[HTML][HTML] Therapeutic interleukin-6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease

S Schreiber, K Aden, JP Bernardes, C Conrad, F Tran… - Gastroenterology, 2021 - Elsevier
S Schreiber, K Aden, JP Bernardes, C Conrad, F Tran, H Höper, V Volk, N Mishra, JI Blase…
Gastroenterology, 2021Elsevier
Background & Aims A large unmet therapeutic need exists in inflammatory bowel disease
(IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a
complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression.
Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by
trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor
without the need for membrane-bound IL6R. We have developed a decoy protein …
Background & Aims
A large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression.
Methods
We present a 12-week, open-label, prospective phase 2a trial (FUTURE) in 16 patients with active IBD treated with the trans-signaling inhibitor olamkicept (sgp130Fc) to assess the molecular mechanisms, safety, and effectiveness of IL6 trans-signaling blockade in vivo. We performed in-depth molecular profiling at various timepoints 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–tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) therapies was identified.
Conclusions
Our data suggest that blockade of IL6 trans-signaling holds great promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy for IBD. (EudraCT no., Nu 2016-000205-36)
Elsevier