Ustekinumab in treatment of Crohn’s disease: Design, development, and potential place in therapy

Drug Design, Development and Therapy

Volumn 10, Issue , 2016, Pages 3685-3698

  Deepak, Parakkal ^a   Loftus, Edward V ^a  

^a MAYO CLINIC   (United States)

Author keywords

Crohn s disease; Inflammatory bowel disease; Interleukin 12; Interleukin 12 23 monoclonal antibody; Interleukin 23; Ustekinumab

Indexed keywords

GUSELKUMAB; INTERLEUKIN 12; INTERLEUKIN 23; PLACEBO; RISANKIZUMAB; USTEKINUMAB; MONOCLONAL ANTIBODY; NONSTEROID ANTIINFLAMMATORY AGENT;

ADAPTIVE IMMUNITY; ADVERSE OUTCOME; ARTHRALGIA; CARDIOVASCULAR DISEASE; CLOSTRIDIUM DIFFICILE INFECTION; CROHN DISEASE; CYTOKINE PRODUCTION; DEMYELINATING DISEASE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG MONITORING; DRUG RESPONSE; DRUG SAFETY; ENDOSCOPY; HEADACHE; HUMAN; IMMUNOGENICITY; IMMUNOMODULATION; INFECTION; NON MELANOMA SKIN CANCER; NONHUMAN; PERIANAL ABSCESS; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PREGNANCY; PROTEIN EXPRESSION; PSORIASIS; REMISSION; REVIEW; RHINOPHARYNGITIS; STAPHYLOCOCCUS INFECTION; TREATMENT DURATION; URINARY TRACT INFECTION; VAGINA DISEASE; VAGINAL ABSCESS; VIRAL GASTROENTERITIS; ANTAGONISTS AND INHIBITORS; ARTHRITIS, PSORIATIC; CHEMISTRY; METABOLISM; PATHOPHYSIOLOGY;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ARTHRITIS, PSORIATIC; CROHN DISEASE; HUMANS; INTERLEUKIN-12; INTERLEUKIN-23; USTEKINUMAB;

EID: 84995684222     PISSN: None     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S102141     Document Type: Review

References (89)

