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Innovations in Oral Therapies for Inflammatory Bowel Disease

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Abstract

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn’s disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.

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References

  1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389:1756–70.

    PubMed  Google Scholar 

  2. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389:1741–55.

    PubMed  Google Scholar 

  3. Rawla P, Sunkara T, Raj JP. Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives. J Inflamm Res. 2018;11:215–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.

    CAS  PubMed  Google Scholar 

  5. Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386:1825–34.

    PubMed  Google Scholar 

  6. Colombel JF, Panaccione R, Bossuyt P, Lukas M, Baert F, Vanasek T, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390:2779–89.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Qiu Y, Chen BL, Mao R, Zhang SH, He Y, Zeng ZR, et al. Systematic review with meta-analysis: loss of response and requirement of anti-TNFalpha dose intensification in Crohn’s disease. J Gastroenterol. 2017;52:535–54.

    CAS  PubMed  Google Scholar 

  9. Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Ther Adv Gastroenterol. 2018;11:1756283X17750355.

    Google Scholar 

  10. Wentworth BJ, Buerlein RCD, Tuskey AG, Overby MA, Smolkin ME, Behm BW. Nonadherence to biologic therapies in inflammatory bowel disease. Inflamm Bowel Dis. 2018;24:2053–61.

    PubMed  Google Scholar 

  11. Nyboe Andersen N, Pasternak B, Friis-Moller N, Andersson M, Jess T. Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study. BMJ. 2015;350:h2809.

    PubMed  PubMed Central  Google Scholar 

  12. Yu H, MacIsaac D, Wong JJ, Sellers ZM, Wren AA, Bensen R, et al. Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Aliment Pharmacol Ther. 2018;47:364–70.

    CAS  PubMed  Google Scholar 

  13. Hindryckx P, Vande Casteele N, Novak G, Khanna R, D’Haens G, Sandborn WJ, et al. The expanding therapeutic armamentarium for inflammatory bowel disease: how to choose the right drug[s] for our patients? J Crohns Colitis. 2018;12:105–19.

    PubMed  Google Scholar 

  14. Olivera P, Danese S, Peyrin-Biroulet L. Next generation of small-molecules in inflammatory bowel disease. Gut. 2017;66:199–209.

    CAS  PubMed  Google Scholar 

  15. 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;376:1723–36.

    CAS  PubMed  Google Scholar 

  16. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007;6:881–90.

    CAS  PubMed  Google Scholar 

  17. Morrow T, Felcone LH. Defining the difference: what makes biologics unique. Biotechnol Healthc. 2004;1:24–9.

    PubMed  PubMed Central  Google Scholar 

  18. Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small-molecules in inflammatory bowel disease. Mucosal Immunol. 2018;11:1558–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu B, Wang Z, Zhang Q. Cost-effectiveness of different strategies for the treatment of moderate-to-severe ulcerative colitis. Inflamm Bowel Dis. 2018;24:2291–302.

    PubMed  Google Scholar 

  20. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2:1041–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang Y, Parker CE, Bhanji T, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;4:CD000543.

    PubMed  Google Scholar 

  22. Wang Y, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016. https://doi.org/10.1002/14651858.CD000544.pub4.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hemperly A, Sandborn WJ, Vande Casteele N. Clinical pharmacology in adult and pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2018;24:2527–42.

    PubMed  Google Scholar 

  24. Frieri G, Giacomelli R, Pimpo M, Palumbo G, Passacantando A, Pantaleoni G, et al. Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis. Gut. 2000;47:410–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hamedani R, Feldman RD, Feagan BG. Review article: drug development in inflammatory bowel disease: budesonide—a model of targeted therapy. Aliment Pharmacol Ther. 1997;11:98–107.

    CAS  PubMed  Google Scholar 

  26. Limketkai BN, Parian AM, Shah ND, Colombel JF. Short bowel syndrome and intestinal failure in Crohn’s disease. Inflamm Bowel Dis. 2016;22:1209–18.

    PubMed  Google Scholar 

  27. Rana SV, Sharma S, Malik A, Kaur J, Prasad KK, Sinha SK, et al. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci. 2013;58:2594–8.

    CAS  PubMed  Google Scholar 

  28. Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut. 2001;48:571–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Salim SY, Soderholm JD. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17:362–81.

    PubMed  Google Scholar 

  30. Sousa T, Yadav V, Zann V, Borde A, Abrahamsson B, Basit AW. On the colonic bacterial metabolism of azo-bonded prodrugs of 5-aminosalicylic acid. J Pharm Sci. 2014;103:3171–5.

