Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Emma Guttman-Yassky; Robert Bissonnette; Benjamin Ungar; Mayte Suárez-Fariñas; Marius Ardeleanu; Hitokazu Esaki; Maria Suprun; Yeriel Estrada; Hui Xu; Xiangyu Peng; Jonathan I. Silverberg; Alan Menter; James G. Krueger; Rick Zhang; Usman Chaudhry; Brian Swanson; Neil M.H. Graham; Gianluca Pirozzi; George D. Yancopoulos; Jennifer D. Jennifer

doi:10.1016/j.jaci.2018.08.022

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Emma Guttman-Yassky^*, Robert Bissonnette, Benjamin Ungar, Mayte Suárez-Fariñas, Marius Ardeleanu, Hitokazu Esaki, Maria Suprun, Yeriel Estrada, Hui Xu, Xiangyu Peng, Jonathan I. Silverberg, Alan Menter, James G. Krueger, Rick Zhang, Usman Chaudhry, Brian Swanson, Neil M.H. Graham, Gianluca Pirozzi, George D. Yancopoulos, Jennifer D. Jennifer

^*Corresponding author for this work

Dermatology

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

489 Scopus citations

Abstract

Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and T_H17/T_H22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

Original language	English (US)
Pages (from-to)	155-172
Number of pages	18
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2018.08.022
State	Published - Jan 2019

Funding

Research was sponsored by Sanofi and Regeneron Pharmaceuticals . Editorial assistance was funded by Sanofi Genzyme and Regeneron Pharmaceuticals . Disclosure of potential conflict of interest: E. Guttman-Yassky has been an investigator for AbbVie, Celgene, Eli Lilly, GlaxoSmithKline, Regeneron-Sanofi, Leo Pharma, Pfizer, Galderma, and Glenmark; has been a consultant for Abbvie, Anacor, Eli Lilly, Galderma, GlaxoSmithKline, Leo Pharma, Menlo Therapeutics, Kiniksa, Pfizer, Realm, Regeneron-Sanofi, Asana Biosciences, DBV, Kyowa, Daiichi Sankyo, Glenmark, Novartis, and Dermira; and has received grants from Regeneron/Sanofi, Pfizer, Galderma, Janssen, Celgene, Novartis, Dermira, AbbVie, Innovaderm, and Leo Pharma. R. Bissonnette has been an investigator, consultant, advisory board member, and speaker and/or receives honoraria from Aquinox Pharma, Antiobix, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GlaxoSmithKline-Stiefel, Hoffman-LaRoche Ltd, Leo Pharma, Neokera, Pfizer, Regeneron, and Vitae and is also a shareholder of Innovaderm Research. M. Suárez-Fariñas has been an investigator for Pfizer, Quorum, Regeneron, and Genisphere and a consultant for DBV and NEA. M. Ardeleanu, R. Zhang, U. Chaudhry, N. M. H. Graham, G. D. Yancopoulos, and J. D. D. Hamilton are employees and shareholders of Regeneron Pharmaceuticals. J. I. Silverberg has been an investigator for AbbVie, Celgene, Chugai, Eli Lilly, GlaxoSmithKline, and Regeneron-Sanofi; a consultant for AbbVie, Anacor, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Leo, Menlo, Kiniksa, Pfizer, Realm, and Regeneron-Sanofi; and a speaker for Regeneron-Sanofi. A. Menter has been an advisory board participant, consultant, investigator, and speaker for and received grants and honoraria from Abbvie, Amgen, Janssen Biotech, and LEO Pharmaceuticals; has been an advisory board participant, consultant, and investigator for and received grants and honoraria from Allergan; has been an advisory board participant and investigator for and received grants and honoraria from Boehringer Ingelheim; has been a consultant and investigator for and received grants and honoraria from Novartis, Pfizer, and XenoPort; has been an investigator for and received grants from Anacor, Celgene, Dermira, Merck, Neothetics, Regeneron Pharmaceuticals, and Symbio/Maruho; has been an advisory board participant, consultant, and investigator for and received honoraria from Eli-Lilly; and has been a consultant for and received honoraria from Galderma and Vitae. J. G. Krueger has been a consultant for and received grants paid to his institution by Amgen, BMS, Boehringer, Dermira, Innovaderm, Janssen, Kadmon, Kyowa, Lilly, Merck, Novartis, Paraxel, and Pfizer; has been a consultant for and recipient of personal fees from AbbVie, Baxter, BiogenIdec, Delenex, Kineta, Sanofi, Serono, and Xenoport; and has been an investigator for Regeneron Pharmaceuticals. B. Swanson and G. Pirozzi are employees and might hold stock and/or stock options in Sanofi. The rest of the authors declare that they have no relevant conflicts of interest. Research was sponsored by Sanofi and Regeneron Pharmaceuticals. Editorial assistance was funded by Sanofi Genzyme and Regeneron Pharmaceuticals.Disclosure of potential conflict of interest: E. Guttman-Yassky has been an investigator for AbbVie, Celgene, Eli Lilly, GlaxoSmithKline, Regeneron-Sanofi, Leo Pharma, Pfizer, Galderma, and Glenmark; has been a consultant for Abbvie, Anacor, Eli Lilly, Galderma, GlaxoSmithKline, Leo Pharma, Menlo Therapeutics, Kiniksa, Pfizer, Realm, Regeneron-Sanofi, Asana Biosciences, DBV, Kyowa, Daiichi Sankyo, Glenmark, Novartis, and Dermira; and has received grants from Regeneron/Sanofi, Pfizer, Galderma, Janssen, Celgene, Novartis, Dermira, AbbVie, Innovaderm, and Leo Pharma. R. Bissonnette has been an investigator, consultant, advisory board member, and speaker and/or receives honoraria from Aquinox Pharma, Antiobix, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GlaxoSmithKline-Stiefel, Hoffman-LaRoche Ltd, Leo Pharma, Neokera, Pfizer, Regeneron, and Vitae and is also a shareholder of Innovaderm Research. M. Su?rez-Fari?as has been an investigator for Pfizer, Quorum, Regeneron, and Genisphere and a consultant for DBV and NEA. M. Ardeleanu, R. Zhang, U. Chaudhry, N. M. H. Graham, G. D. Yancopoulos, and J. D. D. Hamilton are employees and shareholders of Regeneron Pharmaceuticals. J. I. Silverberg has been an investigator for AbbVie, Celgene, Chugai, Eli Lilly, GlaxoSmithKline, and Regeneron-Sanofi; a consultant for AbbVie, Anacor, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Leo, Menlo, Kiniksa, Pfizer, Realm, and Regeneron-Sanofi; and a speaker for Regeneron-Sanofi. A. Menter has been an advisory board participant, consultant, investigator, and speaker for and received grants and honoraria from Abbvie, Amgen, Janssen Biotech, and LEO Pharmaceuticals; has been an advisory board participant, consultant, and investigator for and received grants and honoraria from Allergan; has been an advisory board participant and investigator for and received grants and honoraria from Boehringer Ingelheim; has been a consultant and investigator for and received grants and honoraria from Novartis, Pfizer, and XenoPort; has been an investigator for and received grants from Anacor, Celgene, Dermira, Merck, Neothetics, Regeneron Pharmaceuticals, and Symbio/Maruho; has been an advisory board participant, consultant, and investigator for and received honoraria from Eli-Lilly; and has been a consultant for and received honoraria from Galderma and Vitae. J. G. Krueger has been a consultant for and received grants paid to his institution by Amgen, BMS, Boehringer, Dermira, Innovaderm, Janssen, Kadmon, Kyowa, Lilly, Merck, Novartis, Paraxel, and Pfizer; has been a consultant for and recipient of personal fees from AbbVie, Baxter, BiogenIdec, Delenex, Kineta, Sanofi, Serono, and Xenoport; and has been an investigator for Regeneron Pharmaceuticals. B. Swanson and G. Pirozzi are employees and might hold stock and/or stock options in Sanofi. The rest of the authors declare that they have no relevant conflicts of interest.

