Exploring the Pipeline of Novel Therapies for Inflammatory Bowel Disease; State of the Art Review

Yasmin Zurba 1, Beatriz Gros 2 3, Mohammad Shehab 1

Affiliations

01 March 2023

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doi: 10.3390/biomedicines11030747

Abstract

Crohn's disease (CD) and ulcerative colitis (UC), known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. Over the last two decades, numerous medications have been developed and repurposed to induce and maintain remission in IBD patients. Despite the approval of multiple drugs, the major recurring issues continue to be primary non-response and secondary loss of response, as well as short- and long-term adverse events. Most clinical trials show percentages of response under 60%, possibly as a consequence of strict inclusion criteria and definitions of response. That is why these percentages appear to be more optimistic in real-life studies. A therapeutic ceiling has been used as a term to define this invisible bar that has not been crossed by any drug yet. This review highlights novel therapeutic target agents in phases II and III of development, such as sphingosine-1-phosphate receptor modulators, selective Janus kinase inhibitors, anti-interleukins, and other small molecules that are currently under research until 1 January 2023. Emerging treatments for CD and UC that have just received approval or are undergoing phase III clinical trials are also discussed in this review.

Keywords: Crohn’s disease; IBD; Janus kinase inhibitor; interleukins; small molecules; ulcerative colitis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1 List of different biologics and small molecule drugs with their targets and current clinical trial status.

Figure 1 List of different biologics and small molecule drugs with their targets and current clinical trial status.

Figure 2 Timeline for the different biologics and small molecules approved by the FDA and in the development process for the treatment of IBD.

Figure 2 Timeline for the different biologics and small molecules approved by the FDA and in the development process for the treatment of IBD.

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References

  1.  
    1. de Souza H.S.P., Fiocchi C. Immunopathogenesis of IBD: Current state of the art. Nature Reviews. Gastroenterol. Hepatol. 2015;13:13–27. - PubMed
  2.  
    1. Klenske E., Bojarski C., Waldner M., Rath T., Neurath M.F., Atreya R. Targeting mucosal healing in Crohn’s disease: What the clinician needs to know. Ther. Adv. Gastroenterol. 2019;12:1756284819856865. doi: 10.1177/1756284819856865. - DOI - PMC - PubMed
  3.  
    1. Molodecky N.A., Soon I.S., Rabi D.M., Ghali W.A., Ferris M., Chernoff G., Benchimol E.I., Panaccione R., Ghosh S., Barkema H.W., et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.e42. doi: 10.1053/j.gastro.2011.10.001. - DOI - PubMed
  4.  
    1. Peyrin-Biroulet L., Sandborn W., Sands B.E., Reinisch W., Bemelman W., Bryant R.V., D’Haens G., Dotan I., Dubinsky M., Feagan B., et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am. J. Gastroenterol. 2015;110:1324–1338. doi: 10.1038/ajg.2015.233. - DOI - PubMed
  5.  
    1. Turner D., Ricciuto A., Lewis A., D’Amico F., Dhaliwal J., Griffiths A.M., Bettenworth D., Sandborn W.J., Sands B.E., Reinisch W., 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;160:1570–1583. doi: 10.1053/j.gastro.2020.12.031. - DOI - PubMed
  6.  
    1. Sabino J., Verstockt B., Vermeire S., Ferrante M. New biologics and small molecules in inflammatory bowel disease: An update. Ther. Adv. Gastroenterol. 2019;12:3208. doi: 10.1177/1756284819853208. - DOI - PMC - PubMed
  7.  
    1. Eftychi C., Schwarzer R., Vlantis K., Wachsmuth L., Basic M., Wagle P., Neurath M.F., Becker C., Bleich A., Pasparakis M., et al. Temporally Distinct Functions of the Cytokines IL-12 and IL-23 Drive Chronic Colon Inflammation in Response to Intestinal Barrier Impairment. Immunity. 2019;51:367–380.e4. doi: 10.1016/j.immuni.2019.06.008. - DOI - PubMed
  8.  
