The excellent news: a monoclonal antibody treatment called benralizumab proved quite effective in a clinical trial at depleting the variety of eosinophils present in the blood and digestive tract tissues of patients with eosinophilic gastritis.

The not-so-good news: eliminating eosinophils was not enough to stop the symptoms people feel with this unusual and severe type of food allergy. Nor did the treatment affect key measures of gut tissue health and related gene expression patterns.

These paradigm-shifting Phase 2 clinical trial results were published online June 16, 2023, in The Lancet Gastroenterology & Hepatology.

“Our findings suggest that the mechanisms driving this disease are largely independent of excessive eosinophil production. Meaning our attention should turn towards other therapeutic targets to seek out curative treatments and that how we define remission for this disease must be reconsidered,” says Marc Rothenberg, MD, PhD, corresponding creator for the study and certainly one of the world’s foremost authorities on eosinophilic gastrointestinal disorders (EGID).

Rothenberg directs the Division of Allergy and Immunology at Cincinnati Kid’s. He also leads the Cincinnati Center for Eosinophilic Disorders (CCED) at Cincinnati Kid’s and serves as principal investigator and co-leader of the national Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

Rothenberg has devoted a long time to studying and treating children living with this collection of severe inflammatory reactions to otherwise common foods. For a lot of, the allergic reactions are so strong that they need to follow extremely strict and limited diets. The eating difficulties can limit growth and result in other longer-term complications.

What are EGIDs?

EGIDs have been distinguished from other food allergies because symptoms typically don’t occur immediately after consuming the offending food. Patients with EGID have abnormally high levels of eosinophils of their digestive tract tissues. Eosinophils are certainly one of several kinds of white blood cells which are a part of our normally protective immune system. But they occur in high amounts in certain diseases corresponding to EGID and asthma. Within the case of asthma, eosinophils can promote excessive inflammation and tissue damage and reducing their levels can have substantial clinical profit. But the precise role of eosinophils in EGID has not yet been determined.

Eosinophilic esophagitis (EoE) is essentially the most common EGID, affecting an estimated 1 in 2,000 people (or about 166,000 people within the US). Lower than 50,000 people within the US, combined, are believed to produce other EGIDs including eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis.

Over time, eosinophil counts have emerged as the important thing biomarker for tracking the severity of EGID. Pharmaceutical firms even have been testing recent and existing biologics and other treatments for his or her ability to cut back eosinophil counts. Benralizumab, made by AstraZeneca, is one such drug, because it safely removes eosinophils from the body and is now approved therapy for severe asthma related to eosinophils.

Mixed results for eosinophil-depleting drug

The study conducted by Kara Kliewer, PhD, Rothenberg, and their colleagues involved 26 patients with lively eosinophilic gastritis disease, ages 12 to 60, who were randomly assigned to receive either the treatment drug or a placebo. Participants received three injections each across 12 weeks.

Of the 13 who received the drug, 10 achieved technical “remission.” Meaning the variety of eosinophils of their blood and stomach dropped substantially, the truth is, almost to zero.

Nonetheless, there have been no statistically significant differences in symptoms including pain, endoscopic findings, quality of life scores, or other measures reported between the drug and placebo groups. Although structural tissue abnormalities improved for six of the 13 drug-treated participants, they worsened or remained the identical for the opposite seven. Meanwhile, an evaluation of 48 genes known to be affected by eosinophilic disorders showed no improvement in abnormal expression patterns.

“These findings provide compelling evidence for a modified paradigm, shifting attention away from eosinophils because the major contributor and biomarker in eosinophilic gastrointestinal diseases,” says Kliewer. “Thus, successful management of eosinophilic gastritis may require inhibiting pathways that more broadly reduce type 2 inflammation moderately than only targeting eosinophils.”

What does this mean for patients and families?

Mostly, these results suggest that patients can have to attend longer for improved treatments to be developed for eosinophilic gastritis, Rothenberg says. Nonetheless, our Cincinnati Kid’s research team’s multiprong research approach implies that several other treatment avenues were already being pursued in parallel to eosinophil-depleting possibilities.

Current standard treatments, corresponding to weight loss plan management, anti-inflammatory steroid medications and pain relievers, should proceed. If patients are receiving off-label treatments with IL-5 blockers (eosinophil-depleting drugs), they usually are not more likely to see significant advantages, Rothenberg says.

Families with specific questions are encouraged to contact the specialist managing their child’s care.

Next steps

Researchers are more likely to shift their focus to accentuate studying therapies that act against other facets of eosinophilic disease.

In 2022, the US Food and Drug Administration approved the usage of dupilumab-;a drug already approved for treating eczema and asthma–as the primary treatment specifically approved within the US for EoE. This drug, also a monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, thus targeting type 2 inflammation moderately than simply eosinophils.

Rothenberg was a co-first creator of the study that laid out the Phase 3 clinical trial results, which were published in The Recent England Journal of Medicine. The symptom improvement seen in dupilumab- treated patients with EoE suggests that it might also work for the opposite less common types of EGID. Through CEGIR, Rothenberg and other national experts are currently testing the speculation that dupilumab could also be helpful for other types of EGID, corresponding to eosinophilic gastritis.

Meanwhile, Rothenberg says CEGIR is using the present findings to revise practice guidelines for EGID treatment in order that they rely less heavily on eosinophil counts as a biomarker.

“Many individuals had high hopes that depleting eosinophils would make a big impact on EGIDs, but for this reason clinical trials are so essential,” Rothenberg says. “Even when results are disappointing, we learn from them and that enables us to maneuver on to other potential approaches to enhance outcomes.”

About this study

Along with Rothenberg, Cincinnati Kid’s co-authors for this study included first creator Kara Kliewer, PhD, Cristin Murray-Petzold, BS, Margaret Collins, MD, Juan Abonia, MD, Scott Bolton, MD, Lauren DiTommaso, BS, Lisa Martin, MD, Xue Zhang, MD, Vincent Mukkada, MD, Philip Putnam, MD, Erinn Kellner, MD, Ashley Devonshire, MD, Justin Schwartz, MD, Chen Rosenberg, MD, John Lyles, MD, and Tetsuo Shoda, MD.

Co-authors also included Vidhya Kunnathur, MD, from the University of Cincinnati College of Medicine, and Amy Klion, MD, with the National Institute of Allergy and Infectious Disease (NIAID).

This study was funded primarily by AstraZeneca.

Source:

Cincinnati Kid’s Hospital Medical Center

Journal reference:

Kliewer, K. L., et al. (2023) Benralizumab for eosinophilic gastritis: A phase 2, randomized, double-blind, placebo-controlled trial. The Lancet Gastroenterology & Hepatology. doi.org/10.1016/S2468-1253(23)00145-0.