Novel and emerging drugs for the treatment of Crohn’s disease: a review of phase II and III trials

References

• Torres J, Mehandru S, Colombel J-F, et al. Crohn’s disease. Lancet. 2017;389:1741–1755. doi: 10.1016/S0140-6736(16)31711-1
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Loftus EV, Colombel J-F, et al. The natural history of adult Crohn’s disease in population-based cohorts. Am J Gastroenterol. 2010;105(2):289–297. doi: 10.1038/ajg.2009.579
   PubMed Web of Science ®Google Scholar
• Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology. 2010;139:1147–1155. doi: 10.1053/j.gastro.2010.06.070
   PubMed Web of Science ®Google Scholar
• Roda G, Chien Ng S, Kotze PG, et al. Crohn’s disease. Nat Rev Dis Primers. 2020;6(1):22. doi: 10.1038/s41572-020-0156-2
   PubMed Web of Science ®Google Scholar
• Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12(4):205–217. doi: 10.1038/nrgastro.2015.34
   PubMed Web of Science ®Google Scholar
• Ananthakrishnan AN, Bernstein CN, Iliopoulos D, et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. 2018;15(1):39–49. doi: 10.1038/nrgastro.2017.136
   PubMed Web of Science ®Google Scholar
• Wetwittayakhlang P, Gonczi L, Golovics PA, et al. Time trends of environmental and socioeconomic risk factors in patients with inflammatory bowel disease over 40 years: a population-based inception cohort 1977–2020. J Clin Med. 2023;12(8):3026. doi: 10.3390/jcm12083026
   PubMed Web of Science ®Google Scholar
• Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769–2778. doi: 10.1016/S0140-6736(17)32448-0
   PubMed Web of Science ®Google Scholar
• Danese S, Fiorino G, Peyrin-Biroulet L. Early intervention in Crohn’s disease: towards disease modification trials. Gut. 2017;66(12):2179–2187. doi: 10.1136/gutjnl-2017-314519
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324–1338. doi: 10.1038/ajg.2015.233
   PubMed Web of Science ®Google Scholar
• Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (stride) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570–1583. doi: 10.1053/j.gastro.2020.12.031
   PubMed Web of Science ®Google Scholar
• Geyl S, Guillo L, Laurent V, et al. Transmural healing as a therapeutic goal in Crohn’s disease: a systematic review. Lancet Gastroenterol Hepatol. 2021;6(8):659–667. doi: 10.1016/S2468-1253(21)00096-0
   PubMed Web of Science ®Google Scholar
• Zacharopoulou E, Craviotto V, Fiorino G, et al. Targeting the gut layers in Crohn’s disease: mucosal or transmural healing? Expert Rev Gastroenterol Hepatol. 2020;14(9):775–787. doi: 10.1080/17474124.2020.1780914
   PubMed Web of Science ®Google Scholar
• Sabino J, Verstockt B, Vermeire S, et al. New biologics and small molecules in inflammatory bowel disease: an update. Therap Adv Gastroenterol. 2019;12:1756284819853208. doi: 10.1177/1756284819853208
   Web of Science ®Google Scholar
• Al-Bawardy B, Shivashankar R, Proctor DD. Novel and emerging therapies for inflammatory bowel disease. Front Pharmacol. 2021;12:651415. doi: 10.3389/fphar.2021.651415
   PubMed Web of Science ®Google Scholar
• Damião AOMC, Azevedo MFCD, Carlos ADS, et al. Conventional therapy for moderate to severe inflammatory bowel disease: a systematic literature review. WJG. 2019;25(9):1142–1157. doi: 10.3748/wjg.v25.i9.1142
   PubMed Web of Science ®Google Scholar
• Peyrin–Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621–1628.e5. doi: 10.1053/j.gastro.2011.06.050
   PubMed Web of Science ®Google Scholar
• Chupin A, Perduca V, Meyer A, et al. Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease. Aliment Pharmacol Ther [Internet]. 2020 [cited 2023 Jan 26]; 52(8):1289–1297. doi: 10.1111/apt.16050