    1. Aggeletopoulou I., Assimakopoulos S.F., Konstantakis C., Triantos C.C. Interleukin 12/interleukin 23 pathway: Biological basis and therapeutic effect in patients with Crohn’s disease. World J. Gastroenterol. 2018;24:4093. doi: 10.3748/wjg.v24.i36.4093. - DOI - PMC - PubMed
  9.  
    1. Leach M.W., Rennick Natalie JDavidson D.M., Hudak S.A., Lesley R.E. IL-10-Deficient Mice Sustaining the Chronic Phase of Colitis in, Plays a Major Role in γ IL-12, But Not IFN. 2022. [(accessed on 7 January 2023)]. Available online: http://www.jimmunol.org/content/161/6/3143. - PubMed
  10.  
    1. Mannon P.J., Fuss I.J., Mayer L., Elson C.O., Sandborn W.J., Present D., Dolin B., Goodman N., Groden C., Hornung R.L., et al. Anti–Interleukin-12 Antibody for Active Crohn’s Disease. N. Engl. J. Med. 2004;351:2069–2079. doi: 10.1056/NEJMoa033402. - DOI - PubMed
  11.  
    1. Jefremow A., Neurath M.F. All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD–A Clinical Perspective. Immunotargets Ther. 2020;9:289. doi: 10.2147/ITT.S282466. - DOI - PMC - PubMed
  12.  
    1. Duerr R.H., Taylor K.D., Brant S.R., Rioux J.D., Silverberg M.S., Daly M.J., Dolin B., Goodman N., Groden C., Hornung R.L., et al. A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene. Science. 2006;314:1461. doi: 10.1126/science.1135245. - DOI - PMC - PubMed
  13.  
    1. Jostins L., Ripke S., Weersma R.K., Duerr R.H., McGovern D.P., Hui K.Y., Lee J.C., Schumm L.P., Sharma Y., Anderson C.A., et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:7422. doi: 10.1038/nature11582. - DOI - PMC - PubMed
  14.  
    1. Mizoguchi A., Yano A., Himuro H., Ezaki Y., Sadanaga T., Mizoguchi E. Clinical importance of IL-22 cascade in IBD. J. Gastroenterol. 2017;53:465–474. doi: 10.1007/s00535-017-1401-7. - DOI - PMC - PubMed
  15.  
    1. Coskun M., Salem M., Pedersen J., Nielsen O.H. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res. 2013;76:1–8. doi: 10.1016/j.phrs.2013.06.007. - DOI - PubMed
  16.  
    1. Goldsmith J.R., Uronis J.M., Jobin C. Mu opioid signaling protects against acute murine intestinal injury in a manner involving Stat3 signaling. Am. J. Pathol. 2011;179:673–683. doi: 10.1016/j.ajpath.2011.04.032. - DOI - PMC - PubMed
  17.  
    1. Neubauer H., Cumano A., Müller M., Wu H., Huffstadt U., Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998;93:397–409. doi: 10.1016/S0092-8674(00)81168-X. - DOI - PubMed
  18.  
    1. Rodig S.J., Meraz M.A., White J.M., Lampe P.A., Riley J.K., Arthur C.D., King K.L., Sheehan K.C., Yin L., Pennica D., et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373–383. doi: 10.1016/S0092-8674(00)81166-6. - DOI - PubMed
  19.  
    1. Sphingosine-1 Phosphate Receptor Modulators: The Next Wave of Oral Therapies in Inflammatory Bowel Disease–Gastroenterology & Hepatology. [(accessed on 9 January 2023)]. Available online: https://www.gastroenterologyandhepatology.net/archives/may-2022/sphingos... - PMC - PubMed
  20.  
    1. D’Haens G., Panaccione R., Baert F., Bossuyt P., Colombel J.F., Danese S., Dubinsky M., Feagan B.G., Hisamatsu T., Lim A., et al. Risankizumab as induction therapy for Crohn’s disease: Results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399:2015–2030. doi: 10.1016/S0140-6736(22)00467-6. - DOI - PubMed
  21.  
