Update on Janus Kinase Antagonists in Inflammatory Bowel Disease

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Key points

  • Janus kinase (JAK) inhibitors represent a novel small-molecule therapy that will likely become a new medical treatment for inflammatory bowel disease (IBD).

  • JAK inhibitors target small intracellular molecules responsible for transducing signals from inflammatory cytokines believed to be involved in the pathogenesis of IBD.

  • Based on phase 2 clinical trials, tofacitinib, a JAK1 and JAK3 inhibitor, has a dose-dependent effect in ulcerative colitis and potentially an effect in Crohn disease.

Janus kinase family

The JAK proteins are a family of nonreceptor tyrosine kinases that possess a highly conserved kinase domain responsible for its enzymatic activity. The family consists of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2); these proteins associate with the intracellular portion of cytokine or hormone receptors.6 The family has been shown to play a central role in the signal transduction pathways for multiple cytokines, including proinflammatory cytokines involved in the pathogenesis of autoimmune

Tofacitinib: JAK inhibitor

Knowledge of the JAK-STAT signaling pathways has been applied to the development of orally administered small-molecule inhibitors, which are being tested in clinical trials for the treatment of autoimmune diseases. Tofacitinib (CP-690550) was the first small-molecule JAK inhibitor tested in clinical trials for the treatment of autoimmune diseases, such as psoriasis, RA, prevention of allograft rejection, and IBD.5 Tofacitinib interferes with the JAK-STAT signaling by competing with adenosine

Safety and tolerability profile of tofacitinib

The safety profile of tofacitinib has been primarily derived from the large phase 3 and extension trials of tofacitinib in RA, typically with dosages of 5 or 10 mg twice daily. A meta-analysis that included 8 randomized controlled studies of tofacitinib in RA reported no significant increase in serious adverse events. In terms of tolerability, there was no increase in adverse events leading to cessation of therapy during the first 3 months of treatment.39 The cumulative safety data for

Future JAK inhibitors in inflammatory bowel disease

Although tofacitinib is the only JAK inhibitor currently in clinical trials for IBD, there has been an explosion of JAK inhibitors with differing selectivity for the JAK family members that are being tested in RA and other autoimmune diseases. The new drugs have different specificities, changing both the precise effects of the drug and the safety profiles (Table 4).

Ruxolitinib (Incyte) selectively inhibits JAK1 and JAK2, and was initially shown to be effective in the treatment of myelofibrosis.

Summary

JAK inhibitors are an emerging and promising treatment for IBD and autoimmune diseases. These drugs target small intracellular molecules responsible for transducing the signals by potent inflammatory cytokines that orchestrate the immune response. These agents can be administered through an oral route and are not immunogenic. Based on biological plausibility, extensive molecular studies, and now early studies in IBD, tofacitinib has a dose-dependent effect in UC, and potentially an effect in

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    Disclosures: W.J. Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys Inc, Atlantic Healthcare Ltd, Aptalis, BioBalance Corp, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene Inc, Eli Lilly, Enteromedics, Exagen Diagnostics Inc, Ferring Pharmaceuticals, Flexio Therapeutics Inc, Funxional Therapeutics Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GSK, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc, PDL Biopharma, Pfizer, Procter & Gamble, Prometheus Laboratories, ProtAb Ltd, Purgenesis Technologies Inc, Relypsa Inc, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plow, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner Chilcott UK Ltd and Wyeth; research grants from Abbott, Bristol-Myers Squibb, Genentech, GSK, Janssen, Millennium Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals and UCB Pharma; payments for lectures/speakers bureaux from Abbott, Bristol-Myers Squibb and Janssen; and holds stock/stock options in Enteromedics. J.T. Chang and B.S. Boland have no disclosures.

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