   PubMed Web of Science ®Google Scholar
• Stalgis C, Deepak P, Mehandru S, et al. Rational combination therapy to overcome the plateau of drug efficacy in inflammatory bowel disease. Gastroenterology. 2021;161(2):394–399. doi: 10.1053/j.gastro.2021.04.068
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Lémann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease: review: remission rates in IBD. Aliment Pharmacol Ther. 2011;33(8):870–879. doi: 10.1111/j.1365-2036.2011.04599.x
   PubMed Web of Science ®Google Scholar
• Cholapranee A, Hazlewood GS, Kaplan GG, et al. Systematic review with meta-analysis: 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(10):1291–1302. doi: 10.1111/apt.14030
   PubMed Web of Science ®Google Scholar
• Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2015;64:1539–1545. doi: 10.1136/gutjnl-2014-307883
   PubMed Web of Science ®Google Scholar
• Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147(6):1296–1307.e5. doi: 10.1053/j.gastro.2014.08.035
   PubMed Web of Science ®Google Scholar
• Marsal J, Barreiro-de Acosta M, Blumenstein I, et al. Management of non-response and loss of response to anti-tumor necrosis factor therapy in inflammatory bowel disease. Front Med. 2022;9:897936. doi: 10.3389/fmed.2022.897936
   Web of Science ®Google Scholar
• Chen C, Hartzema AG, Xiao H, et al. Real-world pattern of biologic use in patients with inflammatory bowel disease: treatment persistence, switching, and importance of concurrent immunosuppressive therapy. Inflamm Bowel Dis. 2019;25(8):1417–1427. doi: 10.1093/ibd/izz001
   PubMed Web of Science ®Google Scholar
• Barré A, Colombel J-F, Ungaro R. Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2018;47(7):896–905. doi: 10.1111/apt.14550
   PubMed Web of Science ®Google Scholar
• Shivaji UN, Sharratt CL, Thomas T, et al. Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2019;49(6):664–680. doi: 10.1111/apt.15097
   PubMed Web of Science ®Google Scholar
• Solitano V, Facciorusso A, Jess T, et al. Comparative risk of serious infections with biologic agents and oral small molecules in inflammatory bowel diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023;21(4):907–921.e2. doi: 10.1016/j.cgh.2022.07.032
   PubMed Web of Science ®Google Scholar
• 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. doi: 10.1056/NEJMoa1215739
   PubMed Web of Science ®Google Scholar
• Loftus EV, Feagan BG, Panaccione R, et al. Long-term safety of vedolizumab for inflammatory bowel disease. Aliment Pharmacol Ther. 2020;52(8):1353–1365. doi: 10.1111/apt.16060
   PubMed Web of Science ®Google Scholar
• Dubash S, Marianayagam T, Tinazzi I, et al. Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease. Rheumatology. 2019;58(6):963–968. doi: 10.1093/rheumatology/key267
   PubMed Web of Science ®Google Scholar
• Atzeni F, Popa CD, Nucera V, et al. Safety of JAK inhibitors: focus on cardiovascular and thromboembolic events. Expert Rev Clin Immunol. 2022;18(3):233–244. doi: 10.1080/1744666X.2022.2039630
   PubMed Web of Science ®Google Scholar
• Burmester GR, Cohen SB, Winthrop KL, et al. Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis. RMD Open. 2023;9(1):e002735. doi: 10.1136/rmdopen-2022-002735
   PubMed Web of Science ®Google Scholar
• Singh S, Murad MH, Fumery M, et al. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(12):1002–1014. doi: 10.1016/S2468-1253(21)00312-5
   PubMed Web of Science ®Google Scholar
• Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohn’s Colitis. 2020;14(1):4–22. doi: 10.1093/ecco-jcc/jjz180
