for analysis and the results showed that p38-MAPK inhibition achieves a better level of ACR20 improvement vs. placebo, but showed no meaningful difference in ACR50, DAS28 or CRP levels past week 12. Due to the inadequate number and quality of...

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Ibrutinib and novel BTK inhibitors in clinical development

Journal of Hematology & Oncology 2013;6:59

Bruton’s tyrosine kinase (BTK) is a part of the cytokine signalling pathways involved in malignancies and autoimmune disorders.. Akinleye et al. provide a review of all the current BTK inhibitors in preclinical and clinical trials for B-cell malignancies and autoimmune disorders, including rheumatoid arthritis. Particular focus is placed on ibrutinib, a novel human BTK-inhibitor, currently in phase III clinical trials. The authors also discuss four new compounds with potential indications in rh...

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September 2013

Inhibitors of switch kinase ‘spleen tyrosine kinase’ in inflammation and immune-mediated disorders: A review

European Journal of Medicinal Chemistry 2013 67:434–446

SYK plays a significant role in the immune cell signalling of B cells, mast cells, macrophages and neutrophils. Kaur et al. provide a comprehensive review of the molecule, its role in autoimmune disease and clinical data on its inhibition. The paper covers the basic chemistry of SYK including structure, mechanism of action, synthetic derivatives and function, and the relevance of SYK as a therapeutic target for many autoimmune diseases is discussed. The SYK inhibitors currently in clinical trial...

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Kinase Inhibitors: A new tool for the treatment of rheumatoid arthritis

Clinical Immunology 2013;148:66–78

Chakravaty et al. provide a comprehensive review of the scientific basis for kinase inhibitor use, and summarise experience from clinical trials in tofacitinib and fostamatinib, plus promising clinical data for p38-MAPK inhibitors and P13K? and P13Kd. The authors highlight potential future directions and challenges in kinase inhibitor research, including the emergence of kinases upstream of p38, such as MKK-3 and MKK-6, and the potential of BTK inhibition. One of the challenges of kinase inhibit...

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Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies

Br J Clin Pharmacol. 2013 Jul;76(1):78–88

Fostamatinib (R778) is a prodrug designed to deliver the active metabolite R406 which is an inhibitor of SYK and is currently under investigation for treatment of RA. The three clinical trials, conducted in healthy subjects, included two ascending dose studies and a formulation study. The first was a single ascending dose of R406, from 80-600mg, the second was a single and multiple dose study of fostamatinib in aqueous solution with single doses from 80-400mg and multiple doses of 160mg twice da...

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