Chronisch-entzündliche Darmerkrankungen

Der Gastroenterologe - Tập 14 - Trang 462-469 - 2019
Sebastian Zeißig1,2
1Medizinische Klinik I, Universitätsklinikum Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Deutschland
2Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Deutschland

Tóm tắt

Das Spektrum medikamentöser Therapieoptionen bei chronisch-entzündlichen Darmerkrankungen (CED), einst beschränkt auf wenige klassische Immunmodulatoren und Immunsuppressiva, hat mit der Einführung der Antikörper gegen Tumornekrosefaktor(TNF)-α und später der Zulassung von Antikörpern gegen Interleukin(IL)-12/IL-23 und gegen Integrine eine deutliche Erweiterung erfahren. Während damit neue wirksame und sichere Therapien zur CED-Behandlung zugelassen wurden, bleibt ein signifikanter ungedeckter Bedarf in der klinischen Versorgung von CED-Patienten, da nur ein Teil der Patienten auf zugelassene Therapeutika anspricht, ein relevanter Anteil von Patienten einen sekundären Wirkverlust entwickelt und weiterhin große Problemfelder in der CED-Therapie vor allem mit dem fistulierenden M. Crohn sowie der Prävention stenosierender Erkrankungsverläufe existieren. Entsprechend dieses ungedeckten Bedarfs zeigt sich aktuell eine hochdynamische Phase der Entwicklung und Weiterentwicklung von medikamentösen Therapiestrategien bei CED mit einer Vielzahl laufender und teils fortgeschrittener Phase-III-Studien. Dies umfasst neue Antikörper gegen Zytokine und Integrine sowie kleine Moleküle („small molecules“) mit Zielstrukturen im Bereich der Signaltransduktion von Zytokinen und von Regulatoren der Lymphozytenmigration. Auch findet weiterhin aktive Entwicklung im Bereich der zellbasierten Therapien und mikrobieller Therapieansätze statt. Im Folgenden soll ein Überblick über diese Entwicklungen gegeben werden.