   Google Scholar
• Danese S, Fiorino G, Raine T, et al. ECCO position statement on the use of biosimilars for inflammatory bowel disease—an update. ECCOJC. 2017;11(1):26–34. doi: 10.1093/ecco-jcc/jjw198
   Google Scholar
• Reinisch W, Gecse K, Halfvarson J, et al. Clinical Practice of Adalimumab and Infliximab Biosimilar Treatment in Adult Patients With Crohn’s Disease. Inflamm Bowel Dis. 2021;27(1):106–122. doi: 10.1093/ibd/izaa078
   PubMed Web of Science ®Google Scholar
• Ferrante M, Feagan BG, Panés J, et al. Long-term safety and efficacy of risankizumab treatment in patients with Crohn’s disease: results from the phase 2 open-label extension study. J Crohn’s Colitis. 2021;15(12):2001–2010. doi: 10.1093/ecco-jcc/jjab093
   Google Scholar
• Feagan BG, Sandborn WJ, D’Haens G, et al. 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. 2017;389(10080):1699–1709. doi: 10.1016/S0140-6736(17)30570-6
   PubMed Web of Science ®Google Scholar
• D’Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399(10340):2015–2030. doi: 10.1016/S0140-6736(22)00467-6
   PubMed Web of Science ®Google Scholar
• Bossuyt P, Bresso F, Dubinsky M, et al. OP40 efficacy of risankizumab induction and maintenance therapy by baseline Crohn’s disease location: post hoc analysis of the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies. J Crohn’s Colitis. 2022;16(Supplement_1):i048. doi: 10.1093/ecco-jcc/jjab232.039
   Google Scholar
• Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022;399(10340):2031–2046. doi: 10.1016/S0140-6736(22)00466-4
   PubMed Web of Science ®Google Scholar
• 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(2):175–187. doi: 10.1136/annrheumdis-2017-211555
   PubMed Web of Science ®Google Scholar
• Misselwitz B, Juillerat P, Sulz MC, et al. Emerging treatment options in inflammatory bowel disease: janus kinases, stem cells, and more. Digestion. 2020;101(Suppl. 1):69–82. doi: 10.1159/000507782
   PubMed Web of Science ®Google Scholar
• AbbVie. A phase 3, multicenter, randomized, efficacy assessor-blinded study of risankizumab compared to ustekinumab for the treatment of adult subjects with moderate to severe Crohn’s disease who have failed anti-TNF therapy [internet] clinicaltrials.Gov; 2022. Report No: NCT04524611. [cited 2023 Sep 22]. Available from: https://clinicaltrials.gov/study/NCT04524611.
   Google Scholar
• AbbVie’s SKYRIZI® (risankizumab) met all primary and secondary endpoints versus stelara® (ustekinumab) in head-to-head study in Crohn’s disease | AbbVie news center [Internet]. [cited 2023 Sep 25]. Available from: https://news.abbvie.com/news/press-releases/abbvies-skyrizi-risankizumab-met-all-primary-and-secondary-endpoints-versus-stelara-ustekinumab-in-head-to-head-study-in-crohns-disease.htm.
   Google Scholar
• Thomas H. UEG Week 2023. Lancet Gastroenterol Hepatol. 2023;8(12):1076. doi: 10.1016/S2468-1253(23)00371-0
   PubMedGoogle Scholar
• Sandborn WJ, Feagan BG, Loftus EV, et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology. 2020;158(8):2123–2138.e8. doi: 10.1053/j.gastro.2020.01.047
   PubMed Web of Science ®Google Scholar
• Loftus EV, Panés J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2023;388(21):1966–1980. doi: 10.1056/NEJMoa2212728
   PubMed Web of Science ®Google Scholar
• Healthcare G Crohn’s disease market will experience major growth during next decade [internet]. Pharmaceutical Technology. 2020 [cited 2023 Aug 29]. Available from: https://www.pharmaceutical-technology.com/comment/chrohns-disease-market-growth/.
