#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Current and prospective biologics and small molecules in the treatment of inflammatory bowel diseases


Authors: Milan Buc
Authors‘ workplace: Imunologický ústav LF UK, Bratislava, Slovenská republika
Published in: Vnitř Lék 2018; 64(3): 280-289
Category: Reviews

Overview

Crohn′s disease (CD) and ulcerative colitis (UC) belong to chronic inflammatory bowel diseases, which are induced by autoimmune processes. While CD is characterized by over-activity of Th1, ILC1, and MAIT cells, UC is mediated by exaggerated activities of Th2 and ILC2 cells and cytokines they produce. Knowledge of the pathogenesis enabled a rational therapy based mostly on biologics and small molecules. TNF is the principal proinflammatory cytokine in both diseases. Anti-TNF monoclonal antibodies, mostly infliximab or adalimumab were therefore introduced to their treatment. Approximately 50–70 % of CD and more than 33 % of UC patients respond to primary treatment only, which resulted in the development of other biologics and small molecules. Out of them, monoclonal antibodies targeting adhesive molecules (vedolizumab, etrolizumab) and p40 chains shared by IL12 and IL23 (ustekinumab) have been already in clinical practice. There are also other small molecules in clinical trials: mongersen, tafacitinib, and ozanimod. Mongersen supports immunosuppressive activity of TGFβ; it has been tried for the treatment of CD. Tofacitinib inhibits activity of JAK kinases; it was shown to be effective in UC management. Ozanimod interferes with migrations of activated T cells to the site of inflammation and is a promising drug for the UC treatment.

Key words:
Crohn′s disease – mongersen – monoclonal antibodies – ozanimod – tofacitinib – ulcerative colitis


Sources

1. Lukáš M. Etiologie a patogeneze idiopatických střevních zánětů. Vnitř Lék 2014; 60(7–8): 640–644.

2. Ambružová B, Redová M, Michálek J et al. Nové poznatky v patogenezi Crohnovy choroby. Vnitř Lék 2012; 58(4): 291–298.

3. Olaison G, Leandersson P, Sjodahl R et al. Intestinal permeability to polyethyleneglycol 600 in Crohn‘s disease. Peroperative determination in a defined segment of the small intestine. Gut 1988; 29(2): 196–199.

4. Ukabam SO, Clamp JR, Cooper BT. Abnormal small intestinal permeability to sugars in patients with Crohn‘s disease of the terminal ileum and colon. Digestion 1983; 27(2): 70–74.

5. Marks DJ, Harbord MW, MacAllister R et al. Defective acute inflammation in Crohn‘s disease: a clinical investigation. Lancet 2006; 367(9511): 668–678. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(06)68265–2>. Erratum in Lancet 2007 Jul; 370(9584): 318.

6. Jurickova I, Collins MH, Chalk C et al. Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity. Clin Exp Immunol 2013; 172(3): 455–465. Dostupné z DOI: <http://dx.doi.org/10.1111/cei.12076>.

7. Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol 2011; 12(7): 597–606. Dostupné z DOI: <http://dx.doi.org/10.1038/ni.2059>.

8. Baumgart DC, Sandborn WJ. Crohn‘s disease. Lancet 2012; 380(9853): 1590–1605. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(12)60026–9>.

9. Fujino S, Andoh A, Bamba S et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003; 52(1): 65–70.

10. Verdier J, Begue B, Cerf-Bensussan N et al. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm Bowel Dis 2012; 18(7): 1260–1266. Dostupné z DOI: <http://dx.doi.org/10.1002/ibd.21905>.

11. Serriari NE, Eoche M, Lamotte L et al. Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin Exp Immunol 2014; 176(2): 266–274. Dostupné z DOI: <http://dx.doi.org/10.1111/cei.12277>.

12. Hinks TS. Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease. Immunology 2016; 148(1): 1–12. Dostupné z DOI: <http://dx.doi.org/10.1111/imm.12582>.

