Ustekinumab – eine Standortbestimmung

Zusammenfassung

Die vorliegende Übersicht der IBD-Dach-Gruppe legt eine Übersicht zu Wirkmechanismus, klinischer Entwicklung, Zulassung, Wirksamkeit und Sicherheitsaspekten des neuen Anti-p40-Antikörpers Ustekinumab vor, der für die Therapie des moderaten bis schweren Morbus Crohn zugelassen ist. Die Arbeit fasst die aktuelle Datenlage zusammen und enthält somit sowohl die Daten der Zulassungsstudien als auch die Daten aus kleineren und auch fachübergreifenden Arbeiten, mit denen die Aspekte zu besonderen Situationen diskutiert werden können. Alle Arbeiten zusammen zeigen, dass mit Ustekinumab eine wirksame und sichere Option für den Morbus Crohn zur Verfügung steht.

Abstract

The present review by the IBD-Dach group provides a comprehensive summary of the mode of action, clinical development, approval, efficacy and safety aspects of the novel anti-p40 antibody Ustekinumab. The review provides current data, including the large clinical trials as well as smaller case series and work outside the field of inflammatory bowel diseases for shedding more light into special situations. Together, the data indicate that Ustekinumab shows clinical efficacy as well as a good safety profile for the treatment of Crohnʼs disease.