   Google Scholar
• Crohn’s disease (CD) treatment market [internet]. [cited 2023 Aug 29]. Available from: https://www.futuremarketinsights.com/reports/crohns-disease-treatment-market.
   Google Scholar
• Crohn?s disease treatment market size and forecast to 2030 [internet]. [cited 2023 Aug 29]. Available from: https://www.coherentmarketinsights.com/market-insight/crohns-disease-treatment-market-1237.
   Google Scholar
• Hamdeh S, Aziz M, Altayar O, et al. Early vs late use of anti-TNFa therapy in adult patients with Crohn disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2020;26(12):1808–1818. doi: 10.1093/ibd/izaa031
   PubMed Web of Science ®Google Scholar
• Ben-Horin S, Novack L, Mao R, et al. Efficacy oF biologic drugs in short-duration versus long-duration inflammatory bowel disease: a systematic review and an individual-patient data meta-analysis of randomized controlled trials. Gastroenterology. 2022;162(2):482–494. doi: 10.1053/j.gastro.2021.10.037
   PubMed Web of Science ®Google Scholar
• de Chambrun G P, Peyrin-Biroulet L, Lémann M, et al. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol. 2010;7(1):15–29. doi: 10.1038/nrgastro.2009.203
   PubMed Web of Science ®Google Scholar
• Feagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;S2468-1253(22):00427–7.
   Google Scholar
• Ahluwalia B, Moraes L, Magnusson MK, et al. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol. 2018;53(4):379–389. doi: 10.1080/00365521.2018.1447597
   PubMed Web of Science ®Google Scholar
• Fernández-Clotet A, Castro-Poceiro J, Panés J. Tofacitinib for the treatment of ulcerative colitis. Expert Rev Clin Immunol. 2018;14(11):881–892. doi: 10.1080/1744666X.2018.1532291
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–1736. doi: 10.1056/NEJMoa1606910
   PubMed Web of Science ®Google Scholar
• Panés J, Sandborn WJ, Schreiber S, et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut. 2017;66:1049–1059. doi: 10.1136/gutjnl-2016-312735
   PubMed Web of Science ®Google Scholar
• 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. doi: 10.1016/S0140-6736(16)32537-5
   PubMed Web of Science ®Google Scholar
• Feagan BG, Danese S, Loftus EV, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397(10292):2372–2384. doi: 10.1016/S0140-6736(21)00666-8
   PubMed Web of Science ®Google Scholar
• Galapagos NV. Combined phase 3, double-blind, randomized, placebo-controlled studies evaluating the efficacy and safety of filgotinib in the induction and maintenance of remission in subjects with moderately to severely active Crohn’s disease [Internet]. clinicaltrials. gov; 2022. Report No.: NCT02914561. [cited 2023 Aug 16]. Available from: https://clinicaltrials.gov/study/NCT02914561.
   Google Scholar
• Galapagos NV A long-term extension study to evaluate the safety of filgotinib in subjects with Crohn’s disease [Internet]. clinicaltrials.gov; 2023. Report No.: NCT02914600. [cited 2023 Aug 16]. Available from: https://clinicaltrials.gov/study/NCT02914600.
   Google Scholar
• D’Haens GR, Lee S, Taylor SA, et al. Filgotinib for the treatment of small bowel Crohn’s disease: the DIVERGENCE 1 trial. Gastroenterology. 2023;165(1):289–292.e3. doi: 10.1053/j.gastro.2023.03.234
   PubMed Web of Science ®Google Scholar
• Beattie DT, Pulido-Rios MT, Shen F, et al. Intestinally-restricted janus kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy. J Inflamm (Lond). 2017;14(1):28. doi: 10.1186/s12950-017-0175-2
   PubMedGoogle Scholar
• Sandborn WJ, Nguyen DD, Beattie DT, et al. Development of gut-selective pan-janus kinase inhibitor TD-1473 for ulcerative colitis: a translational medicine programme. J Crohns Colitis. 2020;14(9):1202–1213. doi: 10.1093/ecco-jcc/jjaa049
   PubMed Web of Science ®Google Scholar
• Biopharma T. A phase 2 multi-center, randomized, double-blind, placebo˗Controlled, parallel-group study to evaluate the efficacy and safety of induction therapy with 2 doses of TD-1473 in subjects with moderately-to-severely active Crohn’s disease [Internet]. clinicaltrials.gov; 2023. Report No.: NCT03635112. [cited 2023 Aug 20]. Available from: https://clinicaltrials.gov/study/NCT03635112.
