Cx-601, Alofisel (Tigenix/Takeda) has proven to be efficacious to induce and maintain fistula closure, when applied locally close to the tract in conjunction with surgical preparation of the fistula track . have also shown efficacy BMS-214662 in patients with ulcerative colitis (UC) (Sandborn et al. in N Engl J Med 374(18):1754C1762, 2016). Oral brokers inhibiting cell signaling have been explored successfully in IBD. Tofacitinib, a non-selective oral Janus kinase (JAK) inhibitor, is effective in patients with UC and several other more or less selective Jak1, 2 and 3 BMS-214662 inhibitors are being developed for the treatment of CD and UC (Sandborn et al. in N Engl J Med 376(18):1723C1736, 2017; Vermeire et al. in Lancet 389(10066):266C275, 2017; De Vries et al. in J Crohns Colitis 11(7):885C93, 2017). Finally, despite initial disappointing results with systemic administration of mesenchymal stem cells, Alofisel, adipose tissue derived, allogeneic mesenchymal stem cells, locally injected in perianal fistula tracts, induce long-lasting beneficial effects and the drug has been approved in Europe (Panes et al. in Gastroenterology, 2017). In summary, the quest for new treatment options in IBD is very active and justified by the high medical need and unresolved problems patients are facing. mechanism of action, Crohns disease, ulcerative colitis The role of ustekinumab pharmacokinetics is usually unclear at BMS-214662 this moment, but cohort data suggest that endoscopic healing is related to ustekinumab trough levels , which was also observed in a post hoc sub-analysis of the phase III program . In contrast to infliximab, the immunogenic profile of ustekinumab is very limited (2.3% of all 1154 patients included in the UNITI trials developed auto-antibodies against ustekinumab, measured via a drug-tolerant assay) . This might explain why immunomodulators do not seem to influence ustekinumab pharmacokinetics . Though the efficacy and security of blocking p40 has been established, it is not clear BMS-214662 if direct modulation of the IL12 axis via p40 contributes to the efficacy BMS-214662 or has potential risks related to IL12s role in tumor immune surveillance and in host defense against intracellular pathogens . Hence, selectively blocking IL23p19 might offer important differentiation in efficacy and security (Fig.?1). Open in a separate windows Fig.?1 Pro-inflammatory cytokine pathways in IBD MEDI2070 (AMG-139, Amgen and MedImmune) is a fully human IgG2 monoclonal antibody, which selectively binds p19. The results Rabbit Polyclonal to Nuclear Receptor NR4A1 (phospho-Ser351) of a phase IIa induction study recently exhibited clinical efficacy in 121 patients with moderate-to-severe CD, who previously experienced failed anti-TNF therapy . After administration of 700?mg MEDI2070 intravenously at week 0C4, clinical effect (>?100 drop from baseline CDAI-score OR CDAI?150) at week eight was achieved in 49.2% of patients, compared to 26.7% of patients receiving placebo (p?=?0.010). Through week 12, no increased rate of adverse events (AE) with active treatment was observed compared to placebo. Similarly to MEDI2070, risankizumab (BI-655066, Boehringer Ingelheim and Abbvie) potently binds to p19 and prevents its binding to the IL23R. The results of a phase II trial in moderately-to-severely active CD were favorable . Selective blockade of IL23p19 with risankizumab was superior to placebo in achieving clinical remission (30.5% vs 15.4% respectively, p?=?0.049) and clinical response (39.0% vs 20.5% respectively, p?=?0.027). Ninety-four per cent of all included patients had been exposed to anti-TNF before, with approximately one-third (30%) going through primary non-response and another third (28%) secondary loss of response, reflecting a very refractory population. In addition, significantly more patients achieved endoscopic remission with risankizumab compared to placebo (17.1% vs 2.6%,.