    1. Deepak P., Sandborn W.J. Ustekinumab and Anti-Interleukin-23 Agents in Crohn’s Disease. Gastroenterol. Clin. N. Am. 2017;46:603–626. doi: 10.1016/j.gtc.2017.05.013. - DOI - PubMed
  22.  
    1. Feagan B.G., Sandborn W.J., D’Haens G., Panés J., Kaser A., Ferrante M., Louis E., Franchimont D., Dewit O., Seidler U., 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;389:1699–1709. doi: 10.1016/S0140-6736(17)30570-6. - DOI - PubMed
  23.  
    1. Ferrante M., Panaccione R., Baert F., Bossuyt P., Colombel J.F., Danese S., Dubinsky M., Feagan B.G., Hisamatsu T., Lim A., 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;399:2031–2046. doi: 10.1016/S0140-6736(22)00466-4. - DOI - PubMed
  24.  
    1. Feagan B.G., Panés J., Ferrante M., Kaser A., D’Haens G.R., Sandborn W.J., Louis E., Neurath M.F., Franchimont D., Dewit O., et al. Risankizumab in patients with moderate to severe Crohn’s disease: An open-label extension study. Lancet Gastroenterol. Hepatol. 2018;3:671–680. doi: 10.1016/S2468-1253(18)30233-4. - DOI - PubMed
  25.  
    1. Ferrante M., Feagan B.G., Panés J., Baert F., Louis E., Dewit O., Kaser A., Duan W.R., Pang Y., Lee W.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. Crohns Colitis. 2021;15:2001–2010. doi: 10.1093/ecco-jcc/jjab093. - DOI - PMC - PubMed
  26.  
    1. Long-Term Safety in the Open-Label Period of a Phase 2a Stud..: Official Journal of the American College of Gastroenterology|ACG. [(accessed on 7 October 2022)]. Available online: https://journals.lww.com/ajg/fulltext/2018/10001/long_term_safety_in_the....
  27.  
    1. Janssen Announces u.s. Fda Approval of Tremfyatm (Guselkumab) for the Treatment of Moderate to Severe Plaque Psoriasis|Johnson & Johnson. [(accessed on 11 January 2023)]. Available online: https://www.jnj.com/media-center/press-releases/janssen-announces-us-fda....
  28.  
    1. Cdjjlgaoaa S. The efficacy and safety OF guselkumab induction therapy IN patients with moderately to severely active CROHN’S disease: Week 12 interim analyses from the phase 2 GALAXI 1 study. United Eur. Gastroenterol. J. 2020;8:64.
  29.  
    1. Sandborn W.J., D’Haens G.R., Reinisch W., Panés J., Chan D., Gonzalez S., Weisel K., Germinaro M., Frustaci M.E., Yang Z., et al. Guselkumab for the Treatment of Crohn’s Disease: Induction Results From the Phase 2 GALAXI-1 Study. Gastroenterology. 2022;162:1650–1664.e8. doi: 10.1053/j.gastro.2022.01.047. - DOI - PubMed
  30.  
    1. Sandborn W.J., Ferrante M., Bhandari B.R., Berliba E., Feagan B.G., Hibi T., Tuttle J.L., Klekotka P., Friedrich S., Durante M., et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis. Gastroenterology. 2020;158:537–549.e10. doi: 10.1053/j.gastro.2019.08.043. - DOI - PubMed
  31.  
    1. Sandborn W.J., Ferrante M., Bhandari B.R., Berliba E., Hibi T., D’Haens G.R., Tuttle J.L., Klekotka P., Friedrich S., Durante M., et al. Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients with Ulcerative Colitis. Clin. Gastroenterol. Hepatol. 2022;20:105–115.e14. doi: 10.1016/j.cgh.2020.09.028. - DOI - PubMed
  32.  
    1. Harris M.S., Hartman D., Lemos B.R., Erlich E.C., Spence S., Kennedy S., Ptak T., Pruitt R., Vermeire S., Fox B.S. AVX-470, an Orally Delivered Anti-Tumour Necrosis Factor Antibody for Treatment of Active Ulcerative Colitis: Results of a First-in-Human Trial. J. Crohns Colitis. 2016;10:631–640. doi: 10.1093/ecco-jcc/jjw036. - DOI - PubMed
  33.  