   Google Scholar
• Pfizer. A phase 2a, double-blind, randomized, placebo-controlled, parallel group study to evaluate the efficacy and safety of oral pf-06651600 and pf-06700841 as induction and open label extension treatment in subjects with moderate to severe crohn’s disease [Internet]. clinicaltrials.gov; 2022. Report No.: NCT03395184. [cited 2023 Aug 24]. Available from: https://clinicaltrials.gov/study/NCT03395184.
   Google Scholar
• Danese S, Panaccione R, D‘Haens G, et al. DOP42 Efficacy and safety of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with moderately-to-severely active Ulcerative Colitis: 12-week results from the Phase 2 LATTICE-UC study. Journal of Crohn’s and Colitis. 2022 Jan;16(Supplement_1):i091–i092. doi: 10.1093/ecco-jcc/jjab232.081
   PubMedGoogle Scholar
• Squibb B-M. A phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of BMS-986165 in subjects with moderate to severe Crohn’s disease [Internet clinicaltrials.gov]. 2023. Report No.: NCT03599622. [cited 2023 Aug 24] Available from: https://clinicaltrials.gov/study/NCT03599622.
   Google Scholar
• Ventyx Biosciences Inc. A phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of VTX958 in participants with moderately to severely active Crohn’s disease [Internet] clinicaltrials.gov;. 2023. Report No.: NCT05688852. [cited 2023 Aug 24]. Available from: https://clinicaltrials.gov/study/NCT05688852.
   Google Scholar
• Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis. Gastroenterology. 2020;158(3):537–549.e10. doi: 10.1053/j.gastro.2019.08.043
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of continued treatment with mirikizumab in a phase 2 trial of patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2022;20(1):105–115.e14. doi: 10.1016/j.cgh.2020.09.028
   PubMed Web of Science ®Google Scholar
• Sands BE, Peyrin-Biroulet L, Kierkus J, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Crohn’s disease. Gastroenterology. 2022;162(2):495–508. doi: 10.1053/j.gastro.2021.10.050
   PubMed Web of Science ®Google Scholar
• Eli Lilly and Company. A phase 3, multicenter, open-label, long-term extension study to evaluate the long-term efficacy and safety of mirikizumab in patients with Crohn’s disease [Internet] clinicaltrials.gov. 2023. Report No.: NCT04232553. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT04232553.
   Google Scholar
• Eli Lilly and Company. A master protocol for a phase 3, multicenter, open-label, long-term extension study to evaluate the long-term efficacy and safety of Mirikizumab in children and adolescents with moderate-to-severe ulcerative colitis or Crohn’s disease [Internet]. clinicaltrials.gov; 2023. Report No.: NCT04844606. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT04844606.
   Google Scholar
• Eli Lilly and Company. A phase 3, multicenter, randomized clinical study to evaluate mirikizumab in pediatric Crohn’s disease [Internet]. clinicaltrials .gov; 2023. Report No.: NCT05509777. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT05509777.
