Dupilumab significantly reduced stomach eosinophilic inflammation and improved tissue and endoscopic signs of disease in patients with eosinophilic gastritis (EoG), according to results from the phase 2 DEGAS trial. Although patients did not report significantly greater symptom improvement than those receiving placebo over 12 weeks, The findings add randomized evidence supporting type 2 inflammation as a treatment target in a rare disease with no approved therapies..
“The findings support the allergic origin of EoG and the potential benefit of the study medicine dupilumab for EoG,” the study’s senior author, Marc E. Rothenberg, MD, PhD, of the division of allergy and immunology in the department of pediatrics at Cincinnati Children’s Hospital and Medical Center, told GI & Hepatology News.
The study, published in The Lancet Gastroenterology & Hepatology, enrolled 41 adolescents and adults ages 12-70 years with histologically active eosinophilic gastritis and moderate to severe symptoms at 11 US centers. Patients were randomly assigned to receive subcutaneous dupilumab or placebo for 12 weeks in a double-blind phase, followed by a 24-week open-label extension in which all participants received dupilumab.
Eligible patients had at least 30 eosinophils per high-power field in five stomach biopsy samples and ongoing symptoms, including abdominal pain, nausea, bloating, feeling full quickly, loss of appetite, vomiting, or diarrhea. Patients remained on stable background treatments, including dietary therapy or low-dose corticosteroids, throughout the study.
Twenty-one patients received dupilumab and 20 received placebo. One patient in the placebo group withdrew before week 12 because of worsening symptoms, leaving 40 patients in the primary efficacy analysis. Most participants were White, about two-thirds were female, and nearly half also had eosinophilic esophagitis.
The primary endpoint was the change in the average number of gastric eosinophils in the five biopsy samples with the highest eosinophil counts after 12 weeks. Dupilumab reduced eosinophil counts by an estimated 50% from baseline, compared with a 4% reduction with placebo, for a 47-percentage-point difference between the groups.
Several secondary objective endpoints also favored dupilumab. Patients who received dupilumab showed greater improvements in tissue inflammation, as measured by the Eosinophilic Gastritis Histologic Scoring System, larger reductions in gastric eosinophil counts, and greater improvement in endoscopic findings, as assessed with the Eosinophilic Gastritis Endoscopic Reference System.
By contrast, symptom improvement did not differ significantly between the groups. Overall symptom scores on the Eosinophilic Gastritis Symptom Questionnaire improved in both the dupilumab and placebo groups, but the difference between treatments was not statistically significant. Because the prespecified statistical analysis ended at this endpoint, the remaining symptom and patient-reported outcomes were summarized descriptively rather than formally tested.
Histologic remission, defined as fewer than 30 eosinophils per high-power field in each of the five most affected biopsy samples, was achieved by 24% of patients treated with dupilumab, compared with 11% of those who received placebo at week 12. Physician-rated disease severity and patients' overall assessments of their condition also improved more with dupilumab, although these outcomes were not formally tested under the study's statistical analysis plan.
The benefits appeared to last over time. Among patients who continued dupilumab during the 24-week open-label extension, improvements in gastric eosinophil counts, tissue inflammation, and endoscopic findings were maintained through week 36. Patients who switched from placebo to dupilumab showed similar improvements after starting active treatment.
Exploratory analyses suggested that dupilumab's effects may extend beyond reducing eosinophil counts. Post hoc analyses showed improvements in several microscopic features of the disease, including thickening of smooth muscle in the stomach lining. Molecular analyses also found favorable changes in patterns of gene activity linked to type 2 inflammation. Patients with higher levels of disease-related gene activity at baseline appeared to have larger biologic responses, although the study was not designed to confirm differences between subgroups.
“I was pleased to see so many of the endpoints positively affected by the study,” Dr. Rothenberg said. “We were surprised to discover that basic disease features at baseline distinguished patients that screen failed vs those that ended up randomized, such as elevated blood eosinophil levels.”
The safety findings were consistent with the known safety profile of dupilumab. Treatment-emergent adverse events occurred in 81% of patients who received dupilumab and 85% of those who received placebo during the double-blind phase. The most common adverse event was elevated blood eosinophil counts, which occurred in about 30% of patients in both groups. Injection-site reactions and nasal congestion were somewhat more common with dupilumab. No serious adverse events or treatment-related deaths were reported.
The investigators acknowledged several limitations. The proof-of-concept trial enrolled only 41 patients and was not designed to detect differences beyond the primary endpoint. No validated symptom questionnaire was available when the study was designed, making the patient-reported outcomes more difficult to interpret. Most participants were White, which may limit how well the findings apply to other populations, and the 12-week placebo-controlled phase was relatively short. In addition, endoscopic findings were scored at each study site rather than by a central reviewer, raising the possibility of differences between observers.
“This study provides proof-of-concept for the potential value of blocking type 2 immunity for the treatment of EoG,” Dr. Rothenberg said. “I am grateful to all of the different groups that came together to make this study happen, especially its execution in an extraordinary manner.”
Funding was provided by the National Institutes of Health, Regeneron Pharmaceuticals, and Sanofi. Dr. Rothenberg and several coauthors reported consulting relationships, research funding, employment, stock ownership, or other financial relationships with Regeneron, Sanofi, and other pharmaceutical companies developing therapies for eosinophilic gastrointestinal diseases.