In a phase 2 trial in eosinophilic gastritis and duodenitis, an anti–Siglec-8 antibody greatly reduced populations of eosinophilic cells, and also led to improved symptoms. The sponsoring company, Alkalos, is currently conducting a phase 3 trial in eosinophilic gastritis or duodenitis and a phase 2-3 trial in eosinophilic esophagitis.
The news is welcome to clinicians who treat these rare conditions, since the only current treatment option is steroids. This is particularly challenging because most patients with these conditions present in their 30s and 40s, according to Carol Semrad, MD, professor of medicine at the University of Chicago, who was asked to comment on the study. She noted that the study’s results were impressive, but it will take a phase 3 trial to convince. It’s also unclear if the clinical benefit tracks with the impressive reduction seen in eosinophil count. “There’s somewhat of a disconnect between symptom reduction and reduction of the eosinophil counts. Sometimes just blocking the inflammation [isn’t enough]. Maybe there is other damage to the bowel.”
Still, “it looks like they have a proof of concept that it’s very effective at blocking the eosinophils and mast cells that are thought to be causing eosinophilic gastritis and duodenitis in human disease. That, along with improvement in symptoms, is highly promising, given that we have no other treatment beside steroids,” said Dr. Semrad.
The research, led by Evan S. Dellon, MD, MPH, of the University of North Carolina at Chapel Hill, and Ikuo Hirano, MD, of Northwestern University, Chicago, appeared in the.
The antibody (lirentelimab) targets sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8), which is an inhibitory receptor found on mature eosinophils and mast cells, and expressed at low levels on basophils. The antibody reduces eosinophil population through natural killer cell-mediated cellular cytotoxicity and apoptosis, and other antibodies against the same target have been shown to inhibit activation of mast cells.
At 22 sites across the United States, researchers randomized 65 adults with active, uncontrolled eosinophilic gastritis or eosinophilic duodenitis, or both, to receive four monthly low doses (0.3, 1, 1, and 1 mg/kg) or high-dose lirentelimab (0.3, 1, 3, and 3 mg/kg), or placebo. A total of 10 patients had gastritis, 25 had duodenitis, and 30 had both.
In the intention-to-treat analysis, there was a mean 86% reduction in eosinophil count in patients in the treatment groups, compared with a 9% increase in controls (P < .001). In the per-protocol analysis, there was a 95% reduction versus a 10% increase (P < .001). Of treated patients, 95% had a gastrointestinal eosinophil count of 6 or fewer per high-powered field, compared with 0% in the placebo group.
In the intention-to-treat analysis, 63% of treated patients experienced a treatment response, defined as at least a 30% reduction in total symptom score and at least a 75% reduction in eosinophil count. About 5% of patients had a response in the placebo group (P < .001). The mean percentage change in total symptom score was –48 versus –22 in the placebo group (P = .004). In the per-protocol analysis, 69% responded versus 5% (P < .001). The mean percentage change in total symptom score was –53 versus –24 (P = .001).
91% of patients in the treatment groups experienced at least one adverse event, compared with 82% in the placebo group. About 60% in the treatment group had an infusion-related reaction versus 23% who received placebo; 93% of reactions were mild to moderate. Serious adverse events occurred in 9% of the treatment group and 14% of patients on placebo. The only serious adverse event thought to be related to the drug was a single grade 4 infusion-related event in the high-dose treatment group, which led to discontinuation of the drug and withdrawal from the trial. 86% of patients in the treatment group experienced transient lymphopenia, as did 47% of the placebo group, but there were no clinical consequences.
One potential concern with the therapy is the effect that long-term suppression of eosinophils and mast cells, and to a lesser extent basophils, could have on the immune system. Eosinophils are key to defenses against parasites, so that will need to be looked at in further studies, according to Dr. Semrad: “How is blocking those inflammatory cells going to impact gut function and the ability to fight off certain organisms? That’s going to be one of the real questions.”
The study was funded by Alkalos. Dr. Semrad has no relevant financial disclosures.
SOURCE: Dellon ES et al. N Engl J Med. 2020 Oct 22. .