   Google Scholar
• Sands BE, Gasser RAJ, Gommoll C, et al. Long-term safety in the open-label period of a phase 2a study of Brazikumab, an antibody against interleukin-23: 590. Official J Am Coll Gastroenterol ACG. 2018;113(Supplement):S339. doi: 10.14309/00000434-201810001-00590
   PubMedGoogle Scholar
• Sands BE, Chen J, Feagan BG, et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology. 2017;153(1):77–86.e6. doi: 10.1053/j.gastro.2017.03.049
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, D’Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn’s disease: induction results from the phase 2 GALAXI-1 study. Gastroenterology. 2022;162(6):S1650–1664.e8. doi: 10.1053/j.gastro.2022.01.047
   PubMed Web of Science ®Google Scholar
• Janssen Research & Development, LLC. A phase 2/3, randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter protocol to evaluate the efficacy and safety of guselkumab in participants with moderately to severely active Crohn’s disease [Internet]. clinicaltrials.gov; 2023. Report No.: NCT03466411. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT03466411.
   Google Scholar
• Janssen-Cilag Ltd. A phase 3, randomized, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of guselkumab in participants with fistulizing, Perianal Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT05347095.[cited 2023 Aug 24]. Available from: https://clinicaltrials.gov/study/NCT05347095.
   Google Scholar
• Janssen Research & Development, LLC. A phase 2b randomized, double-blind, active-and placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of induction and maintenance combination therapy with guselkumab and golimumab in participants with moderately to severely active Crohn’s disease [Internet]. clinicaltrials.gov; 2023. Report No.: study/NCT05242471. [cited 2023 May 21]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT05242471.
   Google Scholar
• Ganesan R, Raymond EL, Mennerich D, et al. Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies. MAbs [Internet]. 2017;9(7):1143–1154. [cited 2023 Sep 3]. Available from. https://pubmed.ncbi.nlm.nih.gov/28726542/
   PubMed Web of Science ®Google Scholar
• Boehringer Ingelheim. An open label, long term safety trial of spesolimab treatment in patients with crohn’s disease who have completed previous spesolimab trials. [Internet] clinicaltrials.gov; 2023. Report No.: NCT04362254. [cited 2023 Sep 1]. Available from: https://clinicaltrials.gov/study/NCT04362254.
   Google Scholar
• Boehringer Ingelheim. Mechanism of action and clinical effect of BI 655130 in patients with fistulizing Crohn’s disease [Internet]. clinicaltrials.gov; 2022. Report No.: NCT03752970. [cited 2023 Sep 1]. Available from: https://clinicaltrials.gov/study/NCT03752970.
   Google Scholar
• Schreiber S, Aden K, Bernardes JP, et al. Therapeutic interleukin-6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease. Gastroenterology. 2021;160(7):2354–2366.e11. doi: 10.1053/j.gastro.2021.02.062
   PubMed Web of Science ®Google Scholar
• Danese S, Vermeire S, Hellstern P, et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut. 2019;68(1):40–48. doi: 10.1136/gutjnl-2017-314562
   PubMed Web of Science ®Google Scholar
• Wang J, Goren I, Yang B, et al. Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis - a unique therapeutic target in inflammatory bowel disease. Aliment Pharmacol Ther. 2022;55(3):277–291. doi: 10.1111/apt.16741
   PubMed Web of Science ®Google Scholar
• Zou F, Wang S, Xu M, et al. The role of sphingosine-1-phosphate in the gut mucosal microenvironment and inflammatory bowel diseases. Front Physiol. 2023;14:1235656. doi: 10.3389/fphys.2023.1235656
   PubMed Web of Science ®Google Scholar
• Dal Buono A, Gabbiadini R, Alfarone L, et al. Sphingosine 1-phosphate modulation in inflammatory bowel diseases: keeping lymphocytes out of the intestine. Biomedicines. 2022;10(7):1735. doi: 10.3390/biomedicines10071735
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE study. J Crohns Colitis. 2021;15(7):1120–1129. doi: 10.1093/ecco-jcc/jjab012
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280–1291. doi: 10.1056/NEJMoa2033617
   PubMed Web of Science ®Google Scholar
• Feagan BG, Sandborn WJ, Danese S, et al. Ozanimod induction therapy for patients with moderate to severe Crohn’s disease: a single-arm, phase 2, prospective observer-blinded endpoint study. Lancet Gastroenterol Hepatol. 2020;5(9):819–828. doi: 10.1016/S2468-1253(20)30188-6
   PubMed Web of Science ®Google Scholar
• Celgene. Induction study #1 - a phase 3, multicenter, randomized, double-blind, placebo-controlled study of oral ozanimod as induction therapy for moderately to severely active Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT03440372. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT03440372.
