Emerging Therapies: What Are Promising in the Near Future?

Geom Seog Seo; Sung Hee Lee

doi:10.4166/kjg.2018.71.2.81

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Seo and Lee: Emerging Therapies: What Are Promising in the Near Future?

Review Article

Korean J Gastroenterol 2018;71(2):81-88.

Published online: 4 October 2018

DOI: https://doi.org/10.4166/kjg.2018.71.2.81

Emerging Therapies: What Are Promising in the Near Future?

Geom Seog Seo, Sung Hee Lee¹

Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Korea

¹Institute of Pharmaceutical Research and Development, Wonkwang University College of Pharmacy, Iksan, Korea

Correspondence to: Geom Seog Seo, Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University School of Medicine, 895 Muwangro, Iksan 54538, Korea. Tel: +82-63-859-2565, Fax: +82-63-855-2025, E-mail: medsgs@wonkwang.ac.kr

Received 30 December 2017 Revised 12 February 2018 Accepted 14 February 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The treatment of inflammatory bowel disease has evolved with the development of anti-TNF agents. In spite of long-term effectiveness, many patients do not respond or no longer responds to these drugs. Therefore, the development of new drugs that act on different inflammatory pathways has become necessary. Vedolizumab, a gut-specific biological agent, inhibits interaction α4β7 integrin with mucosal addressin cell adhesion molecule-1 without inhibiting systemic immune responses. Long-term vedolizumab therapy in patients with Crohn's disease and ulcerative colitis was safe and effective. Additionally, vedolizumab can be used in patients already failed an anti-TNF therapy. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23. Ustekinumab will be a clinically effective agent to use in medically-refractory Crohn's disease especially as a second line drug. Tofacitinib is an oral, small molecule that inhibits JAK1, JAK3 and in a lesser extent, JAK2. Perhaps the most attractive things of these JAK inhibitors is that they are given orally instead of parenterally. Early results showed that patients with moderately to severely active ulcerative colitis receiving tofacitinib were more likely to achieve remission at 8 weeks than those receiving placebo. However, these results have not been as robust in Crohn's disease. Much of the positioning will depend on the safety profile such as opportunistic infection and atherogenic risk. The challenges for the future are to determine the therapeutic drug monitoring-guided dose optimization, optimal timing and drug combinations to produce the most effective, and safest outcomes for IBD patients.

Keywords: Ulcerative colitis, Crohn's disease, Vedolizumab, Ustekinumab, Tofacitinib

References

1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359:1541–1549.

2. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007; 132:52–65.

3. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007; 357:239–250.

4. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010; 4:355–366.

5. D'Haens GR, Panaccione R, Higgins PD, et al. The London position statement of the world congress of gastroenterology on biological therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011; 106:199–212.

6. Seo GS, Chae SC. Biological therapy for ulcerative colitis: an update. World J Gastroenterol. 2014; 20:13234–13238.

7. Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017; 85:103–116.

8. Cohen BL, Sachar DB. Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease. BMJ. 2017; 357:j2505.

9. Jovani M, Danese S. Vedolizumab for the treatment of IBD: a selective therapeutic approach targeting pathogenic α4β7 cells. Curr Drug Targets. 2013; 14:1433–1443.

10. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369:699–710.

11. Feagan BG, Rubin DT, Danese S, et al. Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2017; 15:229–239.e5.

12. Loftus EV Jr, Colombel JF, Feagan BG, et al. Longterm efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 2017; 11:400–411.

13. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013; 369:711–721.

14. Sands BE, Sandborn WJ, Van Assche G, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease in patients naïve to or who have failed tumor necrosis factor antagonist therapy. Inflamm Bowel Dis. 2017; 23:97–106.

15. Vermeire S, Loftus EV Jr, Colombel JF, et al. Longterm efficacy of vedolizumab for Crohn's disease. J Crohns Colitis. 2017; 11:412–424.

16. Noman M, Ferrante M, Bisschops R, et al. Vedolizumab induces long-term mucosal healing in patients with Crohn's disease and ulcerative colitis. J Crohns Colitis. 2017; 11:1085–1089.

17. Vedolizumab IV 300 mg in the treatment of fistulizing Crohn's disease (ENTERPRISE). [Internet]. Bethesda (MD): National Institutes of Health;2015 Dec 15. [updated 2015 Feb 12;cited 2017 Dec 30]. Available from:. https://clinicaltrials.gov/ct2/show/NCT02630966.

18. Bethge J, Meffert S, Ellrichmann M, Conrad C, Nikolaus S, Schreiber S. Combination therapy with vedolizumab and etanercept in a patient with pouchitis and spondylarthritis. BMJ Open Gastroenterol. 2017; 4:e000127.

19. Fischer S, Rath T, Geppert CI, et al. Longterm combination therapy with anti-TNF plus vedolizumab induces and maintains remission in therapy-refractory ulcerative colitis. Am J Gastroenterol. 2017; 112:1621–1623.