    CAS  PubMed  Google Scholar 

  31. Dubey R, Dubey R, Omrey P, Vyas SP, Jain SK. Development and characterization of colon specific drug delivery system bearing 5-ASA and camylofine dihydrochloride for the treatment of ulcerative colitis. J Drug Target. 2010;18:589–601.

    CAS  PubMed  Google Scholar 

  32. Prantera C, Scribano ML. Budesonide multi-matrix system formulation for treating ulcerative colitis. Expert Opin Pharmacother. 2014;15:741–3.

    CAS  PubMed  Google Scholar 

  33. McCormack PL, Robinson DM, Perry CM. Delayed-release multi matrix system (MMX) mesalazine: in ulcerative colitis. Drugs. 2007;67:2635–42.

    CAS  PubMed  Google Scholar 

  34. Horst SN, Kane S. Multi-matrix system (MMX(R)) mesalamine for the treatment of mild-to-moderate ulcerative colitis. Expert Opin Pharmacother. 2012;13:2225–32.

    CAS  PubMed  Google Scholar 

  35. Ibekwe VC, Khela MK, Evans DF, Basit AW. A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology. Aliment Pharmacol Ther. 2008;28:911–6.

    CAS  PubMed  Google Scholar 

  36. Bolondi L, Gaiani S, Brignola C, Campieri M, Rigamonti A, Zironi G, et al. Changes in splanchnic hemodynamics in inflammatory bowel disease. Non-invasive assessment by Doppler ultrasound flowmetry. Scand J Gastroenterol. 1992;27:501–7.

    CAS  PubMed  Google Scholar 

  37. Waljee AK, Wiitala WL, Govani S, Stidham R, Saini S, Hou J, et al. Corticosteroid use and complications in a US inflammatory bowel disease cohort. PLoS One. 2016;11:e0158017.

    PubMed Central  PubMed  Google Scholar 

  38. Rezaie A, Kuenzig ME, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH, et al. Budesonide for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015. https://doi.org/10.1002/14651858.CD000296.pub4.

    Article  PubMed  Google Scholar 

  39. Kuenzig ME, Rezaie A, Seow CH, Otley AR, Steinhart AH, Griffiths AM, et al. Budesonide for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD002913.pub3.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Warner B, Johnston E, Arenas-Hernandez M, Marinaki A, Irving P, Sanderson J. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol. 2018;9:10–5.

    CAS  PubMed  Google Scholar 

  41. Beaugerie L, Brousse N, Bouvier AM, Colombel JF, Lemann M, Cosnes J, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374:1617–25.

    CAS  PubMed  Google Scholar 

  42. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Heap GA, Weedon MN, Bewshea CM, Singh A, Chen M, Satchwell JB, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014;46:1131–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wilson A, Jansen LE, Rose RV, Gregor JC, Ponich T, Chande N, et al. HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2018;47:615–20.

    CAS  PubMed  Google Scholar 

  45. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Soendergaard C, Bergenheim FH, Bjerrum JT, Nielsen OH. Targeting JAK-STAT signal transduction in IBD. Pharmacol Ther. 2018;192:100–11.

    CAS  PubMed  Google Scholar 

  47. Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, et al. Constitutive STAT3 activation in intestinal T cells from patients with Crohn’s disease. J Biol Chem. 2003;278:16777–81.

    CAS  PubMed  Google Scholar 

  48. Schreiber S, Rosenstiel P, Hampe J, Nikolaus S, Groessner B, Schottelius A, et al. Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut. 2002;51:379–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Shuai K, Liu B. Regulation of JAK–STAT signalling in the immune system. Nat Rev Immunol. 2003;3:900–11.

    CAS  PubMed  Google Scholar 

  50. 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;367:616–24.

    CAS  PubMed  Google Scholar 

  51. Panés 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.

    PubMed  PubMed Central  Google Scholar 

  52. Panés J, Vermeire S, Lindsay JO, Sands BE, Su C, Friedman G, et al. Tofacitinib in patients with ulcerative colitis: health-related quality of life in phase 3 randomised controlled induction and maintenance studies. J Crohns Colitis. 2017;12:145–56.

    PubMed Central  Google Scholar 

  53. Winthrop KL, Melmed GY, Vermeire S, Long MD, Nduaka CI, Su C, et al. Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib. Inflamm Bowel Dis. 2018;24:2258–65.

