Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis

TY - JOUR

T1 - Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis

AU - Hirano, Ikuo

AU - Dellon, Evan S.

AU - Hamilton, Jennifer D.

AU - Collins, Margaret H.

AU - Peterson, Kathryn

AU - Chehade, Mirna

AU - Schoepfer, Alain M.

AU - Safroneeva, Ekaterina

AU - Rothenberg, Marc E.

AU - Falk, Gary W.

AU - Assouline-Dayan, Yehudith

AU - Zhao, Qiong

AU - Chen, Zhen

AU - Swanson, Brian N.

AU - Pirozzi, Gianluca

AU - Mannent, Leda

AU - Graham, Neil M.H.

AU - Akinlade, Bolanle

AU - Stahl, Neil

AU - Yancopoulos, George D.

AU - Radin, Allen

PY - 2020/1

Y1 - 2020/1

N2 - Background & Aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. Methods: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. Results: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P =. 0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P <. 0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P <. 0001 vs placebo), and the endoscopic reference score by 1.6 (P =. 0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P <. 0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052

AB - Background & Aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. Methods: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. Results: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P =. 0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P <. 0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P <. 0001 vs placebo), and the endoscopic reference score by 1.6 (P =. 0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P <. 0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052

KW - EREFS

KW - Esophagus

KW - Food Allergy

KW - HSS

UR - http://www.scopus.com/inward/record.url?scp=85076252562&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076252562&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2019.09.042

DO - 10.1053/j.gastro.2019.09.042

M3 - Article

C2 - 31593702

AN - SCOPUS:85076252562

VL - 158

SP - 111-122.e10

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -