New Therapeutic Strategies

  • Klaartje Kok
  • Ana Ibarra
  • James LindsayEmail author


Despite major advances in the management of inflammatory bowel diseases (IBD) a considerable proportion of patients remain refractory to conventional and currently licenced biologic therapies. This chapter summarises the immunological pathways that drive intestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC) and then reviews emerging drugs targeting different components of these pathways. These include biological agents against integrins and cytokines, small molecules; anti-sense oligonucleotides and cell based therapies.


Leukocyte trafficking Antisense therapy Interleukin-12/23 JAK/STAT pathway SMAD7/TGF-β pathway Emerging treatments 

List of Abbreviations


Chemokine receptor 9


Crohn’s disease


Disease activity index


European Medicines Agency


Faecal microbiota transplantation


Food and Drug Administration


Haematopoietic stem cell transplan-tation


Inflammatory bowel disease


Interferon γ




Intracellular adhesion molecule-1


Janus kinase


Mesenchymal stem cells

Treg cells

Regulatory T cells


Signal transducer and activator of transcription


Sphingosine 1-phosphate

Th cells

T-helper cells


Therapeutic drug monitoring


Tumour necrosis factor-α


Ulcerative colitis


  1. Abraham C, Dulai PS, Vermeire S, Sandborn WJ (2017) Lessons learned from trials targeting cytokine pathways in patients with inflammatory bowel diseases. Gastroenterology 152(2):374–388.e4CrossRefGoogle Scholar
  2. Ala A, Dhillon AP, Hodgson HJ (2003) Role of cell adhesion molecules in leukocyte recruitment in the liver and gut. Int J Exp Pathol 84(1):1–16CrossRefGoogle Scholar
  3. Baeyens A, Fang V, Chen C, Schwab SR (2015) Exit strategies: S1P signaling and T cell migration. Trends Immunol 36(12):778–787CrossRefGoogle Scholar
  4. Boirivant M, Pallone F, Di Giacinto C, Fina D, Monteleone I, Marinaro M et al (2006) Inhibition of Smad7 with a specific antisense oligonucleotide facilitates. Gastroenterology 131(6):1786–1798CrossRefGoogle Scholar
  5. Chirila TV, Rakoczy PE, Garrett KL, Lou X, Constable IJ (2002) The use of synthetic polymers for delivery of therapeutic antisense oligodeoxynucleotides. Biomaterials 23(2):321–342CrossRefGoogle Scholar
  6. Chiu H-Y, Chen C-H, Wu M-S, Cheng Y-P, Tsai T-F (2013) The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C. Br J Dermatol 169(6):1295–1303CrossRefGoogle Scholar
  7. D’Haens G, Sandborn WJ, Colombel JF, Rutgeerts P, Brown K, Barkay H et al (2015) A phase II study of laquinimod in Crohn’s disease. Gut 64(8):1227–1235CrossRefGoogle Scholar
  8. Danese S (2012) New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61(6):918–932CrossRefGoogle Scholar
  9. Danese S, Vermeire S, Hellstern P, Panaccione R, Rogler G, Fraser G et al (2016) 764 results of Andante, a randomized clinical study with an anti-IL6 antibody (PF-04236921) in subjects with Crohn’s disease who are anti-TNF inadequate responders. Gastroenterology 150(4):S155CrossRefGoogle Scholar
  10. Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y et al (2012) Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 143(5):1207–1217.e1CrossRefGoogle Scholar
  11. van Deventer SJH, Tami JA, Wedel MK (2004) A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut 53(11):1646–1651CrossRefGoogle Scholar
  12. van Deventer SJH, Wedel MK, Baker BF, Xia S, Chuang E, Miner PBJ (2006) A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther 23(10):1415–1425CrossRefGoogle Scholar
  13. Dudakov JA, Hanash AM, van den Brink MRM (2015) Interleukin-22: immunobiology and pathology. Annu Rev Immunol 33:747–785CrossRefGoogle Scholar
  14. Duijvestein M, Vos ACW, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW et al (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59(12):1662–1669CrossRefGoogle Scholar
  15. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ et al (2013) Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 369(8):699–710CrossRefGoogle Scholar
  16. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR et al (2016) Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 375(20):1946–1960CrossRefGoogle Scholar
  17. Feagan BG, Sandborn WJ, D’Haens G, Panes J, Kaser A, Ferrante M et al (2017) Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389(10080):1699–1709CrossRefGoogle Scholar
  18. Francis G, Kappos L, O’Connor P, Collins W, Tang D, Mercier F et al (2014) Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler Houndmills Basingstoke Engl 20(4):471–480CrossRefGoogle Scholar
  19. Ghosh S, Panaccione R (2010) Anti-adhesion molecule therapy for inflammatory bowel disease. Ther Adv Gastroenterol 3(4):239–258CrossRefGoogle Scholar
  20. Greuter T, Biedermann L, Rogler G, Sauter B, Seibold F (2016) Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: a case series. United European Gastroenterol J 4(1):97–104CrossRefGoogle Scholar
  21. Hawkey CJ, Hommes DW (2017) Is stem cell therapy ready for prime time in treatment of inflammatory bowel diseases? Gastroenterology 152(2):389–397.e2CrossRefGoogle Scholar
  22. Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E et al (2015) Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA 314(23):2524–2534CrossRefGoogle Scholar