    PubMed Central  PubMed  Google Scholar 

  54. Sandborn WJ, Panés J, D’Haens GR, Sands BE, Su C, Moscariello M, et al. Safety of tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials. Clin Gastroenterol Hepatol. 2019;17:1541–50.

    CAS  PubMed  Google Scholar 

  55. Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017;76:1253–62.

    CAS  PubMed  Google Scholar 

  56. Pfizer announces modification to ongoing tofacitinib FDA post-marketing requirement study in patients with rheumatoid arthritis. 2019. https://investors.pfizer.com/investor-news/press-release-details/2019/Pfizer-Announces-Modification-to-Ongoing-Tofacitnib-FDA-Post-Marketing-Requirement-Study-in-Patients-with-Rheumatoid-Arthritis/default.aspx. Accessed 18 Apr 2019.

  57. Mease PJ, Kremer J, Cohen S, Curtis JR, Charles-Schoeman C, Loftus EV, et al. SAT0243 incidence of thromboembolic events in the tofacitinib rheumatoid arthritis, psoriasis, psoriatic arthritis and ulcerative colitis development programmes. Ann Rheum Dis. 2018;77:983.

    Google Scholar 

  58. Sandborn WJ, Feagan BG, Panes J, D’Haens GR, Colombel JF, Zhou Q, et al. Safety and efficacy of ABT-494 (upadacitinib), an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: results from CELEST. Gastroenterology. 2017;152:S1308–9.

    Google Scholar 

  59. D’Haens GR, Loftus EV, Higgins PD, Panes J, Panaccione R, Zhou W, et al. Tu1727 Rapidity of symptomatic and inflammatory biomarker improvements following upadacitinib induction treatment: data from the U-ACHIEVE study. Gastroenterology. 2019;156:S-1101.

    Google Scholar 

  60. Sands BE, Sandborn WJ, Feagan BG, Lichtenstein GR, Zhang H, Strauss R, et al. Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study. J Crohns Colitis. 2018;12:1158–69.

    PubMed  Google Scholar 

  61. Wang C, Mao J, Redfield S, Mo Y, Lage JM, Zhou X. Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues. Exp Mol Pathol. 2014;97:259–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol. 2009;5:428–34.

    CAS  PubMed  Google Scholar 

  63. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    CAS  PubMed  Google Scholar 

  64. Sandborn WJ, Feagan BG, Wolf DC, D’Haens G, Vermeire S, Hanauer SB, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374:1754–62.

    CAS  PubMed  Google Scholar 

  65. Jain N, Bhatti MT. Fingolimod-associated macular edema: incidence, detection, and management. Neurology. 2012;78:672–80.

    CAS  PubMed  Google Scholar 

  66. Camm J, Hla T, Bakshi R, Brinkmann V. Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J. 2014;168:632–44.

    CAS  PubMed  Google Scholar 

  67. Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol. 2006;6:244–50.

    CAS  PubMed  Google Scholar 

  68. Sandborn WJ, Peyrin-Biroulet L, Trokan L, Zhang J, Kuhbacher T, Chiorean M, et al. A randomized, double-blind, placebo-controlled trial of a selective, oral sphingosine 1-phosphate (S1P) receptor modulator, etrasimod (APD334), in moderate to severe ulcerative colitis (UC): results from the OASIS study. Am J Gastroenterol. 2018;113:S327.

    Google Scholar 

  69. Peyrin-Biroulet L, Panés J, Chiorean MV, Zhang J, Vermeire S, Jairath V, et al. Histologic remission and mucosal healing in a randomized, placebo-controlled, phase 2 study of etrasimod in patients with moderately to severely active ulcerative colitis. Gastroenterology. 2019;156:S-217.

    Google Scholar 

  70. Spadaccini M, D’Alessio S, Peyrin-Biroulet L, Danese S. PDE4 inhibition and inflammatory bowel disease: a novel therapeutic avenue. Int J Mol Sci. 2017;18:1276–90.

    PubMed Central  Google Scholar 

  71. Abdulrahim H, Thistleton S, Adebajo AO, Shaw T, Edwards C, Wells A. Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015;16:1099–108.

    CAS  PubMed  Google Scholar 

  72. Danese S, Neurath M, Kopon A, Zakko S, Simmons T, Fogel R, Maccarone J, Zhan X, Usiskin K, Chitkara D. OP006 Apremilast for active ulcerative colitis: a phase 2, randomised, double-blind, placebo-controlled induction study. J Crohn's Colitis. 2018;12(Supp 1):S004–5.

    Google Scholar 

  73. Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res. 2010;339:269–80.