Schlüsselwörter

chronisch-entzündliche Darmerkrankung - Morbus Crohn - Biologika - Ustekinumab

Key words

inflammatory bowel disease - Crohn’s disease - biologicals - ustekinumab

• Literatur

• 1 Oppmann B, Lesley R, Blom B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715-725
• 2 Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19: 281-286
• 3 Neurath MF, Fuss I, Kelsall BL. et al. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 1995; 182: 1281-1290
• 4 Mannon PJ, Fuss IJ, Mayer L. et al. Anti-interleukin-12 antibody for active Crohnʼs disease. N Engl J Med 2004; 351: 2069-2079
• 5 Duerr RH, Taylor KD, Brant SR. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461-1463
• 6 Tremelling M, Cummings F, Fisher SA. et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 2007; 132: 1657-1664
• 7 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: 309-318
• 8 Feagan BG, Sandborn WJ, D’Haens G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohnʼs disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2017; 389: 1699-1709
• 9 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: 567-577
• 10 Sandborn WJ, Gasink C, Gao LL. et al. Ustekinumab induction and maintenance therapy in refractory Crohnʼs disease. N Engl J Med 2012; 367: 1519-1528
• 11 Sandborn WJ, Gasink C, Gao JJ. et al. Ustekinumab induction and maintenance therapy in refractory Crohnʼs disease. N Engl J Med 2012; 367: 1519-1528
• 12 Feagan BG, Sandborn WJ, Gasink C. et al. Ustekinumab as Induction and Maintenance Therapy for Crohnʼs Disease. N Engl J Med 2016; 375: 1946-1960
• 13 Adedokun OJ, Xu Y, Gasink C. et al. Pharmacokinetics and Exposure-Response Relationships of Ustekinumab during IV Induction and SC Maintenance Treatment of Patients with Crohnʼs Disease With Ustekinumab: Results from the UNITI-1, UNITI-2, and IM-UNITI Studies. Gastroenterology 2017; 150: S408
• 14 Sands B, Han C, Gasink C. et al. Ustekinumab Improves General Health Status and Disease-Specific HEalth Related Quality of Lie of Patients with Moderate to Severe Crohnʼs Disease: Results from the UNITI and IM-UNITI Phase 3 Clinical Trials. Gastroenterology 2017; 150: S1004
• 15 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: 1665-1674
• 16 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: 1675-1684
• 17 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: 844-854
• 18 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: 706-714
• 19 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; 31: 780-789
• 20 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: 990-999
• 21 Sandborn WJ, Rutgeerts P, Gasnik C. et al. Long-term efficacy and safety of Ustekinumab for Crohnʼs disease: Results from IM-UNITI long-term extension through 2 years. J Crohns Colitis 2017; 11 (Suppl. 01) S6(OP010)
• 22 Khorrami S, Ginard D, Marin-Jimenez I. et al. Ustekinumab for the Treatment of Refractory Crohnʼs Disease: The Spanish Experience in a Large Multicentre Open-label Cohort. Inflamm Bowel Dis 2016; 22: 1662-1669
• 23 Kopylov U, Afif W, Cohen A. et al. Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohnʼs disease--the McGill experience. J Crohns Colitis 2014; 8: 1516-1522
• 24 Wils P, Bouhnik Y, Michetti P. et al. Subcutaneous Ustekinumab Provides Clinical Benefit for Two-Thirds of Patients With Crohnʼs Disease Refractory to Anti-Tumor Necrosis Factor Agents. Clin Gastroenterol Hepatol 2016; 14: 242-250 e241–242
• 25 Ghosh S, Sands B, de Villiers WJ. A pooled safety analysis from the Ustekinumab Crohnʼs disease and psoriatric phase 2 and 4 clinical trial programs. United European Gastroenterology Journal 2016; 4 (Suppl. 01) A258-A259
• 26 Ahn CS, Dothard EH, Garner ML. et al. To test or not to test? An updated evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis and psoriatic arthritis. J Am Acad Dermatol 2015; 73: 420-428 e421
• 27 Tsai TF, Ho V, Song M. et al. The safety of ustekinumab treatment in patients with moderate-to-severe psoriasis and latent tuberculosis infection. Br J Dermatol 2012; 167: 1145-1152
• 28 Tsai TF, Chiu HY, Song M. et al. A case of latent tuberculosis reactivation in a patient treated with ustekinumab without concomitant isoniazid chemoprophylaxis in the PEARL trial. Br J Dermatol 2013; 168: 444-446
• 29 Bonifati C, Lora V, Graceffa D. et al. Management of psoriasis patients with hepatitis B or hepatitis C virus infection. World J Gastroenterol 2016; 22: 6444-6455
• 30 Sanz-Bueno J, Vanaclocha F, Garcia-Doval I. et al. Risk of Reactivation of Hepatitis B Virus Infection in Psoriasis Patients Treated With Biologics: A Retrospective Analysis of 20 Cases From the BIOBADADERM Database. Actas Dermosifiliogr 2015; 106: 477-482
• 31 Paparizos V, Rallis E, Kirsten L. et al. Ustekinumab for the treatment of HIV psoriasis. J Dermatolog Treat 2012; 23: 398-399
• 32 Saeki H, Ito T, Hayashi M. et al. Successful treatment of ustekinumab in a severe psoriasis patient with human immunodeficiency virus infection. J Eur Acad Dermatol Venereol 2015; 29: 1653-1655
• 33 Llamas-Velasco M, Concha-Garzon MJ, Garcia-Diez A. et al. Liver Injury in Psoriasis Patients Receiving Ustekinumab: A Retrospective Study of 44 Patients Treated in the Clinical Practice Setting. Actas Dermosifiliogr 2015; 106: 470-476
• 34 Hoffmann JH, Knoop C, Enk AH. et al. Routine Laboratory Parameter Dynamics and Laboratory Adverse Events in Psoriasis Patients on Long-term Treatment with Adalimumab, Etanercept, and Ustekinumab. Acta Derm Venereol 2017; 97: 705-710
• 35 Segal BM, Constantinescu CS, Raychaudhuri A. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008; 7: 796-804
• 36 Dickson L, Menter A. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) in a Psoriasis Patient Treated With Ustekinumab. J Drugs Dermatol 2017; 16: 177-179
• 37 Gratton D, Szapary P, Goyal K. et al. Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature. Arch Dermatol 2011; 147: 1197-1202
• 38 Kalb RE, Fiorentino DF, Lebwohl MG. et al. Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol 2015; 151: 961-969
• 39 Papp KA, Strober B, Augustin M. et al. PSOLAR: design, utility, and preliminary results of a prospective, international, disease-based registry of patients with psoriasis who are receiving, or are candidates for, conventional systemic treatments or biologic agents. J Drugs Dermatol 2012; 11: 1210-1217
• 40 Loftus E, Augustin M, Bissonnette R. et al. P626 Prevalence of inflammatory bowel disease amongst patients with psoriasis and incidence of serious infections in this subset: results from the PSOLAR Registry. J Crohns Colitis 2016; 10: 418
• 41 Sands BGC, Jacobstein D, Gao LL. et al. Fistula Healing in Pivotal Studies of Ustekinumab in Crohnʼs Disease. Gastroenterology 2017; 152: 185
• 42 Kavanaugh A, Puig L, Gottlieb AB. et al. Maintenance of Clinical Efficacy and Radiographic Benefit Through Two Years of Ustekinumab Therapy in Patients With Active Psoriatic Arthritis: Results From a Randomized, Placebo-Controlled Phase III Trial. Arthritis Care Res (Hoboken) 2015; 67: 1739-1749
• 43 Naureckas S, Gearhart N, Nissinen R. et al. Pregnancy outcomes in women with psoriasis and psoriatic arthritis exposed to ustekinumab (P3106). J American Academy of Dermatology 2016; 74: AB264
• 44 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000958/human_med_001065.jsp&mid=WC0b01ac058001d124 . Letzter Zugriff am 19.07.2018
• 45 Kimball AB, Calabro S, Crow JA. et al. Pregnancy outcomes in women with moderate-to-severe psoriasis: The PSOLAR experience. J Am Acad Dermatol 2015; 70: AB 179
• 46 Harris KA, Horst S, Gadani A. et al. Patients with Refractory Crohnʼs Disease Successfully Treated with Ustekinumab. Inflamm Bowel Dis 2016; 22: 397-401
• 47 Ma C, Fedorak RN, Kaplan GG. et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohnʼs disease: real world experience from a multicentre cohort. Aliment Pharmacol Ther 2017; 45: 1232-1243