20. Triple combination therapy in high risk Crohn's disease. [Internet]. Bethesda (MD): National Institutes of Health;2016 May 6. [updated 2017 Dec 19;cited 2017 Dec 30]. Available from:. https://clinicaltrials.gov/ct2/show/NCT02764762.

21. Chakraborti TK. Pharmacology review(s) of vedolizumab (Entyvio, MLN0002),. 2013. [Internet]. Silver Spring (MD): Food and Drug Administration Center For Drug Evaluation and Research [cited 2017 Dec 30]. Available from:. http://www.accessdata.fda.gov/drug-satfda_docs/nda/2014/125476Orig1s000PharmR.pdf.

22. Mahadevan U, Vermeire S, Lasch K, et al. Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease. Aliment Pharmacol Ther. 2017; 45:941–950.

23. OTIS vedolizumab pregnancy exposure registry. [Internet]. Bethesda (MD): National Institutes of Health;2016 Feb 9. [updated 2017 Jun 7;cited 2017 Dec 30]. Available from:. https://clinicaltrials.gov/ct2/show/NCT02678052.

24. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 2017; 66:839–851.

25. McAuliffe ME, Lanes S, Leach T, et al. Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database. Curr Med Res Opin. 2015; 31:1655–1664.

26. Milch C, Wyant T, Xu J, et al. Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype. J Neuroimmunol. 2013; 264:123–126.

27. Dulai PS, Singh S, Jiang X, et al. The real-world effectiveness and safety of vedolizumab for moderate-severe Crohn's disease: results from the US VICTORY Consortium. Am J Gastroenterol. 2016; 111:1147–1155.

28. Kotze PG, Ghosh S, Bemelman WA, Panaccione R. Preoperative use of anti-tumor necrosis factor therapy in Crohn's disease: promises and pitfalls. Intest Res. 2017; 15:160–165.

29. Yamada A, Komaki Y, Patel N, et al. Risk of postoperative complications among inflammatory bowel disease patients treated preoperatively with vedolizumab. Am J Gastroenterol. 2017; 112:1423–1429.

30. Ferrante M, de Buck van Overstraeten A, Schils N, et al. Perioperative use of vedolizumab is not associated with postoperative infectious complications in patients with ulcerative colitis undergoing colectomy. J Crohns Colitis. 2017; 11:1353–1361.

31. Lightner AL, McKenna NP, Moncrief S, Pemberton JH, Raffals LE, Mathis KL. Surgical outcomes in vedolizumab-treated patients with ulcerative colitis. Inflamm Bowel Dis. 2017; 23:2197–2201.

32. Lightner AL, Raffals LE, Mathis KL, et al. Postoperative outcomes in vedolizumab-treated patients undergoing abdominal operations for inflammatory bowel disease. J Crohns Colitis. 2017; 11:185–190.

33. Wittig BM. Drug evaluation: CNTO-1275, a mAb against IL-12/IL-23p40 for the potential treatment of inflammatory diseases. Curr Opin Investig Drugs. 2007; 8:947–954.

34. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2016; 375:1946–1960.

35. Hibi T, Imai Y, Murata Y, Matsushima N, Zheng R, Gasink C. Efficacy and safety of ustekinumab in Japanese patients with moderately to severely active Crohn's disease: a subpopulation analysis of phase 3 induction and maintenance studies. Intest Res. 2017; 15:475–486.

36. Ma C, Fedorak RN, Kaplan GG, et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn's disease: real world experience from a multicentre cohort. Aliment Pharmacol Ther. 2017; 45:1232–1243.

37. Lightner AL, McKenna NP, Tse CS, et al. Postoperative outcomes in ustekinumab-treated patients undergoing abdominal operations for Crohn's disease. J Crohns Colitis. 2017 Dec 6. [Epub ahead of print].

38. Andrulonis R, Ferris LK. Treatment of severe psoriasis with ustekinumab during pregnancy. J Drugs Dermatol. 2012; 11:1240.

39. Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D. Spontaneous abortion during ustekinumab therapy. J Dermatol Case Rep. 2012; 6:105–107.

40. Venturin C, Nancey S, Danion P, et al. Fetal death in utero and mis-carriage in a patient with Crohn's disease under therapy with ustekinumab: case-report and review of the literature. BMC Gastroenterol. 2017; 17:80.

41. Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017; 376:1551–1560.

42. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis. 2018; 77:175–187.

43. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003; 3:900–911.

44. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007; 178:2623–2629.

45. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009; 228:273–287.

46. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017; 376:1723–1736.

47. Cholapranee A, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with metaanalysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials. Aliment Pharmacol Ther. 2017; 45:1291–1302.

