A broader search is needed to improve eosinophilic food allergy outcomes

The good news: a monoclonal antibody treatment called benralizumab has been shown to be moderately effective in clinical trials at reducing the number of eosinophils found in the blood and digestive tract tissues of patients with eosinophilic gastritis.

Not so good news: Eliminating eosinophils isn’t enough to stop the symptoms people with this uncommon and severe form of food allergy feel. Treatment also did not affect key measures of gut tissue health and associated gene expression patterns.

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

“Our findings suggest that the mechanisms driving this disease are largely independent of overproduction of eosinophils. That means our attention must turn to other therapeutic targets to find a curative treatment and how we define remission for this disease must be reconsidered,” said Marc Rothenberg, MD, PhD, corresponding author of the study and one of the world’s leading authorities on eosinophilia. gastrointestinal disorders (EGID).

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

Rothenberg has devoted decades to studying and treating children living with this collection of severe inflammatory reactions to ordinary foods. For many people, the allergic reaction is so strong that they have to follow a very strict and restricted diet. Feeding difficulties can limit growth and cause other long-term complications.

What is EGID?

EGID has been distinguished from other food allergies in that symptoms usually do not appear immediately after ingestion of the offending food. Patients with EGID have very high levels of eosinophils in their digestive tract tissue. Eosinophils are one of several types of white blood cells that are part of our normally protective immune system. But they occur in high numbers in certain diseases such as EGID and asthma. In the case of asthma, eosinophils can promote excessive inflammation and tissue damage and reducing their levels can provide great clinical benefit. But the exact role of eosinophils in EGID has not been determined.

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

Over the years, eosinophil count has emerged as a key biomarker for tracking EGID severity. Pharmaceutical companies have also tested new and existing biologic drugs and other treatments for their ability to reduce eosinophil counts. Benralizumab, made by AstraZeneca, is one such drug, as it safely removes eosinophils from the body and is now an approved therapy for severe eosinophil-associated asthma.

Mixed results for eosinophil depletion drugs.

The study by Kara Kliewer, PhD, Rothenberg, and their colleagues involved 26 patients with active eosinophilic gastritis, ages 12 to 60 years, who were randomly assigned to receive either a medication or a placebo. Participants received three injections each over 12 weeks.

Of the 13 who received the drug, 10 achieved technical “remission”. That means the number of eosinophils in their blood and stomach drops drastically, to almost zero.

However, no statistically significant differences in symptoms including pain, endoscopy findings, quality of life scores, or other measures were reported between the drug and placebo groups. Although the structural tissue abnormalities improved for six of the 13 drug-treated participants, they worsened or stayed the same for the other seven. Meanwhile, an analysis of 48 genes known to be affected by eosinophilic disorders did not show any improvement in the abnormal expression patterns.

“These findings provide strong evidence for a paradigm shift, shifting attention away from eosinophils as major contributors and biomarkers in eosinophilic gastrointestinal disease,” said Kliewer. “Thus, the successful management of eosinophilic gastritis may require inhibition pathways that more broadly reduce type 2 inflammation rather than targeting only eosinophils.”

What does this mean for patients and families?

In large part, these results suggest that patients will have to wait longer to develop better treatments for eosinophilic gastritis, Rothenberg said. However, our Cincinnati Children’s research team’s multi-pronged research approach means that several other treatment avenues have been pursued in parallel with the possible depletion of eosinophils.

Current standard treatments, such as diet management, anti-inflammatory steroid medications, and pain relief, should be continued. If patients receive off-label treatment with IL-5 blockers (eosinophil-thinning drugs), they won’t see a significant benefit, says Rothenberg.

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

The next step

Researchers are likely to shift their focus to intensifying studies of therapies that act against other aspects of eosinophilic disease.

In 2022, the US Food and Drug Administration approved the use of dupilumab—a drug already approved to treat eczema and asthma—as the first treatment specifically approved in the US for EoE. This drug, also a monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, thereby targeting type 2 inflammation rather than just eosinophils.

Rothenberg is one of the authors of the study presenting the results of the Phase 3 clinical trial, which was published in New England Journal of Medicine. The symptom improvement seen in patients treated with dupilumab with EoE suggests that it may also work for other, less common forms of EGID. Through CEGIR, Rothenberg and other national experts are testing the theory that dupilumab may be useful for other forms of EGID, such as eosinophilic gastritis.

Meanwhile, Rothenberg said CEGIR is using the current findings to revise its EGID treatment practice guidelines so they rely less on eosinophil count as a biomarker.

“Many people have high hopes that depletion of eosinophils will have a major impact on EGID, but this is why clinical trials are so important,” said Rothenberg. “Even when results are disappointing, we learn from them and that allows us to move on to other potential approaches to improve results.”

About this study

In addition to Rothenberg, Cincinnati Children’s co-authors for the study included first author 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 include Vidhya Kunnathur, MD, of the University of Cincinnati College of Medicine, and Amy Klion, MD, of the National Institute of Allergy and Infectious Disease (NIAID).

This study was funded primarily by AstraZeneca.