   Google Scholar
• Celgene. Induction study #2 - a phase 3, multicenter, randomized, double-blind, placebo-controlled study of oral ozanimod as induction therapy for moderately to severely active Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT03440385. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT03440385.
   Google Scholar
• Celgene. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of oral ozanimod as maintenance therapy for moderately to severely active Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT03464097. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT03464097.
   Google Scholar
• Feagan BG, Schreiber S, Afzali A, et al. Ozanimod as a novel oral small molecule therapy for the treatment of Crohn’s disease: the YELLOWSTONE clinical trial program. Contemp Clin Trials. 2022;122:106958. doi: 10.1016/j.cct.2022.106958
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401(10383):1159–1171. doi: 10.1016/S0140-6736(23)00061-2
   PubMed Web of Science ®Google Scholar
• Multicenter PA, Randomized D-B, Parallel-group study to assess the efficacy and safety of oral etrasimod as induction and maintenance therapy for moderately to severely active Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT04173273. [cited 2023 Aug 22]. Available from: https://clinicaltrials.gov/study/NCT04173273.
   Google Scholar
• D’Haens G, Danese S, Davies M, et al. A phase II, multicentre, randomised, double-blind, placebo-controlled study to evaluate safety, tolerability, and efficacy of amiselimod in patients with moderate to severe active Crohn’s disease. J Crohns Colitis. 2022;16(5):746–756. doi: 10.1093/ecco-jcc/jjab201
   PubMed Web of Science ®Google Scholar
• Lichnog C, Klabunde S, Becker E, et al. Cellular mechanisms of etrolizumab treatment in inflammatory bowel disease. Front Pharmacol. 2019;10:39. doi: 10.3389/fphar.2019.00039
   PubMed Web of Science ®Google Scholar
• Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384(9940):309–318. doi: 10.1016/S0140-6736(14)60661-9
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Panés J, Danese S, et al. Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2023;8(1):43–55. doi: 10.1016/S2468-1253(22)00303-X
   PubMed Web of Science ®Google Scholar
• Reinisch W, Sandborn WJ, Danese S, et al. Long-term safety and efficacy of the anti-MAdCAM-1 monoclonal antibody ontamalimab [SHP647] for the treatment of ulcerative colitis: the open-label study TURANDOT II. J Crohns Colitis. 2021;15(6):938–949. doi: 10.1093/ecco-jcc/jjab023
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Lee SD, Tarabar D, et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn’s disease: report of the OPERA study. Gut. 2018;67(10):1824–1835. doi: 10.1136/gutjnl-2016-313457
   PubMed Web of Science ®Google Scholar
• D’Haens GR, Reinisch W, Lee SD, et al. Long-term safety and efficacy of the anti-mucosal addressin cell adhesion molecule-1 monoclonal antibody ontamalimab (SHP647) for the treatment of Crohn’s disease: the OPERA II study. Inflamm Bowel Dis. 2022;28(7):1034–1044. doi: 10.1093/ibd/izab215
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Cyrille M, Hansen MB, et al. Efficacy and safety of abrilumab in a randomized, placebo-controlled trial for moderate-to-severe ulcerative colitis. Gastroenterology. 2019;156(4):946–957.e18. doi: 10.1053/j.gastro.2018.11.035
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Cyrille M, Hansen MB, et al. OP035 efficacy and safety of abrilumab (AMG 181/MEDI 7183) therapy for moderate to severe Crohn’s disease. J Crohn’s Colitis. 2017;11(suppl_1):S22–S23. doi: 10.1093/ecco-jcc/jjx002.034
   Google Scholar
• Randomized AA, Double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 181 in subjects with moderate to severe Crohn’s disease [Internet]clinicaltrials.gov;. 2019. Report No.: NCT01696396. [cited 2023 Aug 24]. Available from: https://clinicaltrials.gov/study/NCT01696396.
