GSE171770
Therapeutic IL-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease
Background  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.  Methods  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.  Results  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.  Conclusion  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. Overall design: The trial was conducted over 21 months between 2016 and 2019. 600 mg of olamkicept were administered by intravenous infusion every 2 weeks for 12 weeks (i.e. 7 infusions). Clinical disease activity (including endoscopy) was assessed at baseline and weeks 2, 6 and 14. Additional visits for biosampling (blood, sigmoid mucosal biopsies) were conducted 4 h and 24 h after therapy. Whole blood and sigmoid mucosal biopsy samples (collected from the most inflamed region within 30 cm of colon sigmoideum) were collected as a longitudinal dataset from which the RNA for transcriptome analyses was isolated. The samples were gathered at baseline (0 h) and 4 h, 24 h, 2 weeks, 6 weeks and 14 weeks after the first olamkicept infusion. Whole RNA libraries were prepared using TruSeq RNA Library Prep technology and, in total, 104 blood and 105 biopsy samples were sequenced using HiSeq 4000  (both data sets were of paired data with 2x75bp).