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

Ikuo Hirano; Evan S. Dellon; Jennifer D. Hamilton; Margaret H. Collins; Kathryn Peterson; Mirna Chehade; Alain M. Schoepfer; Ekaterina Safroneeva; Marc E. Rothenberg; Gary W. Falk; Yehudith Assouline-Dayan; Qiong Zhao; Zhen Chen; Brian N. Swanson; Gianluca Pirozzi; Leda Mannent; Neil M.H. Graham; Bolanle Akinlade; Neil Stahl; George D. Yancopoulos; Allen Radin

doi:10.1053/j.gastro.2019.09.042

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

Ikuo Hirano^*, Evan S. Dellon, Jennifer D. Hamilton, Margaret H. Collins, Kathryn Peterson, Mirna Chehade, Alain M. Schoepfer, Ekaterina Safroneeva, Marc E. Rothenberg, Gary W. Falk, Yehudith Assouline-Dayan, Qiong Zhao, Zhen Chen, Brian N. Swanson, Gianluca Pirozzi, Leda Mannent, Neil M.H. Graham, Bolanle Akinlade, Neil Stahl, George D. YancopoulosAllen Radin

^*Corresponding author for this work

Medicine, Gastroenterology Division

Research output: Contribution to journal › Article › peer-review

322 Scopus citations

Abstract

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,

Original language	English (US)
Pages (from-to)	111-122.e10
Journal	Gastroenterology
Volume	158
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2019.09.042
State	Published - Jan 2020

Funding

Funding This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Conflicts of interest These authors disclose the following: Ikuo Hirano has been a consultant for Adare, Allakos, Receptos/Celgene, Regeneron Pharmaceuticals, Shire, Gossamer, Esocap and has received research funding from Adare, Allakos, Meritage, Receptos/Celgene, Regeneron Pharmaceuticals, and Shire. Evan S. Dellon has been a consultant for Alivio, Adare, Allakos, Banner, Calypso, Enumeral, EsoCap, GlaxoSmithKline, Receptos/Celgene, Regeneron Pharmaceuticals, Robarts, and Shire; has received research funding from Adare, Allakos, Meritage, Miraca, Nutricia, Receptos/Celgene, Regeneron Pharmaceuticals, and Shire; and received educational grants from Banner and Holoclara. Jennifer D. Hamilton, Qiong Zhao, Zhen Chen, Neil N. M. Graham, Bolanle Akinlade, and Allen Radin are employees and shareholders of Regeneron Pharmaceuticals. Margaret H. Collins has been a consultant for Allakos, Receptos/Celgene, Regeneron Pharmaceuticals, and Shire and has received research funding from Receptos/Celgene, Regeneron Pharmaceuticals, and Shire. Kathryn Peterson has received research funding from Janssen, Receptos/Celgene, and Regeneron Pharmaceuticals. Mirna Chehade has been a consultant for Actelion, Allakos, and Shire and received research funding from Nutricia, Regeneron Pharmaceuticals, and Shire. Alain M. Schoepfer has been a consultant for Adare, Aptalis, Dr Falk Pharma, and Regeneron Pharmaceuticals and has received research funding from AstraZeneca, Aptalis, Dr Falk Pharma, GlaxoSmithKline, Nestlé, Novartis, Receptos/Celgene, and Regeneron Pharmaceuticals. Ekaterina Safroneeva has been a consultant for Aptalis, Novartis, Receptos/Celgene, and Regeneron Pharmaceuticals. Marc E. Rothenberg has been a consultant for AstraZeneca, Celgene, GlaxoSmithKline, NKT Therapeutics, Novartis, PulmOne, Shire, and Spoon Guru; holds equity interest in Immune Pharmaceuticals, NKT Therapeutics, PulmOne, and Spoon Guru; receives royalties from reslizumab from Teva Pharmaceutical; and is the inventor of patents owned by Cincinnati Children's Hospital Medical Center. Gary W. Falk has received research funding from Allakos; has been a consultant for Adare and Banner; and has received research funding from Adare, Meritage, Receptos/Celgene, Regeneron Pharmaceuticals, and Shire. Gianluca Pirozzi and Leda Mannent L are employees of Sanofi and may hold stock and/or stock options in the company. Brian N. Swanson is a former employee of Sanofi and may hold stock and/or stock options in the company. The remaining author discloses no conflicts. Funding This research was sponsored by Sanofi and Regeneron Pharmaceuticals,Inc .

Keywords

EREFS
Esophagus
Food Allergy
HSS

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1053/j.gastro.2019.09.042

Cite this

Hirano, I., Dellon, E. S., Hamilton, J. D., Collins, M. H., Peterson, K., Chehade, M., Schoepfer, A. M., Safroneeva, E., Rothenberg, M. E., Falk, G. W., Assouline-Dayan, Y., Zhao, Q., Chen, Z., Swanson, B. N., Pirozzi, G., Mannent, L., Graham, N. M. H., Akinlade, B., Stahl, N., ... Radin, A. (2020). Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. Gastroenterology, 158(1), 111-122.e10. https://doi.org/10.1053/j.gastro.2019.09.042

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title = "Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis",

abstract = "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,",

keywords = "EREFS, Esophagus, Food Allergy, HSS",

author = "Ikuo Hirano and Dellon, {Evan S.} and Hamilton, {Jennifer D.} and Collins, {Margaret H.} and Kathryn Peterson and Mirna Chehade and Schoepfer, {Alain M.} and Ekaterina Safroneeva and Rothenberg, {Marc E.} and Falk, {Gary W.} and Yehudith Assouline-Dayan and Qiong Zhao and Zhen Chen and Swanson, {Brian N.} and Gianluca Pirozzi and Leda Mannent and Graham, {Neil M.H.} and Bolanle Akinlade and Neil Stahl and Yancopoulos, {George D.} and Allen Radin",

note = "Publisher Copyright: {\textcopyright} 2020 AGA Institute",

year = "2020",

month = jan,

doi = "10.1053/j.gastro.2019.09.042",

language = "English (US)",

volume = "158",

pages = "111--122.e10",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "1",

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Hirano, I, Dellon, ES, Hamilton, JD, Collins, MH, Peterson, K, Chehade, M, Schoepfer, AM, Safroneeva, E, Rothenberg, ME, Falk, GW, Assouline-Dayan, Y, Zhao, Q, Chen, Z, Swanson, BN, Pirozzi, G, Mannent, L, Graham, NMH, Akinlade, B, Stahl, N, Yancopoulos, GD & Radin, A 2020, 'Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis', Gastroenterology, vol. 158, no. 1, pp. 111-122.e10. https://doi.org/10.1053/j.gastro.2019.09.042

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,

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,

KW - EREFS

KW - Esophagus

KW - Food Allergy

KW - HSS

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

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UN SDGs

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