13. Bernink JH, Peters CP, Munneke M et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol 2013; 14(3): 221–229. Dostupné z DOI: <http://dx.doi.org/10.1038/ni.2534>.

14. Sandborn WJ, Hanauer SB, Katz S et al. Etanercept for active Crohn‘s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121(5): 1088–1094.

15. Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 2017; 14(5): 269–278. Dostupné z DOI: <http://dx.doi.org/10.1038/nrgastro.2016.208>.

16. Sultan KS, Berkowitz JC, Khan S. Combination therapy for inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2017; 8(2): 103–113. Dostupné z DOI: <http://dx.doi.org/10.4292/wjgpt.v8.i2.103>.

17. Present DH. Review article: the efficacy of infliximab in Crohn‘s disease--healing of fistulae. Aliment Pharmacol Ther 1999; 13(Suppl 4): 23–28; discussion 38.

18. Gomollon F, Dignass A, Annese V et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn‘s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis 2017; 11(1): 3–25. Dostupné z DOI: <http://dx.doi.org/10.1093/ecco-jcc/jjw168>.

19. Schnitzler F, Fidder H, Ferrante M et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn‘s disease: results from a single-centre cohort. Gut 2009; 58(4): 492–500. Dostupné z DOI: <http://dx.doi.org/10.1136/gut.2008.155812>.

20. Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn‘s disease. Gastroenterology 2004; 126(2): 402–413.

21. Brandse JF, van den Brink GR, Wildenberg ME et al. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology 2015; 149(2): 350–355.e2. Dostupné z DOI: <http://dx.doi.org/10.1053/j.gastro.2015.04.016>.

22. Jurgens M, Mahachie John JM et al. Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn‘s disease. Clin Gastroenterol Hepatol 2011; 9(5): 421–427. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cgh.2011.02.008>.

23. West NR, Hegazy AN, Owens BMJ et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med 2017; 23(5): 579–589. Dostupné z DOI: <http://dx.doi.org/10.1038/nm.4307>. Erratum in Erratum: Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. [Nat Med 2017]

24. Hueber W, Sands BE, Lewitzky S et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn‘s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012; 61(12): 1693–1700. Dostupné z DOI: <http://dx.doi.org/10.1136/gutjnl-2011–301668>.

25. Colombel JF, Sendid B, Jouault T et al. Secukinumab failure in Crohn‘s disease: the yeast connection? Gut 2013; 62(5): 800–801. Dostupné z DOI: <http://dx.doi.org/10.1136/gutjnl-2012–304154>.

26. Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol 2017; 17(9): 535–544. Dostupné z DOI: <http://dx.doi.org/10.1038/nri.2017.50>.

27. Feagan BG, Sandborn WJ, Gasink C et al. Ustekinumab as Induction and Maintenance Therapy for Crohn‘s Disease. N Engl J Med 2016; 375(20): 1946–1960. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1602773>.

28. Argollo M, Fiorino G, Hindryck P et al. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun 2017; 85: 103–116. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jaut.2017.07.004>.

29. Deepak P, Loftus EV Jr. Ustekinumab in treatment of Crohn‘s disease: design, development, and potential place in therapy. Drug Des Devel Ther 2016; 10: 3685–3698. Dostupné z DOI: <http://dx.doi.org/10.2147/DDDT.S102141>.

30. Sandborn WJ, Gasink C, Gao LL et al. Ustekinumab induction and maintenance therapy in refractory Crohn‘s disease. N Engl J Med 2012; 367(13): 1519–1528. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1203572>.

31. Tillack C, Ehmann LM, Friedrich M et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 2014; 63(4): 567–577. Dostupné z DOI: <http://dx.doi.org/10.1136/gutjnl-2012–302853>.

