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Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects

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Abstract

Inflammatory bowel disease (IBD) is caused by a dysregulation of the immune system, inducing the production of proinflammatory cytokines and adhesion molecules. A better understanding of the mucosal immune response in IBD has led to the development of new drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Beyond tumor necrosis factor antagonists and anti-integrin molecules, which act by blocking the interaction between gut-specific lymphocytes and their receptor on vascular endothelium, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD. JAK inhibitors are small molecules able to selectively target the activity of specific JAKs that play a role in signal transmission via interleukins. This review presents an overview of the role of the JAK/STAT signaling pathway and updated information for JAK molecules, which are promising drugs in IBD. Currently developed to treat ulcerative colitis and Crohn’s disease, tofacitinib (in a phase III study) and filgotinib (in a phase II study), respectively, are the JAK inhibitors in the most advanced stage of development for IBD. However, the utility of, and adverse events associated with, these new drugs remain to be determined and clarified (in particular, the risk of herpes zoster infections), depending on the efficacy and tolerance determined from definitive studies. The availability of these drugs could enhance the therapeutic approach to IBD in the coming years, and reinforce the concept of personalized medicine for IBD patients.

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References

  1. M’Koma AE. Inflammatory bowel disease: an expanding global health problem. Clin Med Insights Gastroenterol. 2013;6:33–47.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427–34.

    Article  CAS  PubMed  Google Scholar 

  3. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pedersen J, Coskun M, Soendergaard C, Salem M, Nielsen OH. Inflammatory pathways of importance for management of inflammatory bowel disease. World J Gastroenterol. 2014;20(1):64–77.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Billiet T, Rutgeerts P, Ferrante M, Van Assche G, Vermeire S. Targeting TNF-alpha for the treatment of inflammatory bowel disease. Expert Opin Biol Ther. 2014;14(1):75–101.

    Article  CAS  PubMed  Google Scholar 

  6. Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104(3):760–7.

    Article  CAS  PubMed  Google Scholar 

  7. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol. 2011;106(4):674–84.

    Article  CAS  PubMed  Google Scholar 

  8. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.

    Article  CAS  PubMed  Google Scholar 

  9. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711–21.

    Article  CAS  PubMed  Google Scholar 

  10. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946–60.

    Article  CAS  PubMed  Google Scholar 

  11. Wilks AF. The JAK kinases: not just another kinase drug discovery target. Semin Cell Dev Biol. 2008;19(4):319–28.

    Article  CAS  PubMed  Google Scholar 

  12. Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci USA. 1994;91(14):6374–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016;111:784–803.

    Article  CAS  PubMed  Google Scholar 

  14. Gross V, Andus T, Caesar I, Roth M, Scholmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology. 1992;102(2):514–9.

    Article  CAS  PubMed  Google Scholar 

  15. Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology. 1993;104(5):1285–92.

    Article  CAS  PubMed  Google Scholar 

  16. Liu X, Jones GW, Choy EH, Jones SA. The biology behind interleukin-6 targeted interventions. Curr Opin Rheumatol. 2016;28(2):152–60.

    Article  CAS  PubMed  Google Scholar 

  17. Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O, Sata M, et al. Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J Immunol. 2010;184(3):1543–51.

    Article  CAS  PubMed  Google Scholar 

  18. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967–74.

    Article  CAS  PubMed  Google Scholar 

  19. Dienz O, Rincon M. The effects of IL-6 on CD4 T cell responses. Clin Immunol. 2009;130(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  20. Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L, et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One. 2014;9(3):e85345.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One. 2014;9(12):e114195.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Defendenti C, Sarzi-Puttini P, Saibeni S, Bollani S, Bruno S, Almasio PL, et al. Significance of serum Il-9 levels in inflammatory bowel disease. Int J Immunopathol Pharmacol. 2015;28(4):569–75.

    Article  PubMed  Google Scholar 

  23. Nalleweg N, Chiriac MT, Podstawa E, Lehmann C, Rau TT, Atreya R, et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut. 2015;64(5):743–55.

    Article  CAS  PubMed  Google Scholar 

  24. Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S, et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol. 2014;15(7):676–86.

