Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Background: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B–C). Methods: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B–C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. Findings: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B–C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B–C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was –95·9% (95% CI –96·9 to –94·9) in the weekly dupilumab/weekly dupilumab group, –84·2% (–98·3 to –70·2) in the placebo/weekly dupilumab group, –84·8% (–94·3 to –75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and –91·2% (–95·9 to –86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was –1·0 point (95% CI –1·1 to –0·9) in the weekly dupilumab/weekly dupilumab group and –0·9 points (–1·0 to –0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was –0·9 points (–1·0 to –0·8) in the weekly dupilumab/weekly dupilumab group and –0·9 points (–1·0 to –0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was –30·3 points (95% CI –34·5 to –26·1) in the weekly dupilumab/weekly dupilumab group, –27·3 points (–32·1 to –22·4) in the placebo/weekly dupilumab group, –20·9% (–25·4 to –16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and –23·7% (–29·1 to –18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was –5·4 points (95% CI –6·1 to –4·6) in the weekly dupilumab/weekly dupilumab group, –6·1 points (–7·3 to –4·9) in the placebo/weekly dupilumab group, –5·2% (–6·0 to –4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and –4·3% (–5·4 to –3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B–C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). Interpretation: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. Funding: Sanofi and Regeneron Pharmaceuticals Inc.