Phase 3 study offers evidence on drug dosing for eosinophilic esophagitis

Greater improvements in the histological, symptomatic, endoscopic, and molecular features of eosinophilic esophagitis were seen with 24 weeks of weekly dupilumab treatment compared to placebo or using the drug every two weeks, an industry-funded study found.

Researchers conducted a three-part, double-blind, randomized, placebo-controlled, phase 3 study at 65 hospitals and private clinics in Australia, Canada, Europe, and the U.S. Patients were ages 12 years or older with a diagnosis of eosinophilic esophagitis by endoscopic biopsy from at least one esophageal region, despite eight weeks of high-dose proton-pump inhibitors (PPIs), and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline. Patients were randomized 1:1:1 to receive subcutaneous dupilumab, a fully human monoclonal antibody that blocks the receptor for IL-4 and IL-13, at a dose of 300 mg either weekly or every two weeks or weekly placebo until week 24. The study was funded by Sanofi and Regeneron Pharmaceuticals Inc. Eligible patients who received placebo and continued to the next part of the trial were re-randomized 1:1 to dupilumab weekly or every two weeks, with a regimen of alternating placebo and dupilumab doses. Results were published by The Lancet: Gastroenterology & Hepatology on Aug. 31.

From August 2019 and March 2021, 240 patients were randomized into the first part of the trial, and 227 continued into the next part. Thirty-seven patients switched from placebo to weekly dupilumab and 37 switched from placebo to dupilumab every two weeks. Seventy-four patients continued on weekly dupilumab, and 79 continued on dupilumab every two weeks. At week 52, 85% of patients who had been on weekly dupilumab the whole time had achieved a peak esophageal intraepithelial eosinophil count of 6 eosinophils/high-power field or less, compared to 68% in the placebo/weekly dupilumab group, 74% who had taken dupilumab every two weeks throughout, and 72% in the placebo/every two weeks dupilumab group. At week 52, mean percentage change from baseline in peak eosinophil count was –95.9% (95% CI, –96.9% to –94.9%), –84.2% (95% CI, –98.3% to –70.2%), –84.8% (95% CI, –94.3% to –75.2%) , and –91.2% (95% CI, –95.9% to –86.5%), respectively. Respective mean absolute changes in DSQ score were –30.3 points (95% CI, –34.5 to –26.1 points), –27.3 points (95% CI, –32.1 to –22.4 points), –20.9 points (95% CI, –25.4 to –16.3 points), and –23.7 points (95% CI, –29.1 to –18.3 points).

A few patients received rescue medication: one (3%) in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every two weeks dupilumab group. Other patients underwent a rescue esophageal dilation procedure: one (3%) in the placebo/every two weeks dupilumab group and one (1%) in the group receiving dupilumab every two weeks the whole time. The most common adverse events were injection-site reactions.

An editorial noted that not all patients initially responded to therapy, some needed longer treatment before reaching remission, and no data were available on esophageal distensibility measured by endoluminal functional lumen imaging probe.

“… [D]upilumab is an excellent therapeutic choice for difficult-to-treat patients with eosinophilic oesophagitis who are unresponsive to conventional therapy,” the editorial stated. “At the same time, it is important to underline that in this trial, the long-term efficacy of dupilumab was not compared against other therapies, as all patients received dupilumab after week 24. Another trial has shown clinical, endoscopic, and histological remission in up to 85% of patients treated with a novel formulation of orodispersible budesonide. Thus, whether dupilumab is superior to steroids remains unknown, as does the right positioning of the drug in the therapeutic algorithm of eosinophilic oesophagitis.”

ACP Internist covered eosinophilic esophagitis, which is uncommon but also underdiagnosed, in its September issue.