    1. Almon E., Shaaltiel Y., Sbeit W., Fich A., Schwartz D., Waterman M., Szlaifer M., Reuveni H., Amit-Cohen B.C., Alon S., et al. Novel Orally Administered Recombinant Anti-TNF Alpha Fusion Protein for the Treatment of Ulcerative Colitis: Results From a Phase 2a Clinical Trial. J. Clin. Gastroenterol. 2021;55:134. doi: 10.1097/MCG.0000000000001314. - DOI - PMC - PubMed
  34.  
    1. Vermeire S., O’Byrne S., Keir M., Williams M., Lu T.T., Mansfield J.C., Lamb C.A., Feagan B.G., Panes J., Salas A., et al. Etrolizumab as induction therapy for ulcerative colitis: A randomised, controlled, phase 2 trial. Lancet. 2014;384:309–318. doi: 10.1016/S0140-6736(14)60661-9. - DOI - PubMed
  35.  
    1. A Clinical Trial to Compare Etrolizumab with Placebo and Adalimumab in Patients with Moderate to Severe Ulcerative Colitis Who Have not Received Treatment with Tumour Necrosis Factor Inhibitors (Hibiscus I) [(accessed on 3 January 2023)]. Available online: https://forpatients.roche.com/en/trials/autoimmune-disorder/ulcerative-c....
  36.  
    1. A Clinical Trial to Compare Etrolizumab with Placebo and Adalimumab in Patients with Moderate to Severe Ulcerative Colitis Who Have not Received Treatment with Tumour Necrosis Factor Inhibitors (Hibiscus II) [(accessed on 3 January 2023)]. Available online: https://genentech-clinicaltrials.com/en/trials/autoimmune-disorder/ulcer....
  37.  
    1. Danese S., Colombel J.F., Lukas M., Gisbert J.P., D’Haens G., Hayee B., Panaccione R., Kim H.S., Reinisch W., Tyrrell H., et al. Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): A randomised, double-blind, double-dummy, phase 3 study. Lancet Gastroenterol. Hepatol. 2022;7:118–127. doi: 10.1016/S2468-1253(21)00294-6. - DOI - PubMed
  38.  
    1. Sandborn W.J., Vermeire S., Tyrrell H., Hassanali A., Lacey S., Tole S., Tatro A.R., Etrolizumab Global Steering Committee Etrolizumab for the Treatment of Ulcerative Colitis and Crohn’s Disease: An Overview of the Phase 3 Clinical Program. Adv. Ther. 2020;37:3417–3431. doi: 10.1007/s12325-020-01366-2. - DOI - PMC - PubMed
  39.  
    1. Dai B., Hackney J.A., Ichikawa R., Nguyen A., Elstrott J., Orozco L.D., Sun K.H., Modrusan Z., Gogineni A., Scherl A., et al. Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease. Cell Rep. Med. 2021;2:10038. doi: 10.1016/j.xcrm.2021.100381. - DOI - PMC - PubMed
  40.  
    1. Modi N.B., Cheng X., Mattheakis L., Hwang C.C., Nawabi R., Liu D., Gupta S. Single- and Multiple-Dose Pharmacokinetics and Pharmacodynamics of PN-943, a Gastrointestinal-Restricted Oral Peptide Antagonist of α4β7, in Healthy Volunteers. Clin. Pharmacol. Drug Dev. 2021;10:1263–1278. doi: 10.1002/cpdd.946. - DOI - PMC - PubMed
  41.  
    1. Mattheakis L., Bhandari A., Bai L., Zemede G., Tran V., Celino H., Frederick B., Zhao L., Dogra M., Lister H., et al. P-126 PTG-100, An Oral Peptide Antagonist of Integrin α4β7 that Alters Trafficking of Gut Homing T Cells in Preclinical Animal Models. Inflamm. Bowel Dis. 2016;22((Suppl. 1)):S48. doi: 10.1097/01.MIB.0000480232.55276.b3. - DOI
  42.  