Tài liệu tham khảo

Brian F, William S, Silvio D et al (2018) Endoscopic and clinical efficacy demonstrated with oral ozanimod in active Crohn’s disease in biologic-Naïve and biologic experienced patients: P‑010. Am J Gastroenterol 113:S3 Desreumaux P, Foussat A, Allez M et al (2012) Safety and efficacy of antigen-specific regulatory T‑cell therapy for patients with refractory Crohn’s disease. Gastroenterology 143:1207–1217.e2 D’haens G, Danese S, Davies M et al (2019) DOP48 Amiselimod, a selective S1P receptor modulator in Crohn’s disease patients: a proof-of-concept study. J Crohns Colitis 13:S55–S56 Feagan BG, Sandborn WJ, D’haens G et al (2017) 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 389:1699–1709 Feagan BG, Panes J, Ferrante M et al (2018) Risankizumab in patients with moderate to severe Crohn’s disease: an open-label extension study. Lancet Gastroenterol Hepatol 3:671–680 Moayyedi P, Surette MG, Kim PT et al (2015) Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149:102–109.e6 Panes J, Garcia-Olmo D, Van Assche G et al (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388:1281–1290 Panes J, Sandborn WJ, Schreiber S et al (2017) Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 66:1049–1059 Paramsothy S, Kamm MA, Kaakoush NO et al (2017) Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389:1218–1228 Peyrin-Biroulet L, Christopher R, Behan D et al (2017) Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev 16:495–503 Rossen NG, Fuentes S, Van Der Spek MJ et al (2015) Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149:110–118.e4 Rubin DT, Motoya S, Schreiber S et al (2018) Tofacitinib 15 milligrams twice daily for patients with moderate to severe ulcerative colitis: Results from 8‑week induction studies OCTAVE INDUCTION 1 & 2. United European Gastroenterol J 6(8S) Sandborn WJ, Ghosh S, Panes J et al (2014) A phase 2 study of tofacitinib, an oral Janus Kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol 12:1485–1493.e2 Sandborn WJ, Feagan BG, Wolf DC et al (2016) Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 374:1754–1762 Sandborn WJ, Feagan BG, Panes J et al (2017) Safety and efficacy of ABT-494 (Upadacitinib), an oral Jak1 inhibitor, as induction therapy in patients with Crohn’s disease: results from celest. Gastroenterology 152:S1308–S1309 Sandborn WJ, Su C, Sands BE et al (2017) Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 376:1723–1736 Sandborn WJ, Ferrante M, Bhandari BR et al (2018) Efficacy and safety of anti-Interleukin-23 therapy with mirikizumab (LY3074828) in patients with moderate-to-severe ulcerative colitis in a phase 2 study. Gastroenterology 154:S-1360–S-1361 Sandborn WJ, Lee SD, Tarabar D et al (2018) Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn’s disease: report of the OPERA study. Gut 67:1824–1835 Sandborn WJ, Panes J, D’haens GR et al (2019) Safety of tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials. Clin Gastroenterol Hepatol 17:1541–1550 Sandborn WJ, Baert F, Danese S et al (2018) Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the visible 1 phase 3 trial. United European Gastroenterol J 6(Supplement 1) Sandborn WJ, Bhandari R, Leighton JA et al (2018) The intestinally restricted, orally administered, pan-JAK inhibitor TD-1473 demonstrates favorable safety, tolerability, pharmakokinetics, and signal for clinical activity in subjects with moderately-to-severely active ulcerative colitis. United European Gastroenterol J 6(Suppl. 1) Sandborn WJ, Ghosh S, Panes J et al (2018) Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2B study U‑ACHIEVE. United European Gastroenterol J 6(8_Suppl) Sandborn WJ, Peyrin-Biroulet L, Trokan L et al (2018) A randomized, double-blind, placebo-controlled trial of a selective, oral sphingosine 1‑phosphate (S1P) receptor modulator, etrasimod (APD334), in moderate to severe ulcerative colitis (UC): results from the OASIS study. United Eur Gastroenterol J 6(Supplement 1) Sands BE, Chen J, Feagan BG et al (2017) Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology. 153(1):77–86(e6) Sands BE, Sandborn WJ, Peyrin-Biroulet L et al (2019) Efficacy and safety of mirikizumab (LY3074828) in a phase 2 study of patients with Crohn’s disease. Gastroenterology 156:S-216 Sands BE, Peyrin-Biroulet L, Loftus EV Jr, Danese S, Colombel JF, Törüner M, Jonaitis L, Abhyankar B, Chen J, Rogers R, Lirio RA, Bornstein JD, Schreiber S, VARSITY Study Group (2019) Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med 381(13):1215–1226. https://doi.org/10.1056/NEJMoa1905725 Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, Adedokun OJ, Li K, Peyrin-Biroulet L, Van Assche G, Danese S, Targan S, Abreu MT, Hisamatsu T, Szapary P, Marano C, UNIFI Study Group (2019) Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 381(13):1201–1214. https://doi.org/10.1056/NEJMoa1900750 Stiko (2018) Epid Bull 50:544–566 Vermeire S, O’byrne S, Keir M et al (2014) Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384:309–318 Vermeire S, Sandborn WJ, Danese S et al (2017) Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 390:135–144 Vermeire S, Schreiber S, Petryka R et al (2017) 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 389:266–275 Westhovens R, Wiland P, Zawadzki M et al (2019) A novel formulation of CT-P13 for subcutaneous administration: 30 week results from a part 2 of phase I/III randomized controlled trial in patients with rheumatoid arthritis. Ann Rheum Dis 78:1158–1159 Winthrop KL, Curtis JR, Lindsey S et al (2017) Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant. Therapy 69:1960–1968 Xie JH, Gillooly K, Zhang Y et al (2018) BMS-986165 is a highly potent and selective allosteric inhibitor of TYK2, blocks Il-12, IL-23 and type I interferon signaling and provides for robust efficacy in Preclinical models of inflammatory bowel disease. Gastroenterology 154:S-1357 Yoo D, Jaworski J, Matyska-Piekarska E et al (2019) A novel formulation of CT-P13 (Infliximab biosimilar) for subcutaneous administration: 1‑year results from a part 1 of phase I/III randomized controlled trial in patients with active rheumatoid arthritis. Ann Rheum Dis 78:733