The selective interleukin-6 (IL-6) trans-signaling inhibitor olamkicept was well tolerated and induced clinical remissions in 3 of 16 adults with moderately to severely active inflammatory bowel disease (IBD), and remission was associated with clear alterations in levels of phospho-STAT3 (pSTAT3) in the intestinal mucosa, researchers reported.
In a 12-week, open-label, prospective phase 2a trial, patients received up to seven infusions of 600-mg olamkicept (sgp130Fc) every 2 weeks. Clinical remissions occurred in two of nine patients with ulcerative colitis and one of seven patients with Crohn’s disease. The overall rate of clinical response was 44%, which included five patients with ulcerative colitis and two patients with Crohn’s disease. Transcriptome isolation and high-throughput RNA sequencing of mucosal tissue specimens showed that clinical remitters had a decrease from baseline to week 14 in the expression of TNF, IL-1A, REG1A, IL-8, IL-1B, and LILRA, a known composite molecular surrogate for mucosal inflammation. In addition, exposing whole-blood samples to a recombinant IL-6/IL-6R fusion protein mimicked physiologic IL-6 activity and demonstrated that pSTAT3 levels dropped within 4 hours of the first olamkicept infusion and throughout treatment. “Our overall finding of decreased pSTAT3-positive cells in remission patients indicates that STAT3 is crucially involved in the mechanism of action of olamkicept,” wrote Stefan Schreiber, MD, of University Medical Center Schleswig-Holstein, Campus Kiel (Germany) together with his associates. The study is published in Gastroenterology.
Blocking the IL-6/ILR receptor can induce IBD remissions but causes “profound immunosuppression,” the investigators noted. Building on prior findings that chronic proinflammatory IL-6 activity is primarily mediated by trans-signaling of a complex of IL-6 and soluble IL6R that engages the gp130 receptor, the researchers developed a “decoy protein,” sgp130Fc (now known as olamkicept), which “exclusively blocks” IL-6 proinflammatory trans-signaling. This decoy protein showed promise in preclinical studies, with no evidence of immunosuppression, they wrote. To further evaluate olamkicept, they recruited adults with moderately to severely active ulcerative colitis or Crohn’s disease from two centers in Germany. The primary clinical assessment was remission, defined as a Mayo score under 2, with a bleeding score of 0 and an endoscopy score of less than 1 for patients with ulcerative colitis, and a Crohn’s Disease Activity Index (CDAI) of less than 150 for patients with Crohn’s disease. The primary molecular outcome was change in the composite molecular surrogate score.
Of the 16 patients, 10 completed the trial. At week 14, endoscopic responses were observed in six patients, all of whom also had a clinical response, and all three patients with clinical remissions also had endoscopic remissions. “The drug was well tolerated in all 16 treated individuals, similar to the results of the [two prior] phase 1 trials,” the researchers wrote. Although significant immunosuppression and intestinal perforations were not seen, 13 patients developed adverse events, most commonly seasonal upper respiratory tract infections, recurrence of herpes labialis, and eczema or erythema. There were five serious adverse events, two of which were cardiac in nature. A larger placebo-controlled trial is underway to further evaluate safety. For now, the researchers wrote, it appears that IL-6 trans-signaling inhibition “might open up novel therapeutic avenues for the treatment of IBD.”
University Hospital Schleswig-Holstein sponsored the study. Ferring AG provided funding and donated the olamkicept. Analyses were funded by EU H2020 SYSCID and EU H2020 Innovative Medicines Initiative 2 Joint Undertaking. Dr. Schreiber reported having coinvented IP and having ties to Pfizer, Bristol Myers Squibb, and Roche. Four coinvestigators disclosed ties to Ferring, AbbVie, Chugai, Roche, Regeneron, Pfizer, Sanofi, Conaris, and Genentech Roche. The other researchers reported having no conflicts of interest.