    1. Mattheakis L., Fosser C., Saralaya R., Horsch K., Rao N., Bai L., Zhao L., Annamalai T., Liu D. P113 Model based predictions of the PTG-100 pharmacodynamic responses in ulcerative colitis patients. J. Crohns Colitis. 2017;11((Suppl. 1)):S132–S133. doi: 10.1093/ecco-jcc/jjx002.239. - DOI
  43.  
    1. PN-943 in Adults With Moderate to Severe Active Ulcerative Colitis (UC) [(accessed on 13 October 2022)]; Available online: https://clinicaltrials.gov/ct2/show/NCT04504383.
  44.  
    1. Sandborn W.J., Lee S.D., Tarabar D., Louis E., Klopocka M., Klaus J., Reinisch W., Hébuterne X., Park D.I., Schreiber S., 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;67:1824–1835. doi: 10.1136/gutjnl-2016-313457. - DOI - PMC - PubMed
  45.  
    1. Vermeire S., Sandborn W.J., Danese S., Hébuterne X., Salzberg B.A., Klopocka M., Tarabar D., Vanasek T., Greguš M., Hellstern P.A., et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:135–144. doi: 10.1016/S0140-6736(17)30930-3. - DOI - PubMed
  46.  
    1. Sandborn W.J., Cyrille M., Berner Hansen M., Feagan B.G., Loftus E.V., Vermeire S., Cruz M.L., Mo M., Sullivan B.A., Reinisch W. OP035 Efficacy and safety of abrilumab (AMG 181/MEDI 7183) therapy for moderate to severe Crohn’s disease. J. Crohns Colitis. 2017;11((Suppl. 1)):S22–S23. doi: 10.1093/ecco-jcc/jjx002.034. - DOI
  47.  
    1. Sandborn W.J., Cyrille M., Hansen M.B., Feagan B.G., Loftus E., Rogler G., Vermeire S., Cruz M.L., Yang J., Boedigheimer M.J., et al. Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2019;156:946–957.e18. doi: 10.1053/j.gastro.2018.11.035. - DOI - PubMed
  48.  
    1. Sugiura T., Kageyama S., Andou A., Miyazawa T., Ejima C., Nakayama A., Dohi T., Eda H. 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–e542. doi: 10.1016/j.crohns.2013.03.014. - DOI - PubMed
  49.  
    1. Yoshimura N., Watanabe M., Motoya S., Tominaga K., Matsuoka K., Iwakiri R., Watanabe K., Hibi T., AJM300 Study Group Safety and Efficacy of AJM300, an Oral Antagonist of α4 Integrin, in Induction Therapy for Patients With Active Ulcerative Colitis. Gastroenterology. 2015;149:1775–1783.e2. doi: 10.1053/j.gastro.2015.08.044. - DOI - PubMed
  50.  
    1. Takazoe M., Watanabe M., Kawaguchi T., Matsumoto T., Oshitani N., Hiwatashi N., Toshifumi H. S1066 Oral Alpha-4 Integrin Inhibitor (AJM300) in Patients with Active Crohn’s Disease—A Randomized, Double-Blind, Placebo-Controlled Trial. Gastroenterology. 2009;5((Suppl. 1)):A-181. doi: 10.1016/S0016-5085(09)60816-7. - DOI
  51.  
    1. Fukase H., Kajioka T., Oikawa I., Ikeda N., Furuie H. 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;86:591–600. doi: 10.1111/bcp.14151. - DOI - PMC - PubMed
  52.  
    1. Ladrón Abia P., Alcalá Vicente C., Martínez Delgado S., Bastida Paz G. Fingolimod-induced remission in a patient with ulcerative colitis and multiple sclerosis. Gastroenterol. Hepatol. 2021;44:156–157. doi: 10.1016/j.gastrohep.2020.07.020. - DOI - PubMed
  53.  
    1. Danese S., Furfaro F., Vetrano S. Targeting S1P in Inflammatory Bowel Disease: New Avenues for Modulating Intestinal Leukocyte Migration. J. Crohns Colitis. 2018;12((Suppl. 2)):S678–S686. doi: 10.1093/ecco-jcc/jjx107. - DOI - PubMed
  54.  