32. Singh S, Kroe-Barrett RR, Canada KA et al. Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody. MAbs 2015; 7(4): 778–791. Dostupné z DOI: <http://dx.doi.org/10.1080/19420862.2015.1032491>.

33. Argollo M, Fiorino G, Hindryckx P et al. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun 2017; 85: 103–116. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jaut.2017.07.004>.

34. Gaffen SL, Jain R, Garg AV et al. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 2014; 14(9): 585–600. Dostupné z DOI: <http://dx.doi.org/10.1038/nri3707>.

35. Cohn HM, Dave M, Loftus EV Jr. Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23(8): 1301–1315. Dostupné z DOI: <http://dx.doi.org/10.1097/MIB.0000000000001199>.

36. Soler D, Chapman T, Yang LL et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009; 330(3): 864–875. Dostupné z DOI: <http://dx.doi.org/10.1124/jpet.109.153973>.

37. Ley K, Rivera-Nieves J, Sandborn WJ et al. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 2016; 15(3): 173–183. Dostupné z DOI: <http://dx.doi.org/10.1038/nrd.2015.10>.

38. Vermeire S, O‘Byrne S, Keir M. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384(9940): 309–318. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(14)60661–9>.

39. Ardizzone S, Bevivino G, Monteleone G. Mongersen, an oral Smad7 antisense oligonucleotide, in patients with active Crohn‘s disease. Therap Adv Gastroenterol 2016; 9(4): 527–532. Dostupné z DOI: <http://dx.doi.org/10.1177/1756283X16636781>.

40. Monteleone G, Pallone F, MacDonald TT. Smad7 in TGF-beta-mediated negative regulation of gut inflammation. Trends Immunol 2004; 25(10): 513–517. Dostupné z DOI: <http://dx.doi.org/10.1016/j.it.2004.07.008>.

41. Nakao A, Afrakhte M, Moren A et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997; 389(6651): 631–635. Dostupné z DOI: <http://dx.doi.org/10.1038/39369>.

42. Monteleone G, Di Sabatino A, Ardizzone S et al. Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn‘s disease. Aliment Pharmacol Ther 2016; 43(6): 717–724. Dostupné z DOI: <http://dx.doi.org/10.1111/apt.13526>.

43. Marafini I, Monteleone I, Dinallo V et al. CCL20 is negatively regulated by tgf-beta1 in intestinal epithelial cells and reduced in Crohn‘s disease patients with a successful response to mongersen, a SMAD7 antisense oligonucleotide. J Crohns Colitis 2016; 11(5): 603–609. Dostupné z DOI: <http://dx.doi.org/10.1093/ecco-jcc/jjw191>.

44. Sandborn WJ, Ghosh S, Panes J 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): 1485–1493.e2. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cgh.2014.01.029>.

45. Vermeire S, Schreiber S, Petryka R 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): 266–275. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(16)32537–5>.

46. Drew L. Microbiota: Reseeding the gut. Nature 2016; 540(7634): S109-S112. Dostupné z DOI: <http://dx.doi.org/10.1038/540S109a>.

47. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353(23): 2462–2476. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa050516>. Erratum in N Engl J Med 2006; 354(20): 2200.

48. Armuzzi A, Pugliese D, Danese S et al. Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis. Inflamm Bowel Dis 2014; 20(8): 1368–1374. Dostupné z DOI: <http://dx.doi.org/10.1097/MIB.0000000000000115>.

49. Panaccione R, Ghosh S, Middleton S et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146(2): 392–400. Dostupné z DOI: <http://dx.doi.org/10.1053/j.gastro.2013.10.052>.

50. Fasanmade AA, Adedokun OJ, Olson A et al. Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther 2010; 48(5): 297–308.

51. Thorlund K, Druyts E, Mills EJ et al. Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naive to anti-TNF therapy: an indirect treatment comparison meta-analysis. J Crohns Colitis 2014; 8(7): 571–581. Dostupné z DOI: <http://dx.doi.org/10.1016/j.crohns.2014.01.010>.