  23. Ley K, Rivera-Nieves J, Sandborn WJ, Shattil S (2016) Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15(3):173–183CrossRefGoogle Scholar
  24. Li C, Kuemmerle JF (2014) Mechanisms that mediate the development of fibrosis in patients with Crohn’s disease. Inflamm Bowel Dis 20(7):1250–1258CrossRefGoogle Scholar
  25. Lindsay JO, Allez M, Clark M, Labopin M, Ricart E, Rogler G et al (2017) Autologous stem-cell transplantation in treatment-refractory Crohn’s disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol 2(6):399–406CrossRefGoogle Scholar
  26. Miner P, Wedel M, Bane B, Bradley J (2004) An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Aliment Pharmacol Ther 19(3):281–286CrossRefGoogle Scholar
  27. Miner PBJ, Wedel MK, Xia S, Baker BF (2006a) Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther 23(10):1403–1413CrossRefGoogle Scholar
  28. Miner PBJ, Geary RS, Matson J, Chuang E, Xia S, Baker BF et al (2006b) Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis. Aliment Pharmacol Ther 23(10):1427–1434CrossRefGoogle Scholar
  29. Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT (2001) Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 108(4):601–609CrossRefGoogle Scholar
  30. Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC, Castiglione F et al (2015) Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med 372(12):1104–1113CrossRefGoogle Scholar
  31. Okamoto R, Watanabe M (2016) Investigating cell therapy for inflammatory bowel disease. Expert Opin Biol Ther 16(8):1015–1023CrossRefGoogle Scholar
  32. Otero-Vinas M, Falanga V (2016) Mesenchymal stem cells in chronic wounds: the spectrum from basic to advanced therapy. Adv Wound Care 5(4):149–163CrossRefGoogle Scholar
  33. Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC et al (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388(10051):1281–1290CrossRefGoogle Scholar
  34. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D et al (2017) Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389(10075):1218–1228CrossRefGoogle Scholar
  35. Sandborn WJ (2016) Efficacy and safety of oral tofacitinib as induction therapy in patients with moderate-to-severe ulcerative colitis: results from 2 phase 3 randomised controlled trials. Oral presentation presented at: ECCO; AmsterdamGoogle Scholar
  36. Sandborn WJ, Panés J (2017) Efficacy and safety of oral tofacitinib as maintenance therapy in patients with moderate to severe ulcerative colitis: results from a phase 3 randomised controlled trial. Oral presentation presented at: ECCO; BarcelonaCrossRefGoogle Scholar
  37. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S et al (2012) Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 367(7):616–624CrossRefGoogle Scholar
  38. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE et al (2013) Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 369(8):711–721CrossRefGoogle Scholar
  39. Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W (2014) A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol 12(9):1485–1493 e2CrossRefGoogle Scholar
  40. Sandborn WJ, Feagan BG, Wolf DC, D’Haens G, Vermeire S, Hanauer SB et al (2016) Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 374(18):1754–1762CrossRefGoogle Scholar
  41. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M et al (2002) Mucosal flora in inflammatory bowel disease. Gastroenterology 122(1):44–54CrossRefGoogle Scholar
  42. Teng MWL, Bowman EP, McElwee JJ, Smyth MJ, Casanova J-L, Cooper AM et al (2015) IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 21(7):719–729CrossRefGoogle Scholar
  43. Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45(12):2615–2623CrossRefGoogle Scholar
  44. Vegter S, Tolley K, Wilson Waterworth T, Jones H, Jones S, Jewell D (2013) Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis. Aliment Pharmacol Ther 38(3):284–293CrossRefGoogle Scholar
  45. Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC et al (2014) Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384(9940):309–318CrossRefGoogle Scholar
  46. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X et al (2017) 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 389(10066):266–275CrossRefGoogle Scholar
  47. de Vries L, Wildenberg M, de Jonge W, D’Haens G (2017) The future of Janus kinase inhibitors in inflammatory bowel disease. J Crohns Colitis 11(7):885–893CrossRefGoogle Scholar
  48. William S, Christopher G, Daphne C, Yinghua L, Paul P, Stephen H et al (2017) PD-012 endoscopic healing in the ustekinumab phase 3 UNITI/IMUNITI Crohn’s disease program and relationship of clinical outcomes to baseline ulceration status. Inflamm Bowel Dis. 23:S9. Available from
  49. Yacyshyn BR, Chey WY, Goff J, Salzberg B, Baerg R, Buchman AL et al (2002) Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn’s disease. Gut 51(1):30–36CrossRefGoogle Scholar
  50. Yacyshyn B, Chey WY, Wedel MK, Yu RZ, Paul D, Chuang E (2007) A randomized, double-masked, placebo-controlled study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment of subjects with active Crohn’s disease. Clin Gastroenterol Hepatol 5(2):215–220CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of GastroenterologyBarts Health NHS TrustLondonUK
  2. 2.Centre for ImmunobiologyBlizard Institute, Barts and The London School of Medicine, Queen Mary University of LondonLondonUK

Personalised recommendations