    1. Lassiter G., Melancon C., Rooney T., Murat A.M., Kaye J.S., Kaye A.M., Kaye R.J., Cornett E.M., Kaye A.D., Shah R.J., et al. Ozanimod to Treat Relapsing Forms of Multiple Sclerosis: A Comprehensive Review of Disease, Drug Efficacy and Side Effects. Neurol. Int. 2020;12:89–108. doi: 10.3390/neurolint12030016. - DOI - PMC - PubMed
  55.  
    1. Sandborn W.J., Feagan B.G., Hanauer S., Vermeire S., Ghosh S., Liu W.J., Petersen A., Charles L., Huang V., Usiskin K., 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;15:1120–1129. doi: 10.1093/ecco-jcc/jjab012. - DOI - PMC - PubMed
  56.  
    1. Sandborn W.J., Feagan B.G., D’Haens G., Wolf D.C., Jovanovic I., Hanauer S.B., Ghosh S., Petersen A., Hua S.Y., Lee J.H., et al. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 2021;385:1280–1291. doi: 10.1056/NEJMoa2033617. - DOI - PubMed
  57.  
    1. Sandborn W.J., Feagan B.G., Wolf D.C., D’Haens G., Vermeire S., Hanauer S.B., Ghosh S., Petersen A., Hua S.Y., Lee J.H., et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N. Engl. J. Med. 2016;374:1754–1762. doi: 10.1056/NEJMoa1513248. - DOI - PubMed
  58.  
    1. Dgwshsjigs S. Ozanimod As Induction Therapy in Moderate-To-Severe Ulcerative Colitis: Results from The Phase 3. Randomized, Double-Blind, Placebo-Controlled True North Study. United Eur. Gastroenterol. J. 2020;8:3.
  59.  
    1. Feagan B.G., Sandborn W.J., Danese S., Wolf D.C., Liu W.J., Hua S.Y., Minton N., Olson A., D’Haens G. 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;5:819–828. doi: 10.1016/S2468-1253(20)30188-6. - DOI - PubMed
  60.  
    1. Sandborn W.J., Peyrin-Biroulet L., Zhang J., Chiorean M., Vermeire S., Lee S.D., Kühbacher T., Yacyshyn B., Cabell C.H., Naik S.U., et al. Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology. 2020;158:550–561.e9. doi: 10.1053/j.gastro.2019.10.035. - DOI - PubMed
  61.  
    1. D’Haens G., Danese S., Davies M., Watanabe M., Hibi T. 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;16:746–756. doi: 10.1093/ecco-jcc/jjab201. - DOI - PubMed
  62.  
    1. Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. doi: 10.1038/sigtrans.2017.23. - DOI - PMC - PubMed
  63.  
    1. Papp K., Reich K., Leonardi C.L., Kircik L., Chimenti S., Langley R.G.B., Hu C., Stevens R.M., Day R.M., Gordon K.B., et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM) 1) J. Am. Acad. Dermatol. 2015;73:37–49. doi: 10.1016/j.jaad.2015.03.049. - DOI - PubMed
  64.  
    1. Danese S., Neurath M.F., Kopoń A., Zakko S.F., Simmons T.C., Fogel R., Siegel C.A., Panaccione R., Zhan X., Usiskin K., et al. Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis. Clin. Gastroenterol. Hepatol. 2020;18:2526–2534.e9. doi: 10.1016/j.cgh.2019.12.032. - DOI - PubMed
  65.  
    1. Fernández-Clotet A., Castro-Poceiro J., Panés J. Tofacitinib for the treatment of ulcerative colitis. Expert Rev. Clin. Immunol. 2018;14:881–892. doi: 10.1080/1744666X.2018.1532291. - DOI - PubMed
  66.  
    1. Sandborn W.J., Su C., Sands B.E., D’Haens G.R., Vermeire S., Schreiber S., Danese S., Feagan B.G., Reinisch W., Niezychowski W., et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 2017;376:1723–1736. doi: 10.1056/NEJMoa1606910. - DOI - PubMed
  67.  
