番茄社区

Induction therapy with a novel interleukin 6 (IL-6) inhibitor for active ulcerative colitis yielded significantly higher rates of clinical response, remission, and mucosal healing than placebo, findings from a phase II study conducted in Asia showed.

Clinical response at week 12, the study's primary endpoint, was achieved in 58.6% of patients given 600-mg olamkicept infusions every other week, as compared with 34.5% of those assigned placebo, for an adjusted difference of 26.6% (90% CI 6.2-47.1, P=0.03), reported Minhu Chen, MD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

As described in , treatment with the biweekly 600-mg dose also led to improvements in eight of nine secondary endpoints at week 12, including:

• Clinical remission: 20.7% vs none with placebo (P<0.001)
• Mucosal healing: 34.5% vs 3.4% (P<0.001)

Subgroup analyses of the primary endpoint were generally consistent in favoring olamkicept, but those "with a baseline Mayo score greater than 8 or endoscopic score of 3 had lower response rates," Chen's group noted.

The small randomized, double-blind trial included fewer than 100 patients with an inadequate response to conventional therapy, and a noted limitation was the 5.5% with prior exposure to biologics, which suggests patients did not have severe disease.

In a third arm of the study, a 300-mg biweekly dose of olamkicept led to clinical responses in 43.3% of patients at week 12, which was not significantly better than placebo (P=0.52).

Olamkicept is a first-in-class soluble gp130-Fc-fusion-protein that selectively blocks IL-6 via the trans-signaling mechanism. A pleiotropic proinflammatory cytokine, IL-6 is "a key mediator in chronic inflammation," the researchers explained, with sustained activation of IL-6 triggering the release of soluble IL-6R, which gives rise to IL-6 trans-signaling.

In their paper, Chen and colleagues concluded that "further research is needed for replication and to assess longer-term efficacy and safety," yet to that end, new trials involving olamkicept since these phase II data were at the Digestive Disease Week 2021 annual meeting have been scarce.

In an email to 番茄社区, a spokesperson for the drug's developer, Ferring Pharmaceuticals, said "we right now don't have any planned trials for olamkicept in the U.S."

But the spokesperson confirmed that development of the IL-6 blocker is ongoing, in collaboration with I-Mab: "We are currently evaluating data to support decision-making on which indications to explore further and how to best design our development program."

The trial from Chen and colleagues was conducted at 22 sites in mainland China, Taiwan, and South Korea. From February 2018 to December 2020, a total of 91 patients were randomized 1:1:1 to 600 mg olamkicept, 300 mg olamkicept, or placebo.

Participants all had active ulcerative colitis (total Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2), had an average age of 41 years, and a little over one-fourth were women. About half had moderate disease scores and half severe disease scores on centrally reviewed endoscopy, and Mayo total score was a mean 8.4-8.7 across groups (a 0-12 scale with a higher score indicating worse disease activity). Prior treatments for ulcerative colitis included 5-aminosalicylate in 96%, corticosteroids in 13%, azathioprine in 8%, and biologics in 5.5%.

Ultimately, 79 completed the trial, with week-12 dropout rates of 10% in the 600-mg olamkicept group, 6.5% in the 300-mg dose group, and 23.3% in the placebo group. Overall, 80.0%, 87.1%, and 66.7%, respectively, received all six doses over the 12-week trial.

The primary outcome of clinical response was defined as a decrease of at least 3 points or 30% in total Mayo score, including a decrease of at least 1 point in rectal bleeding, or no greater than 1 on that subscore. A total of 25 secondary outcomes were measured as well. Of these, 16 significantly favored the 600-mg dose and six favored the 300-mg dose of olamkicept over placebo.

For safety, treatment-related adverse events (TRAEs) were slightly more common in the olamkicept groups, at 53.3% with the 600-mg dose, 58.1% with the 300-mg dose, and 50% with placebo. Serious events were rare: 3% in the olamkicept groups and 6.7% (two patients) in the placebo group; no patients died.

The most common TRAEs in the groups receiving the IL-6 inhibitor were bilirubin in the urine (7-16%), hyperuricemia (7-10%), and increases in aspartate aminotransferase (3-10%).

Biomarker analyses showed a significant decline in fecal calprotectin from baseline to week 12 in the olamkicept groups, and an increase in the placebo group. No differences were seen in mean changes for neutrophil counts, platelet counts, C-reactive protein, rate of erythrocyte sedimentation, or levels of IL-6, soluble IL-6Ra, or the soluble IL-6R/IL-6 complex.

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