1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–2078.
2. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427–434.
3. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med. 1995;332(5):292–297.
4. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302(18):981–987.
5. Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol. 2006;12(35):5606–5610.
6. Ryan C, Thrash B, Warren RB, Menter A. The use of ustekinumab in autoimmune disease. Expert Opin Biol Ther. 2010;10(4):587–604.
7. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–1674.
8. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–1684.
9. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780–789.
10. Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990–999.
11. Stelara® [package insert]. Horsham, PA: Janssen Biotech, Inc.; March 2014. Available from: https://www.stelarainfo.com/pdf/prescribinginformation.pdf. Accessed August 9, 2016.
12. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004;351(20):2069–2079.
13. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519–1528.
14. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135(4):1130–1141.
15. FDA Approves STELARA® (ustekinumab) for Treatment of Adults with Moderately to Severely Active Crohn’s Disease. Janssen Biotech, Inc. [press release]. PR Newswire; 2016 [September 26]. Available from: http://www.prnewswire.com/news-releases/fda-approves-stelara-ustekinumab-for-treatment-of-adults-with-moderately-to-severely-active-crohns-disease-300333868.html. Accessed October 7, 2016.
16. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3(2):133–146.
17. Kobayashi M, Fitz L, Ryan M, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989;170(3):827–845.
18. Presky DH, Yang H, Minetti LJ, et al. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci U S A. 1996;93(24):14002–14007.
19. Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12 Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168(11):5699–5708.
20. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278(3):1910–1914.
21. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950–957.
22. Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503–511.
23. Geremia A, Arancibia-Carcamo CV, Fleming MP, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011;208(6):1127–1133.
24. Benson JM, Sachs CW, Treacy G, et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat Biotechnol. 2011;29(7):615–624.
25. Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182(5):1281–1290.
26. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006;25(2):309–318.
27. Becker C, Dornhoff H, Neufert C, et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006;177(5):2760–2764.
28. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1756–1767.
29. Niederreiter L, Adolph TE, Kaser A. Anti-IL-12/23 in Crohn’s disease: bench and bedside. Curr Drug Targets. 2013;14(12):1379–1384.
30. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–558.
31. US FDA Center for Drug Evaluation and Research: Ustekinumab (2013). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125261s086lbl.pdf. Accessed July 18, 2016.
32. Gottlieb AB, Cooper KD, McCormick TS, et al. A phase 1, double-blind, placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis. Curr Med Res Opin. 2007;23(5):1081–1092.
33. Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91(4):635–646.
34. Zhu Y, Hu C, Lu M, et al. Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis. J Clin Pharmacol. 2009;49(2):162–175.
35. Zhou H, Davis HM. Risk-based strategy for the assessment of pharmacokinetic drug-drug interactions for therapeutic monoclonal antibodies. Drug Discov Today. 2009;14(17–18):891–898.
36. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118–128.
37. Toedter GP, Blank M, Lang Y, Chen D, Sandborn WJ, de Villiers WJ. Relationship of C-reactive protein with clinical response after therapy with ustekinumab in Crohn’s disease. Am J Gastroenterol. 2009;104(11):2768–2773.
38. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s disease. N Engl J Med. 2016. In Press.
39. Sandborn W, Gasink C, Blank M, et al. O-001 A multicenter, double-blind, placebo-controlled phase 3 study of ustekinumab, a human IL-12/23P40 mAB, in moderate-service Crohn’s disease refractory to anti-TFNalpha: UNITI-1 (abstract). Inflamm Bowel Dis. 2016;22(Suppl 1):S1.
40. Feagan B, Gasink C, Lang Y, et al. OP054-LB4 A multicenter, double-blind, placebo-controlled Ph3 study of ustekinumab, a human monoclonal antibody to IL-12/23p40, in patients with moderately-severely active Crohn’s disease who are naïve or not refractory to anti-TNFa: UNITI-2 (abstract). United European Gastroenterol J. 2015;3(6):2.
41. Sandborn W, Feagan BG, Gasink C, et al. 768 A phase 3 randomized, multicenter, double-blind, placebo-controlled study of ustekinumab maintenance therapy in moderate-severe Crohn’s disease patients: results from IM-UNITI (abstract). Gastroenterology. 2016;150(4):S157–S158.
42. Batista DD, Yadav S, Harmsen WS, et al. Su1420 Ustekinumab treatment for Crohn’s disease in clinical practice: experience at a tertiary medical center (abstract). Gastroenterology. 2014;146(5):S-464–S-465.
43. Kopylov U, Afif W, Cohen A, et al. Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn’s disease – the McGill experience. J Crohns Colitis. 2014;8(11):1516–1522.
44. Wils P, Bouhnik Y, Michetti P, et al. Subcutaneous ustekinumab provides clinical benefit for two-thirds of patients with Crohn’s disease refractory to anti-tumor necrosis factor agents. Clin Gastroenterol Hepatol. 2016;14(2):242–250.e241–e242.
45. Khorrami S, Ginard D, Marin-Jimenez I, et al. Ustekinumab for the treatment of refractory Crohn’s disease: the Spanish experience in a large multicentre open-label cohort. Inflamm Bowel Dis. 2016;22(7):1662–1669.
46. Adedokun O, Xu Z, Gasink C, et al. Pharmacokinetics and exposure-response relationships of intravenously administered ustekinumab during induction treatment in patients with Crohn’s disease: results from the UNITI-1 and UNITI-2 studies (abstract). J Crohns Colitis. 2016;10:S23–S24.
47. Adedokun OJ, Xu Z, Gasink C, et al. Sa1934 Pharmacokinetics and exposure-response relationships of ustekinumab during IV induction and SC maintenance treatment of patients with Crohn’s disease with ustekinumab: results from the UNITI-1, UNITI-2, and IM-UNITI studies (abstract). Gastroenterology. 2016;150(4):S408.
48. Battat R, Kopylov U, Bessissow T, et al. Association of ustekinumab trough concentrations with clinical, biochemical, and endoscopic outcomes (abstract). J Crohns Colitis. 2016;10:S74.
49. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461–465.
50. Brunda MJ, Luistro L, Warrier RR, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178(4):1223–1230.
51. Khanna R, Feagan BG. Ustekinumab for the treatment of Crohn’s disease. Immunotherapy. 2013;5(8):803–815.
52. Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844–854.
53. Papp K, Gottlieb AB, Naldi L, et al. Safety surveillance for ustekinumab and other psoriasis treatments from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Drugs Dermatol. 2015;14(7):706–714.
54. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494–500.
55. Gratton D, Szapary P, Goyal K, Fakharzadeh S, Germain V, Saltiel P. Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature. Arch Dermatol. 2011;147(10):1197–1202.
56. Loftus EV, Augustin M, Bissonnette R, et al. Mo1884 prevalence of inflammatory bowel disease among patients with psoriasis and incidence of serious infections in this subset: results from the PSOLAR registry (abstract). Gastroenterology. 2016;150(4):S805.
57. Ryan C, Leonardi CL, Krueger JG, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA. 2011;306(8):864–871.
58. Badat Y, Meissner WG, Laharie D. Demyelination in a patient receiving ustekinumab for refractory Crohn’s disease. J Crohns Colitis. 2014;8(9):1138–1139.
59. McConnell RA, Mahadevan U. Use of immunomodulators and biologics before, during, and after pregnancy. Inflamm Bowel Dis. 2016;22(1):213–223.
60. Martin PL, Sachs C, Imai N, et al. Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23p40 monoclonal antibody, during pregnancy and lactation. Birth Defects Res B Dev Reprod Toxicol. 2010;89(5):351–363.
61. Schaufelberg BW, Horn E, Cather J, Rahawi K. Pregnancy outcomes in women exposed to ustekinumab in the psoriasis clinical development program (abstract). J Am Acad Dermatol. 2014;70(5):AB178.
62. Mahadevan U, Martin C, Kane SV, Dubinsky M, Sands BE, Sandborn W. 437 Do infant serum levels of biologic agents at birth correlate with risk of adverse outcomes? Results from the PIANO registry (abstract). Gastroenterology. 2016;150(4):S91–S92.
63. Nguyen GC, Seow CH, Maxwell C, et al. The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology. 2016;150(3):734–757.e731.
64. Deepak P, Bruining DH. Update on the medical management of Crohn’s disease. Curr Gastroenterol Rep. 2015;17(11):41.
65. Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT. American gastroenterological association institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013;145(6):1459–1463.
66. Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease – algorithm for practical management. Aliment Pharmacol Ther. 2016;43(1):30–51.
67. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33(9):987–995.
68. 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):674–684.
69. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(3):618–627.e613.
70. 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.
71. Ben-Horin S, Casteele NV, Schreiber S, Lakatos P. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin Gastroenterol Hepatol. 2016 Epub May 21.
72. Papamichael K, Van Stappen T, Jairath V, et al. Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015;42(10):1158–1169.
73. 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.
74. Freling E, Baumann C, Cuny JF, et al. Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience. Am J Gastroenterol. 2015;110(8):1186–1196.
75. Guerra I, Perez-Jeldres T, Iborra M, et al. Incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease: a nationwide cohort study. Inflamm Bowel Dis. 2016;22(4):894–901.
76. Fahmy M, Ramamoorthy S, Hata T, Sandborn WJ. Ustekinumab for peristomal pyoderma gangrenosum. Am J Gastroenterol. 2012;107(5):794–795.
77. Goldminz AM, Botto NC, Gottlieb AB. Severely recalcitrant pyoderma gangrenosum successfully treated with ustekinumab. J Am Acad Dermatol. 2012;67(5):e237–e238.
78. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147(10):1203–1205.
79. Gheita TA, El G II, El-Fishawy HS, Aboul-Ezz MA, Kenawy SA. Involvement of IL-23 in enteropathic arthritis patients with inflammatory bowel disease: preliminary results. Clin Rheumatol. 2014;33(5):713–717.
80. Levin AA, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014;70(3):555–561.
81. Campa M, Mansouri B, Warren R, Menter A. A review of biologic therapies targeting IL-23 and IL-17 for use in moderate-to-severe plaque psoriasis. Dermatol Ther. 2016;6(1):1–12.
82. Boehringer Ingelheim’s investigational biologic cleared skin better, faster and for longer than ustekinumab in phase II psoriasis study. Boehringer Ingelheim, Inc. [press release]. Boehringer Ingelheim, Inc.; 2015 [October 8]. Available from: https://www.boehringer-ingelheim.com/press-release/boehringer-ingelheim-s-investigational-biologic-cleared-skin-better-faster-and-longer. Accessed October 7, 2016.
83. Papp K, Menter A, Sofen H, et al. Efficacy and safety of different dose regimens of a selective IL-23p19 inhibitor (BI 655066) compared with ustekinumab in patients with moderate-to-severe plaque psoriasis with and without psoriatic arthritis (abstract). Arthritis Rheumatol. 2015;67(Suppl 10). Available from: http://acrabstracts.org/abstract/efficacy-and-safety-of-different-dose-regimens-of-a-selective-il-23p19-inhibitor-bi-655066-compared-with-ustekinumab-in-patients-with-moderate-to-severe-plaque-psoriasis-with-and-without-psoriatic-a/. Accessed October 9, 2016.
84. Janssen Research & Development, LLC. A study of guselkumab in participants with moderate to severe plaque-type psoriasis and an inadequate response to ustekinumab (NAVIGATE). Bethesda (MD): National Library of Medicine (US); 2000 [cited 2016 Oct 7]. NLM Identifier: NCT02203032. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02203032. Accessed October 7, 2016.
85. Sands BE, Chen J, Penney M, et al. 830 Initial evaluation of MEDI2070 (specific anti-IL-23 antibody) in patients with active Crohn’s disease who have failed anti-TNF antibody therapy: a randomized, double-blind placebo-controlled phase 2A induction study (abstract). Gastroenterology. 2015;148(4):S-163–S-164.
86. Feagan BG, Sandborn W, Panés J, et al. 812a Efficacy and safety of induction therapy with the selective IL-23 inhibitor BI 655066, in patients with moderate-to-severe Crohn’s disease: results of a randomized, double-blind, placebo-controlled phase II study (abstract). Gastroenterology. 2016;150(4):S1266.
87. Sun Pharma and Merck & Co. Inc. Enter into Licensing Agreement for Tildrakizumab, Merck & Co., Inc. [press release]. Merck Sharp & Dohme Corp. website; 2014 [September 17]. Available from: http://www.merck.com/licensing/our-partnership/sunpharma_partnership.html. Accessed October 7, 2016.
88. Sandborn WJ. The present and future of inflammatory bowel disease treatment. Gastroenterol Hepatol. 2016;12(7):438–441.
89. Kuehbacher T, Nikolaus S, Schreiber S. Serum soluble IL2-receptor is increased in a subpopulation of Crohns disease patients, who respond to open label use of ustekinumab, a human monoclonal antibody to IL-12/23p40 (abstract). Gastroenterology. 2011;140(5):S-589.