    1. Panés J., Vermeire S., Lindsay J.O., Sands B.E., Su C., Friedman G., Zhang H., Yarlas A., Bayliss M., Maher S., 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. 2019;13:139–140. doi: 10.1093/ecco-jcc/jjy135. - DOI - PMC - PubMed
  68.  
    1. D’Amico F., Parigi T.L., Fiorino G., Peyrin-Biroulet L., Danese S. Tofacitinib in the treatment of ulcerative colitis: Efficacy and safety from clinical trials to real-world experience. Ther. Adv. Gastroenterol. 2019;12:48631. doi: 10.1177/1756284819848631. - DOI - PMC - PubMed
  69.  
    1. Sandborn W.J., Peyrin-Biroulet L., Sharara A.I., Su C., Modesto I., Mundayat R., Gunay L.M., Salese L., Sands B.E. Efficacy and Safety of Tofacitinib in Ulcerative Colitis Based on Prior Tumor Necrosis Factor Inhibitor Failure Status. Clin. Gastroenterol. Hepatol. 2022;20:591–601.e8. doi: 10.1016/j.cgh.2021.02.043. - DOI - PubMed
  70.  
    1. Kim E.S., Keam S.J. Filgotinib in Rheumatoid Arthritis: A Profile of Its Use. Clin. Drug Investig. 2021;41:741. doi: 10.1007/s40261-021-01055-0. - DOI - PMC - PubMed
  71.  
    1. Vermeire S., Schreiber S., Petryka R., Kuehbacher T., Hebuterne X., Roblin X., Klopocka M., Goldis A., Wisniewska-Jarosinska M., Baranovsky A., 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;389:266–275. doi: 10.1016/S0140-6736(16)32537-5. - DOI - PubMed
  72.  
    1. Peyrin-Biroulet L., Loftus E., Danese S., Vermeire S., Sandborn W.J., Fogel R., Nijhawan S., Kempinski R., Filip R., Hospodarskyy I., et al. A17 efficacy and safety of filgotinib as maintenance therapy for patients with moderately to severely active ulcerative colitis: Results from the phase 2B/3 selection study. J. Can. Assoc. Gastroenterol. 2021;4((Suppl. 1)):21–23. doi: 10.1093/jcag/gwab002.016. - DOI - PubMed
  73.  
    1. Ananthakrishnan A.N. Upadacitinib for ulcerative colitis. Lancet. 2022;399:2077–2078. doi: 10.1016/S0140-6736(22)00778-4. - DOI - PubMed
  74.  
    1. Danese S., Vermeire S., Zhou W., Pangan A.L., Siffledeen J., Greenbloom S., Hébuterne X., D’Haens G., Nakase H., Panés J., et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: Results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399:2113–2128. doi: 10.1016/S0140-6736(22)00581-5. - DOI - PubMed
  75.  
    1. Sandborn W.J., Feagan B.G., Loftus E.V., van Assche G., D’Haens G., Schreiber S., Colombel J.F., Lewis J.D., Ghosh S., Peyrin-Biroulet L., et al. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn’s Disease. Gastroenterology. 2020;158:2123–2138.e8. doi: 10.1053/j.gastro.2020.01.047. - DOI - PubMed
  76.  
    1. Parigi T.L., Solitano V., Peyrin-Biroulet L., Danese S. Do JAK inhibitors have a realistic future in treating Crohn’s disease? Clin. Immunol. 2021;18:181–183. doi: 10.1080/1744666X.2022.2020101. - DOI - PubMed
  77.  
    1. Kim J.W., Kim S.Y. The Era of Janus Kinase Inhibitors for Inflammatory Bowel Disease Treatment. Int. J. Mol. Sci. 2021;22:11322. doi: 10.3390/ijms222111322. - DOI - PMC - PubMed
  78.  
    1. Sands B.E., Sandborn W.J., Feagan B.G., Lichtenstein G.R., Zhang H., Strauss R., Szapary P., Johanns J., Panes J., Vermeire S., 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;12:1158–1169. doi: 10.1093/ecco-jcc/jjy085. - DOI - PubMed
  79.  