48. Tran CT, Ducancelle A, Masson C, Lunel-Fabiani F. Herpes zoster: risk and prevention during immunomodulating therapy. Joint Bone Spine. 2017; 84:21–27.

49. Winthrop KL, Wouters AG, Choy EH, et al. The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: a randomized Phase II trial. Arthritis Rheumatol. 2017; 69:1969–1977.

50. Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017; 390:457–468.

51. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014; 41:837–852.

52. Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral janus kinase inhibitor. Semin Arthritis Rheum. 2016; 46:261–271.

53. Bissonnette R, Iversen L, Sofen H, et al. Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J Dermatol. 2015; 172:1395–1406.

54. Wolk R, Armstrong EJ, Hansen PR, et al. Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis. J Clin Lipidol. 2017; 11:1243–1256.

55. Kume K, Amano K, Yamada S, et al. Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study. Rheumatol Int. 2017; 37:2079–2085.

56. Longterm study of CP-690,550 in subjects with ulcerative colitis (OCTAVE). [Internet]. Bethesda (MD): National Institutes of Health;2011 Nov 11. [updated 2018 Feb 6;cited 2017 Dec 30]. Available from:. https://clinicaltrials.gov/ct2/show/NCT01470612.

57. Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016; 39:755–762.

58. Götestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016; 75:795–810.

59. Pouillon L, Bossuyt P, Peyrin-Biroulet L. Tofacitinib Is the right OCTAVE for ulcerative colitis. Gastroenterology. 2017; 153:862–864.

Table 1.

Characteristics and Positioning of Vedolizumab, Ustekinumab and Tofacitinib in the Treatment of Inflammatory Bowel Disease

	Vedolizumab	Ustekinumab	Tofacitinib
Indication	Moderate-to-severe UC and CD (second-line biologic agent in Korea)	Moderate-to-severe CD	Moderate-to-severe UC
Patient profiles	1. Concerns about infection and cancer	1. EIM	1. Intolerable injection side effects
	1. Concerns about infection and cancer	2. Children ^a	2. Prefer oral medication over injectable administration
	2. Uncontrolled heart failure, a history of lymphoma, or multiple sclerosis	3. Anti-TNF induced psoriaform lesions
Route of administration and dosage in clinical trials	IV induction (300 mg, q0–2–6w) and maintenance (300 mg q8w)	IV or sc induction ^b (130 mg or 6 mg/kg), sc maintenance (90 mg q8w or q12w)	Oral induction (10 mg BID) and maintenance (5 mg BID or 10 mg BID)
Induction of remission at week 6 or 8	1. 53.1% (anti-TNF naïve)/39.0% (anti-TNF failure) in UC	15.9% (130 mg)/20.9% (6mg/kg) in anti-TNF failure group	18.5% (10 mg BID)
Induction of remission at week 6 or 8	2. 22.7% (anti-TNF naïve)/13.3% (anti-TNF failure) in CD	30.6% (130 mg)/40.2% (6 mg/kg) in conventional therapy failure group
Sustained clinical remission who had a clinical response to induction therapy	1. 46.9% (anti-TNF naïve)/36.1% (anti-TNF failure) in UC at week 52	48.8% (90 mg q12w)/53.1% (90 mg q8w) at week 44	34.3% (5 mg BID), 40.6% (10 mg BID) at week 52
	2. 48.9% (anti-TNF naïve)/27.7% (anti-TNF failure) in CD at week 52
Mucosal healing	1. 41.9% (VDZ q8w)/47.5% (VDZ q4w) in anti-TNF failure group at week 52	Approximately one quarter (endoscopic or radiologic response; 51.6–76.0%)	1. 31.3% in OCTAVE 1, 28.4% in OCTAVE 2
Mucosal healing	2. 17–63% in CD		2. 37.4% (5 mg BID)/45.7% (10 mg BID) in OCTAVE sustain
Summary of clinical efficacy results	1. Highest as first-line agent for induction of remission and mucosal healing in moderate-to-severe UC	Consistent benefit of induction regimens, irrespective of previous treatment or response to a TNF antagonist	Similar efficacy in UC patients regardless of whether or not they have received prior anti-TNF therapy (highest second-line agent for induction of remission and mucosal healing in moderate-to-severe UC)
Summary of clinical efficacy results	2. The effectiveness of VDZ in anti-TNFα-naive populations tended to be greater than that in anti-TNFα-experienced populations
Safety profile	Favourable safety profile	Contraindicated in patients with hypersensitivity and clinically important active infection (e.g. active TB)	1. Increased risk of herpes zoster
Safety profile	Favourable safety profile		2. Risk of dyslipidemia

UC, ulcerative colitis; CD, Crohn's disease; EIM, extraintestinal manifestation; TNF, tumor necrosis factor; VDZ, vedolizumab.

^a Pediatric CD patients; only case series of UST use are available

^b Various dosage was used.

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