    Article  CAS  PubMed  Google Scholar 

  25. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28(4):546–58.

    Article  CAS  PubMed  Google Scholar 

  26. Hofmann SR, Rosen-Wolff A, Tsokos GC, Hedrich CM. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol. 2012;143(2):116–27.

    Article  CAS  PubMed  Google Scholar 

  27. Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 2003;19(5):641–4.

    Article  CAS  PubMed  Google Scholar 

  28. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O’Shea JJ, Johnston JA. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med. 1995;181(1):399–404.

    Article  CAS  PubMed  Google Scholar 

  29. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007;25:221–42.

    Article  CAS  PubMed  Google Scholar 

  30. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G827–38.

    Article  CAS  PubMed  Google Scholar 

  31. Lindemans CA, Calafiore M, Mertelsmann AM, O’Connor MH, Dudakov JA, Jenq RR, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528(7583):560–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brizzi MF, Aronica MG, Rosso A, Bagnara GP, Yarden Y, Pegoraro L. Granulocyte-macrophage colony-stimulating factor stimulates JAK2 signaling pathway and rapidly activates p93fes, STAT1 p91, and STAT3 p92 in polymorphonuclear leukocytes. J Biol Chem. 1996;271(7):3562–7.

    Article  CAS  PubMed  Google Scholar 

  33. Han X, Uchida K, Jurickova I, Koch D, Willson T, Samson C, et al. Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn’s disease. Gastroenterology. 2009;136(4):1261–71, e1–3.

  34. Zhang SY, Boisson-Dupuis S, Chapgier A, Yang K, Bustamante J, Puel A, et al. Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-alpha/beta, IFN-gamma, and IFN-lambda in host defense. Immunol Rev. 2008;226:29–40.

    Article  CAS  PubMed  Google Scholar 

  35. Hu X, Herrero C, Li WP, Antoniv TT, Falck-Pedersen E, Koch AE, et al. Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat Immunol. 2002;3(9):859–66.

    Article  CAS  PubMed  Google Scholar 

  36. Zhou L, Chong MM, Littman DR. Plasticity of CD4 + T cell lineage differentiation. Immunity. 2009;30(5):646–55.

    Article  CAS  PubMed  Google Scholar 

  37. Hu X, Ivashkiv LB. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009;31(4):539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Menet CJ, Rompaey LV, Geney R. Advances in the discovery of selective JAK inhibitors. Prog Med Chem. 2013;52:153–223.

    Article  CAS  PubMed  Google Scholar 

  39. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57(12):5023–38.

    Article  CAS  PubMed  Google Scholar 

  40. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.

    Article  CAS  PubMed  Google Scholar 

  41. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–24.

    Article  CAS  PubMed  Google Scholar 

  42. Panes J, Su C, Bushmakin AG, Cappelleri JC, Mamolo C, Healey P. Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes. BMC Gastroenterol. 2015;15:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Panes J, Su C, Bushmakin AG, Cappelleri JC, Healey P. Direct and indirect effects of tofacitinib on treatment satisfaction in patients with ulcerative colitis. J Crohns Colitis. 2016;10(11):1310–5.

    Article  PubMed  Google Scholar 

  44. Sandborn WJ, Panes J, Zhang H, Yu D, Niezychowski W, Su C. Correlation between concentrations of fecal calprotectin and outcomes of patients with ulcerative colitis in a phase 2 trial. Gastroenterology. 2016;150(1):96–102.

    Article  CAS  PubMed  Google Scholar 

  45. Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–36. doi:10.1056/NEJMoa1606910.

    Article  PubMed  Google Scholar 

  46. Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12(9):1485–93.e2.

  47. Panes J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D’Haens G, et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut. doi:10.1136/gutjnl-2016-312735. Epub 16 Feb 2017.

  48. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19.

    Article  PubMed  Google Scholar 

  49. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507.

    Article  CAS  PubMed  Google Scholar 

  50. Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(10):2675–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet. 2017;389(10066):266–75.