52. Furfaro F, Bezzio C, Ardizzone S et al. Overview of biological therapy in ulcerative colitis: current and future directions. J Gastrointestin Liver Dis 2015; 24(2): 203–213. Dostupné z DOI: <http://dx.doi.org/10.15403/jgld.2014.1121.242.bezz>.

53. Ben-Horin S, Vande Casteele N, Schreiber S et al. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin Gastroenterol Hepatol 2016; 14(12): 1685–1696. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cgh.2016.05.023>.

54. Strik AS, Berends SE, Mathot RA et al. Golimumab for moderate to severe ulcerative colitis. Expert Rev Gastroenterol Hepatol 2017; 11(5): 401–406. Dostupné z DOI: <http://dx.doi.org/10.1080/17474124.2017.1303376>.

55. Dignass A, Lindsay JO, Sturm A et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012; 6(10): 991–1030. Dostupné z DOI: <http://dx.doi.org/10.1016/j.crohns.2012.09.002>.

56. Sandborn WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn‘s disease. N Engl J Med 2013; 369(8): 711–721. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1215739>.

57. Feagan BG, Rutgeerts P, Sands BE et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8): 699–710. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1215734>.

58. Gilroy L, Allen PB. Is there a role for vedolizumab in the treatment of ulcerative colitis and Crohn‘s disease? Clin Exp Gastroenterol 2014; 7: 163–172. Dostupné z DOI: <http://dx.doi.org/10.2147/CEG.S45261>.

59. Colombel JF, Sands BE, Rutgeerts P et al. The safety of vedolizumab for ulcerative colitis and Crohn‘s disease. Gut 2017; 66(5): 839–851. Dostupné z DOI: <http://dx.doi.org/10.1136/gutjnl-2015–311079>.

60. Zundler S, Becker E, Weidinger C et al. Anti-adhesion therapies in inflammatory bowel disease-molecular and clinical aspects. Front Immunol 2017; 8: 891. Dostupné z DOI: <http://dx.doi.org/10.3389/fimmu.2017.00891>.

61. Sandborn WJ, Su C, Panes J. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017; 377(5): 496–497. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMc1707500>.

62. Martin R, Sospedra M. Sphingosine-1 phosphate and central nervous system. Curr Top Microbiol Immunol 2014; 378: 149–170. Dostupné z DOI: <http://dx.doi.org/10.1007/978–3-319–05879–5_7>.

63. Mullershausen F, Zecri F, Cetin C et al. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 2009; 5(6): 428–434. Dostupné z DOI: <http://dx.doi.org/10.1038/nchembio.173>. Erratum in Nat Chem Biol 2009; 5(12): 954.

64. Peyrin-Biroulet L, Christopher R, Behan D et al. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev 2017; 16(5): 495–503. Dostupné z DOI: <http://dx.doi.org/10.1016/j.autrev.2017.03.007>.

65. Scott FL, Clemons B, Brooks J et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol 2016; 173(11): 1778–1792. Dostupné z DOI: <http://dx.doi.org/10.1111/bph.13476>.

66. Sandborn WJ, Feagan BG. Ozanimod Treatment for Ulcerative Colitis. N Engl J Med 2016; 375(8): e17. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMc1607287>.

67. Baert F. Is There a Role for Therapeutic Drug Monitoring of Anti-TNF Monoclonal Antibodies in Inflammatory Bowel Disease. Dig Dis 2015; 33(Suppl 1): 70–77. Dostupné z DOI: <http://dx.doi.org/10.1159/000437078>.

68. Mould DR. Why therapeutic drug monitoring is needed for monoclonal antibodies and how do we implement this? Clin Pharmacol Ther 2016; 99(4): 351–354. Dostupné z DOI: <http://dx.doi.org/10.1002/cpt.278>.

Labels
Diabetology Endocrinology Internal medicine
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#