NEW YORK (Reuters Health) – Olamkicept, an interleukin (IL)-6 trans-signaling inhibitor, was well tolerated and induced a clinical response in inflammatory bowel disease (IBD) patients in a small safety trial.
“Evidence has emerged that (the) chronic pro-inflammatory activity of IL-6 is mainly mediated by trans-signaling via a complex of IL-6 bound to soluble IL-6R engaging the gp130 receptor, without the need of membrane-bound IL6R,” Dr. Stefan Schreiber of University Medical Center Schleswig-Holstein in Kiel, Germany, and colleagues write in Gastroenterology.
“We have developed a decoy protein, sgp130Fc, which exclusively blocks IL-6 pro-inflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression,” they add.
The new study was a 12-week, open-label, phase-2a trial in 16 patients with active IBD treated with olamkicept (sgp130Fc).
Participants had to have failed conventional therapies with no more than two prior biologics (limited to anti-TNFs and/or vedolizumab). They received up to seven infusions of 600 mg olamkicept every two weeks.
Six patients did not complete the full observation period; 10 – five with ulcerative colitis and five with Crohn’s disease – completed the trial.
Molecular profiling was done at various time points before and after therapy initiation to identify the compound’s mechanism of action.
Olamkicept was well tolerated and induced a clinical response in seven (44%) participants and clinical remission in three (19%). Effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and transcriptional changes in the inflamed mucosa.
An olamkicept-specific transcriptional signature was identified that was distinguishable from remission signatures of anti-TNF (infliximab) or anti-integrin (vedolizumab) therapies.
Neither Dr. Schreiber nor senior author Dr. Philip Rosenstiel responded to requests for a comment, but two U.S. experts provided perspectives in emails to Reuters Health.
Dr. Shannon Chang, associate director of the IBD Center at NYU Langone Health, in New York City, said, “The selective trans-signaling mechanism for inhibiting chronic inflammation in this small study shows promise in the treatment of IBD. Also, the clinical effectiveness of olamkicept coincided with a reduction of phosphorylated STAT3, which could be a future target for predicting treatment response.”
“While these findings are exciting,” she said, “more information is needed regarding safety and efficacy in future trials. The sample size for this phase 2 pilot was small, including both Crohn’s and ulcerative colitis patients; firm conclusions are difficult to make.”
Dr. Bradley Morganstern, co-director of the Inflammatory Bowel Disease Center at Stony Brook Medicine in New York, said, “I am cautiously optimistic about olamkicept as a potential candidate for treatment of IBD.”
“Prior studies have shown elevated IL-6 levels in patients with IBD, making it a potential target for biologic therapy,” he noted. “However, the progress of other candidate drugs in clinical trials targeting this pathway has been hindered by safety concerns, including high rates of abscess and bowel perforation.”
“Olamkicept was designed to block only certain parts of the IL-6 signaling pathway involved in causing chronic inflammation, without blocking IL-6 signaling involving host defenses against infectious pathogens,” he said. “This may convey some additional safety benefit compared to prior IL-6 targeted therapies.”
“While none of the patients in this trial experienced perforation or abscess, it was a very small trial and may not have included enough patients to identify such safety signals,” he said. “The current trial is further limited by its lack of a placebo arm and its lack of stratification of patients by disease type – i.e., Crohn’s disease vs. ulcerative colitis.”
“We will need to wait for results of the ongoing phase II trial to more accurately assess both the safety and efficacy of olamkicept,” Dr. Morganstern concluded.
Ferring AG provided the drug and a research grant to the authors’ institution. Three authors are employed by the company and one by CONARIS Research Institute, which owns the intellectual property rights to olamkicept; two authors are also co-inventors on patents owned by CONARIS.
SOURCE: https://bit.ly/3rSFX8g Gastroenterology, online March 2, 2021.
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