    Article  CAS  PubMed  Google Scholar 

  52. Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. doi:10.1136/annrheumdis-2016-210105. Epub 19 Dec 2016.

  53. Namour F, Desrivot J, Van der Aa A, Harrison P, Tasset C, van’t Klooster G. Clinical confirmation that the selective JAK1 inhibitor filgotinib (GLPG0634) has a low liability for drug–drug interactions. Drug Metab Lett. 2016;10(1):38–48.

  54. Mohamed MF, Camp HS, Jiang P, Padley RJ, Asatryan A, Othman AA. Pharmacokinetics, safety and tolerability of ABT-494, a novel selective JAK 1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis. Clin Pharmacokinet. 2016;55(12):1547–58.

    Article  CAS  PubMed  Google Scholar 

  55. Sprakes MB, Ford AC, Warren L, Greer D, Hamlin J. Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn’s disease: a large single centre experience. J Crohns Colitis. 2012;6(2):143–53.

    Article  PubMed  Google Scholar 

  56. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541–9.

    Article  CAS  PubMed  Google Scholar 

  57. Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):644–59, quiz 60.

  58. Mosli MH, Sandborn WJ, Kim RB, Khanna R, Al-Judaibi B, Feagan BG. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol. 2014;109(7):994–1004.

    Article  CAS  PubMed  Google Scholar 

  59. Atreya R, Neumann H, Neufert C, Waldner MJ, Billmeier U, Zopf Y, et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat Med. 2014;20(3):313–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bendtzen K, Ainsworth M, Steenholdt C, Thomsen OO, Brynskov J. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies. Scand J Gastroenterol. 2009;44(7):774–81.

    Article  CAS  PubMed  Google Scholar 

  61. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Maintenance of clinical effect in patients with moderate-to-severe Crohn’s disease treated with filgotinib, a selective JAK1 inhibitor: exploratory 20-week data analysis of the phase 2 FITZROY study. European Crohn's and colitis organisation. 2017. Available at: https://www.ecco-ibd.eu/index.php/publications/congress-abstract-s/abstracts-2017/item/op023-maintenance-of-clinical-effect-in-patients-with-moderate-to-severe-crohn-s-disease-treated-with-filgotinib-a-selective-jak1-inhibitor-exploratory-20-week-data-analysis-of-the-phase-2-fitzroy-study.html. Accessed 10 May 2017.

  62. Beattie D, Tsuruda P, Shen F, Brassil P, Langrish C, Janc J, et al. TD-1473, a novel, potent, and orally administered, GI-targeted, pan-Janus kinase (JAK) inhibitor. European Crohn's and colitis organisation. 2016. Available at: https://www.ecco-ibd.eu/index.php/publications/congress-abstract-s/abstracts-2016/item/p069-td-1473-a-novel-potent-and-orally-administered-gi-targeted-pan-janus-kinase-jak-inhibitor.html. Accessed 10 May 2017.

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Authors and Affiliations

  1. Hotel Dieu, Institut des Maladies de l’Appareil Digestif, University Hospital of Nantes, Place Alexis Ricordeau, 44093, Nantes Cedex, France

    Mathurin Flamant

  2. Laboratory of Immunology and Immunomonitoring, CIC 1408 INSERM, GIMAP EA3064, University Hospital of Saint-Etienne, Avenue Albert Raimond, 42277, Saint Priest en Jarez, France

    Josselin Rigaill & Stephane Paul

  3. University Hospital of Saint-Etienne, Avenue Albert Raimond, 42277, Saint Priest en Jarez, France

    Xavier Roblin

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Correspondence to Mathurin Flamant.

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Dr. Mathurin Flamant participates in the OCTAVE study as a co-investigator. He has no conflicts of interest and has received no financial assistance for the preparation of this manuscript. Drs. Josselin Rigaill and Stephane Paul have no conflicts of interest and have received no financial assistance. Prof. Xavier Roblin participates in the FITZROY study. He has no conflicts of interest and has received no financial assistance.

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Flamant, M., Rigaill, J., Paul, S. et al. Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects. Drugs 77, 1057–1068 (2017). https://doi.org/10.1007/s40265-017-0755-8

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