A large unmet therapeutic need exists in inflammatory bowel diseases (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL-6/IL-6R blockade is limited by profound immunosuppression. Evidence has emerged, that chronic pro-inflammatory activity of IL-6 is mainly mediated by trans-signalling via a complex of IL-6 bound to soluble IL-6R engaging the gp130 receptor without the need of membrane bound IL6R. We have developed a decoy protein, sgp130Fc, which exclusively blocks IL-6 pro-inflammatory trans-signalling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression.We present a 12-week, open label, prospective phase IIa trial (FUTURE) in 16 patients with active IBD treated with the trans-signalling inhibitor olamkicept (sgp130Fc) to assess molecular mechanisms, safety and effectiveness of IL-6 trans-signalling blockade in vivo. We performed in-depth molecular profiling at various time points before and after therapy induction to identify the mechanism of action of olamkicept.Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-TNF (infliximab) or anti-integrin (vedolizumab) therapies was identified.Our data suggest that blockade of IL-6 trans-signaling holds large promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy of IBD.
Stefan Schreiber, Konrad Aden, Joana P Bernardes, Claudio Conrad, Florian Tran, Hanna Höper, Valery Volk, Neha Mishra, Johanna Ira Blase, Susanna Nikolaus, Johannes Bethge, Tanja Kühbacher, Christoph Röcken, Minhu Chen, Ian Cottingham, Niclas Petri, Birgitte B Rasmussen, Juliane Lokau, Lennart Lenk, Christoph Garbers, Friedrich Feuerhake, Stefan Rose-John, Georg H Waetzig, Philip Rosenstiel