    1. Beattie D.T., Pulido-Rios M.T., Shen F., Ho M., Situ E., Tsuruda P.R., Brassil P., Kleinschek M., Hegde S. Intestinally-restricted Janus Kinase inhibition: A potential approach to maximize the therapeutic index in inflammatory bowel disease therapy. J. Inflamm. 2017;14:1–11. doi: 10.1186/s12950-017-0175-2. - DOI - PMC - PubMed
  80.  
    1. Sandborn W.J., Nguyen D.D., Beattie D.T., Brassil P., Krey W., Woo J., Situ E., Sana R., Sandvik E., Pulido-Rios M., et al. Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme. J. Crohns Colitis. 2020;14:1202–1213. doi: 10.1093/ecco-jcc/jjaa049. - DOI - PMC - PubMed
  81.  
    1. Theravance’s Izencitinib Fails in Phase IIb Ulcerative Colitis Trial. [(accessed on 23 October 2022)]. Available online: https://www.clinicaltrialsarena.com/news/theravance-izencitinib-ulcerati...
  82.  
    1. Muromoto R., Oritani K., Matsuda T. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World J. Biol. Chem. 2022;13:1. doi: 10.4331/wjbc.v13.i1.1. - DOI - PMC - PubMed
  83.  
    1. Nogueira M., Puig L., Torres T. JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors. Drugs. 2020;80:341–352. doi: 10.1007/s40265-020-01261-8. - DOI - PubMed
  84.  
    1. NCT03395184. Study To Evaluate The Efficacy and Safety of Oral PF-06651600 and PF 06700841 in Subjects with Moderate to Severe Crohn’s Disease. [(accessed on 8 January 2023)]. Available online: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01559550/.... - DOI
  85.  
    1. Sandborn W., Danese S., Leszczyszyn J., Romatowski J., Altintas E., Peeva E., Vincent M., Reddy P., Banfield C., Banerjee A., et al. OP33 Oral ritlecitinib and brepocitinib in patients with Moderate to Severe Active Ulcerative Colitis: Data from the VIBRATO umbrella study. J. Crohns Colitis. 2021;15((Suppl. 1)):S030–S031. doi: 10.1093/ecco-jcc/jjab075.032. - DOI
  86.  
    1. Mease P.J., Deodhar A.A., van der Heijde D., Behrens F., Kivitz A.J., Neal J., Kim J., Singhal S., Nowak M., Banerjee S. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022;81:815–822. doi: 10.1136/annrheumdis-2021-221664. - DOI - PMC - PubMed
  87.  
    1. EUCTR2019-004878-26-NL. A Study of the Safety, Efficacy, and Biomarker Response of BMS-986165 in Participants with Moderate to Severe Ulcerative Colitis. [(accessed on 23 October 2022)]. Available online: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-02256022/.... - DOI
  88.  
    1. Bristol Myers Squibb-Bristol Myers Squibb Provides Update on Phase 2 Study of Deucravacitinib in Patients with Moderate to Severe Ulcerative Colitis. [(accessed on 23 October 2022)]. Available online: https://news.bms.com/news/details/2021/Bristol-Myers-Squibb-Provides-Upd....
  89.  
    1. Atreya R., Bloom S., Scaldaferri F., Gerardi V., Admyre C., Karlsson Å., Knittel T., Kowalski J., Lukas M., Löfberg R., et al. Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis. J. Crohns Colitis. 2016;10:1294. doi: 10.1093/ecco-jcc/jjw103. - DOI - PMC - PubMed
  90.  
    1. Atreya R., Peyrin-Biroulet L., Klymenko A., Augustyn M., Bakulin I., Slankamenac D., Miheller P., Gasbarrini A., Hébuterne X., Arnesson K., et al. Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): A phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial. Lancet Gastroenterol. Hepatol. 2020;5:1063–1075. doi: 10.1016/S2468-1253(20)30301-0. - DOI - PubMed
  91.  
    1. Study Record|Beta. [(accessed on 8 January 2023)]; Available online: https://beta.clinicaltrials.gov/study/NCT04985968.

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