   Google Scholar
• Yoshimura N, Watanabe M, Motoya S, et al. Safety and efficacy of AJM300, an oral antagonist of α4 Integrin, in induction therapy for patients with active ulcerative colitis. Gastroenterology. 2015;149(7):1775–1783.e2. doi: 10.1053/j.gastro.2015.08.044
   PubMed Web of Science ®Google Scholar
• Matsuoka K, Watanabe M, Ohmori T, et al. AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Gastroenterol Hepatol. 2022;7(7):648–657. doi: 10.1016/S2468-1253(22)00022-X
   PubMed Web of Science ®Google Scholar
• S1066 Oral Alpha-4 Integrin Inhibitor (AJM300) in patients with active Crohn’s disease — a randomized, double-blind, placebo-controlled trial - ClinicalKey [Internet]. [cited 2023 Aug 25]. Available from: https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S0016508509608167?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0016508509608167%3Fshowall%3Dtrue&referrer=.
   Google Scholar
• Fukase H, Kajioka T, Oikawa I, et al. AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: a randomised controlled trial in healthy male subjects. Br J Clin Pharmacol. 2020;86(3):591–600. doi: 10.1111/bcp.14151
   PubMed Web of Science ®Google Scholar
• Vermeire S, Hébuterne X, Tilg H, et al. Induction and long-term follow-up with ABX464 for moderate-to-severe ulcerative colitis: results of phase IIa trial. Gastroenterology. 2021;160(7):2595–2598.e3. doi: 10.1053/j.gastro.2021.02.054
   PubMed Web of Science ®Google Scholar
• Abivax SAA Phase 2a, randomized, parallel-group,Double-blind, placebo-controlled, multicenter study to evaluate the safety of ABX464 compared with placebo in patients with moderate to severe active Crohn’s disease Who Have Inadequate Response, loss of Response, or intolerance to prior amino-salicylates, immunosuppressant treatment, biologics, and/or corticosteroid treatment [Internet]. clinicaltrials.gov; 2019. Report No.: NCT03905109. [cited 2023 Aug 24]. Available from: https://clinicaltrials.gov/study/NCT03905109.
   Google Scholar
• Admin S European Crohn´s and colitis organisation - ECCO - DOP87 the Anti-TL1A antibody PRA023 demonstrated proof-of-concept in Crohn’s disease: phase 2a APOLLO-CD study results [Internet]. [cited 2023 Sep 12]. Available from: https://www.ecco-ibd.eu/publications/congress-abstracts/item/dop87-the-anti-tl1a-antibody-pra023-demonstrated-proof-of-concept-in-crohn-s-disease-phase-2a-apollo-cd-study-results.html.
   Google Scholar
• VHsquared Ltd. Phase 2 study to investigate the efficacy, safety, and tolerability of six weeks treatment with V565 in subjects with active Crohn’s disease [Internet]. clinicaltrials.gov; 2021. Report No.: NCT02976129. [cited 2023 Sep11]. Available from: https://clinicaltrials.gov/study/NCT02976129.
   Google Scholar
• Agomab Spain SL A phase 2a, randomized, placebo-controlled, double-blind study to assess the safety, pharmacokinetics, and pharmacodynamics of AGMB-129 in patients with fibrostenotic Crohn’s disease [Internet].clinicaltrials.gov; 2023. Report No.: NCT05843578. [cited 2023 Sep 15]. Available from: https://clinicaltrials.gov/study/NCT05843578.
   Google Scholar
• Barberio B, Gracie DJ, Black CJ, et al. Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis. Gut. 2023;72(2):264–274. doi: 10.1136/gutjnl-2022-328052
   PubMed Web of Science ®Google Scholar