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
N1 - Funding Information:
Principal investigators: Oral Alpan, MD, Robert Hardi, MD, John Leung, MD, John Wo, MD, Charles Barish, MD, Glen Gordon, MD, John Garber, MD, Benjamin Mitlyng, MD, Tom Whitlock, MD, and Paul Hendrix, MD. Regeneron Pharmaceuticals, Inc, employees: Linda Williams, RPh, Marcella Ruddy, MD, Usman Chaudhry, Andrew Korotzer, PhD, Joseph Elassal MD, Richard Wu, PhD, Jingdong Chao, PhD, and Dharani Ajithdoss, DVM, MS, PhD. Sanofi employees: Dianne Barry, PhD, Paul Rowe, MD, and Heribert Staudinger, MD, PhD. Writing assistance: The authors received writing/editorial support in the preparation of this manuscript provided by Jennifer L. F. Port, PhD, and Xiomara V. Thomas, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Author contributions: Ikuo Hirano, Evan S. Dellon, Jennifer D. Hamilton, and Allen Radin: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content. Margaret H. Collins, Kathryn Peterson, Mirna Chehade, Alain M. Shoepfer, Ekaterina Safroneeva, and Marc E. Rothenberg: study concept and design, acquisition of data, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content. Gary W. Falk and Yehudith Assouline-Dayan: acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content. Qiong Zhao and Zhen Chen: statistical analysis, analysis, and interpretation of data; critical revision of the manuscript for important intellectual content. Brian N. Swanson, Gianluca Pirozzi, Leda Mannent, Neil M. H. Graham: analysis and interpretation of data, critical revision of the manuscript for important intellectual content. Bolanle Akinlade, Neil Stahl, George D. Yancopoulos: acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
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
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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 -