    CAS  PubMed  Google Scholar 

  74. 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;369:699–710.

    CAS  PubMed  Google Scholar 

  75. 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;369:711–21.

    CAS  PubMed  Google Scholar 

  76. Sugiura T, Kageyama S, Andou A, Miyazawa T, Ejima C, Nakayama A, et al. Oral treatment with a novel small-molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis. 2013;7:e533–42.

    PubMed  Google Scholar 

  77. Yoshimura N, Watanabe M, Motoya S, Tominaga K, Matsuoka K, Iwakiri R, et al. Safety and efficacy of AJM300, an oral antagonist of alpha4 integrin, in induction therapy for patients with active ulcerative colitis. Gastroenterology. 2015;149:1775–83.

    CAS  PubMed  Google Scholar 

  78. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–80.

    CAS  PubMed  Google Scholar 

  79. 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;12:1485–93.

    CAS  PubMed  Google Scholar 

  80. 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. 2017;66:1049–59.

    CAS  PubMed  Google Scholar 

  81. Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol. 2013;191:3568–77.

    PubMed  Google Scholar 

  82. Voss J, Graff C, Schwartz A, Hyland D, Argiriadi M, Camp H, et al. THU0127 Pharmacodynamics of a novel JAK1 selective inhibitor in rat arthritis and anemia models and in healthy human subjects. Ann Rheum Dis. 2014;73:222.

    Google Scholar 

  83. 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;389:266–75.

    CAS  PubMed  Google Scholar 

  84. Panes J, Sandborn WJ, Loftus EV, Van Assche GA, Ghosh S, Zhou Q, et al. Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: results from the CELEST study. Gastroenterology. 2018;154:S-178.

    Google Scholar 

  85. Panaccione R, Atreya R, Ferrante M, Dubinsky M, Sands BE, Abreu MT, et al. Upadacitinib improves steroid-free clinical and endoscopic endpoints in patients with Crohn’s disease: data from the CELEST study. Gastroenterology. 2018;154:S-384.

    Google Scholar 

  86. Peyrin-Biroulet L, Louis E, Loftus EV, Lee WJ, Cataldi F, Lacerda AP, et al. Improvement in patient-reported outcomes with upadacitinib in patients with moderately to severely active Crohn’s disease: 52-week data from the CELEST study. United European Gastroenterol J. 2018;6(Supp 1):A91–2.

    Google Scholar 

  87. Peyrin-Biroulet L, Danese S, Louis E, Higgins PD, Dubinsky M, Cataldi F, et al. Mo1837: effect of upadacitinib on extra-intestinal manifestations in patients with moderate to severe Crohn’s disease: data from the CELEST study. Gastroenterology. 2019;156:S-856.

    Google Scholar 

  88. Brian G. Feagan WJS, Danese S, D’Haens G, Levesque B, Wolf DC, Skolnick BE, Li C, Penenberg D, Aranda R, Olson A. P1272 endoscopic and clinical efficacy demonstrated with oral ozanimod in moderately to severely active Crohn’s disease. World Congress of Gastroenterology at ACG2017 meeting abstracts Orlando, FL: American College of Gastroenterology. 2017.

  89. Feagan BG, D’Haens G, Paul D, Liu J, Usiskin K, Pai RK. P661 Early histological improvement demonstrated with oral ozanimod in patients with moderately to severely active Crohn’s disease in the STEPSTONE trial. J Crohns Colitis. 2019;13:S450-S.

    Google Scholar 

  90. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004;279:13839–48.

    CAS  PubMed  Google Scholar 

  91. Saeed I, McLornan D, Harrison CN. Managing side effects of JAK inhibitors for myelofibrosis in clinical practice. Expert Rev Hematol. 2017;10:617–25.

    CAS  PubMed  Google Scholar 

  92. Feagan B. Update on tofacitinib for inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12:572–4.

    Google Scholar 

  93. Simoens S. Biosimilar medicines and cost-effectiveness. Clinicoecon Outcomes Res. 2011;3:29–36.

    PubMed  PubMed Central  Google Scholar 

  94. Chan W, Chen A, Tiao D, Selinger C, Leong R. Medication adherence in inflammatory bowel disease. Intest Res. 2017;15:434–45.

    PubMed  PubMed Central  Google Scholar 

  95. Greenley RN, Kunz JH, Walter J, Hommel KA. Practical strategies for enhancing adherence to treatment regimen in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1534–45.

    PubMed  Google Scholar 

  96. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18:191–8.

    CAS  PubMed  Google Scholar 

  97. Higgins PD, Rubin DT, Kaulback K, Schoenfield PS, Kane SV. Systematic review: impact of non-adherence to 5-aminosalicylic acid products on the frequency and cost of ulcerative colitis flares. Aliment Pharmacol Ther. 2009;29:247–57.

    CAS  PubMed  Google Scholar 

  98. Machado-Alba J, Machado-Duque M, Granada S. AB0403 adherence and access to biological therapy and tofacitinib in a cohort of colombian patients with rheumatological diseases. Ann Rheum Dis. 2017;76:1190.

    Google Scholar 

  99. Panes J, Bressler B, Colombel JF, Lawendy N, Maller E, Zhang H, et al. Efficacy and safety of tofacitinib retreatment for ulcerative colitis after treatment interruption: results from the OCTAVE clinical trials. J Crohns Colitis. 2018;12:P516.

    Google Scholar 

  100. Hart AL, Lomer M, Verjee A, Kemp K, Faiz O, Daly A, et al. What are the top 10 research questions in the treatment of inflammatory bowel disease? A priority setting partnership with the James Lind Alliance. J Crohns Colitis. 2017;11:204–11.

    PubMed  Google Scholar 

  101. Dulai PS, Boland BS, Singh S, Chaudrey K, Koliani-Pace JL, Kochhar G, et al. Development and validation of a scoring system to predict outcomes of vedolizumab treatment in patients with Crohn’s disease. Gastroenterology. 2018;155:687–95.

    PubMed  Google Scholar 

  102. Schreiber S, Peyrin-Biroulet L, Loftus EV, Danese S, Colombel JF, Abhyankar B, et al. VARSITY: A double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. J Crohns Colitis. 2019;13:S612–3.

    Google Scholar 

  103. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

    Google Scholar 

  104. Hagan LM, Schinazi RF. Best strategies for global HCV eradication. Liver Int. 2013;33:68–79.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Christopher Ma is supported by a Clinician Fellowship from the Canadian Institutes of Health Research, Crohn’s & Colitis Canada and the Canadian Association of Gastroenterology.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, 6D61 Teaching Research Wellness Building, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada

    Christopher Ma

  2. Robarts Clinical Trials, Inc., Suite 200, 100 Dundas Street, London, ON, N6A 5B6, Canada

    Christopher Ma, Claire E. Parker, William J. Sandborn, Brian G. Feagan & Vipul Jairath

  3. Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Robert Battat, Parambir S. Dulai & William J. Sandborn

  4. Division of Gastroenterology, Western University, London, ON, Canada

    Brian G. Feagan & Vipul Jairath

  5. Department of Epidemiology and Biostatistics, Western University, Suite 200, 100 Dundas Street, London, ON, N6A 5B6, Canada

    Brian G. Feagan & Vipul Jairath

  6. Division of Gastroenterology, Department of Medicine, Western University, Suite 200, 100 Dundas Street, London, ON, N6A 5B6, Canada

    Vipul Jairath

Authors
  1. Christopher Ma
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  2. Robert Battat
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  3. Parambir S. Dulai
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  4. Claire E. Parker
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  5. William J. Sandborn
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  6. Brian G. Feagan
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  7. Vipul Jairath
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Corresponding author

Correspondence to Vipul Jairath.

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Conflict of interest

CM has received consulting fees from Robarts Clinical Trials, Inc.; RB has no conflicts of interest to declare; PSD has received research support, honorarium, and travel support from Takeda; research support from Pfizer; and serves on the advisory board for Janssen; CEP is an employee of Robarts Clinical Trials Inc.; WJS has received research Grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly, Celgene/Receptos; consulting fees from Abbvie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Prizer, Precision IBD, Progenity, Prometheus Laboratories, Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Spouse: Opthotech—consultant, stock options; Progenity—consultant, stock; Oppilan Pharma—employee, stock options; Escalier Biosciences—employee, stock options; Precision IBD—employee, stock options; Ventyx Biosciences—employee, stock options; Vimalan Biosciences—employee, stock options. BGF has received Grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG and UCB; consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd. and Zyngenia; speakers bureau fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestle, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma; and is the Senior Scientific Officer of Robarts Clinical Trials Inc. VJ has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials Inc, Topivert and Celltrion; and speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie and Pfizer.

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Ma, C., Battat, R., Dulai, P.S. et al. Innovations in Oral Therapies for Inflammatory Bowel Disease. Drugs 79, 1321–1335 (2019). https://doi.org/10.1007/s40265-019-01169-y

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