NASHVILLE, Tenn. — Adults and adolescents with eosinophilic esophagitis (EoE) treated once-monthly with the monoclonal antibody tezepelumab showed significant improvements in symptoms, histology, and endoscopic measures compared with placebo, according to findings from the phase 3 CROSSING trial.

The trial "met both co-primary endpoints, with tezepelumab every 4 weeks, demonstrating statistically significant and clinically meaningful improvements in histologic remission and DSQ [Dysphagia Symptom Questionnaire] scores versus placebo at week 24 and week 52," said first author Evan S. Dellon, MD, MPH, of the University of North Carolina School of Medicine, Chapel Hill.

EoE, a chronic inflammatory condition with symptoms of chest pain and potential food impaction, can cause significant morbidity in the upper gastrointestinal system, yet current standard medications often fail to adequately address symptoms for many patients, said Dellon, who presented the results here at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting. 

Tezepelumab is designed to block activity of thymic stromal lymphopoietin (TSLP), which plays a key role in the inflammation and is elevated in esophageal tissue in people with EoE, he noted. While the drug is approved in the treatment of asthma and chronic rhinosinusitis with nasal polyps, it has never been studied in the treatment of EoE.

The CROSSING Trial 

To evaluate the safety and efficacy of the drug in the treatment of EoE, Dellon and colleagues conducted the multicenter, double-blind CROSSING trial, enrolling 365 patients with symptomatic and histologically active EoE aged 12-80 years.

Patients with other gastrointestinal disorders, including inflammatory bowel diseases and active Helicobacter pylori infection, were excluded from the study.

The patients were randomized 1:1:1 to receive either tezepelumab 210 mg (n = 122), 420 mg (n = 122), or placebo (n = 121), in subcutaneous injections every 4 weeks for 52 weeks.

Participants had a mean age of about 35, 69% were male, and the mean time from diagnosis was about 5 years. About 12% of patients were adolescents, between the ages of 12 and 17. 

The majority of study participants (90%) had had prior treatment with proton pump inhibitors, 58% had had prior topical corticosteroid treatment, and 3.8% had had prior treatment with other biologics. 

At baseline, 43% were being treated with proton pump inhibitors. 

For the co-primary endpoint of histologic remission at week 24, the remission was achieved by 64.8% in the 210 mg tezepelumab group and 68.9% in the 420 mg group, vs just 3.5% in the placebo group (P < .001 for both vs placebo). 

At week 52, the rates of histologic remission were 67.8% in the 210 mg group and 63.3% in the 420 mg group vs 5.4% with placebo (P < .001 for both vs placebo).

For the co-primary outcome of change from baseline DSQ score, the least-squares (LS) mean change from baseline at week 24 was a reduction of 18.80 in the tezepelumab 210 mg group and a reduction of 22.02 in the 420 mg group, vs a reduction of 14.73 in the placebo group (P = .049 with 210 mg; P < .001 with 420 mg vs placebo).

The LS mean change from baseline to week 24 in the Endoscopic Reference Score (EREFS) was likewise more favorable for the 210 mg tezepelumab group (-3.59) and 420 mg group (-3.65) vs the placebo group (-0.21; P < .001 for both). 

Tezepelumab also showed a clinically meaningful reduction in the EoE histology scoring system (HSS) grade score, with a reduction at 24 weeks of 0.9 in the 210 mg group and 0.9 in the 420 mg group, vs no reduction in the placebo group (P < .001 for both vs placebo).

Furthermore, both dose groups showed a reduction of 0.9 in EoE HSS stage scores, vs a reduction of 0.1 in the placebo group (P < .001 for both vs placebo).

There were no significant differences in the incidence of adverse events and serious adverse events between the two tezepelumab groups and placebo.

"Tezepelumab was generally well tolerated with comparable incidences of adverse events and serious adverse events for tezepelumab and placebo, consistent with the established safety profile of tezepelumab," Dellon said.

"The study met all key secondary endpoints for both tezepelumab doses at week 52," he added.

'Meaningful' Symptom Benefit 

Commenting on the study, Joy W. Chang, MD, an assistant professor of medicine in the Division of Gastroenterology at Michigan Medicine, the University of Michigan, in Ann Arbor, called the results "highly encouraging."

"The symptom benefit seen here is particularly meaningful because we've seen from trials of other biologics that reducing eosinophils alone doesn't necessarily translate into durable symptom benefit," she told Medscape Medical News. 

The role of tezepelumab as the first biologic of its class, targeting TSLP, "is important as a potential new option for patients, but also for how we understand the disease," Chang added.

"Since TSLP is an epithelial alarmin upstream to Th2 inflammatory pathways, we're expanding our understanding of EoE not only as an eosinophil disorder or a Th2-mediated disease," but as a disease of "epithelial-immune interactions where epithelial cells are active participants in immune regulation," she explained. 

While only head-to-head trials can show how tezepelumab may compare with other therapies for EoE, "what stands out here is the consistency across histologic, endoscopic, and symptomatic outcomes and the durability through one year," Chang said.

"If the full data hold up, this could become an important new option for patients, while also strengthening the case that TSLP is a key driver of EoE," she said.

"The once-every-4-week dosing could also be attractive compared with daily proton pump inhibitors, topical steroid use, or weekly dupilumab," she noted. "However, these data don't establish where to position tezepelumab in our current treatment algorithm."

EoE is a relatively new and chronic disease, and effective treatment is still a "substantial unmet need," Chang said. "Having an additional treatment option with a different mechanism and dosing frequency could be valuable for patients who don't respond to current first-line treatments, struggle to sustain their current regimens, or have complications that require changing therapies."

Dellon's disclosures include consulting and/or other relationships with: AbbVie, Adare Pharmaceuticals/Ellodi Pharmaceuticals, Alfasigma Global, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics, Aqilion, Arena Pharmaceuticals/Pfizer, AstraZeneca, Bethanamist, BioCryst Pharmaceuticals, Bryn Pharma, Calypso Biotech, Celgene/Receptos/BMS, Celldex, Cyted Health, Domain Therapeutics, Dr. Falk Pharma, EsoCap Biotech, Eupraxia, Ferring, GI Reviewers, GSK, Holoclara, Invea, Knightpoint, Kymera, LucidDx, Meritage Pharma, Miraca Life Sciences, Nexstone Immunology/Uniquity Bio, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts Clinical Trials/Alimentiv, Roivant, Sanofi, Takeda, Target RWE, Third Harmonic Bio, Uniquity, Upstream Bio. Chang has served as a consultant for Amgen/AstraZeneca before, but was not a principal investigator for this trial. She has also served as a consultant for Sanofi-Regeneron, Takeda, and Apogee Therapeutics/AbbVie.