Keywords

Atopic dermatitis
IL-4 receptor α inhibition
dupilumab
epidermal pathology
gene expression
skin
transcriptome
type 2 inflammation

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2018.08.022

Cite this

Guttman-Yassky, E., Bissonnette, R., Ungar, B., Suárez-Fariñas, M., Ardeleanu, M., Esaki, H., Suprun, M., Estrada, Y., Xu, H., Peng, X., Silverberg, J. I., Menter, A., Krueger, J. G., Zhang, R., Chaudhry, U., Swanson, B., Graham, N. M. H., Pirozzi, G., Yancopoulos, G. D., & Jennifer, J. D. (2019). Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 143(1), 155-172. https://doi.org/10.1016/j.jaci.2018.08.022

@article{4682efbb7c204e5ba865697a28e077ec,

title = "Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis",

abstract = "Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.",

keywords = "Atopic dermatitis, IL-4 receptor α inhibition, dupilumab, epidermal pathology, gene expression, skin, transcriptome, type 2 inflammation",

author = "Emma Guttman-Yassky and Robert Bissonnette and Benjamin Ungar and Mayte Su{\'a}rez-Fari{\~n}as and Marius Ardeleanu and Hitokazu Esaki and Maria Suprun and Yeriel Estrada and Hui Xu and Xiangyu Peng and Silverberg, {Jonathan I.} and Alan Menter and Krueger, {James G.} and Rick Zhang and Usman Chaudhry and Brian Swanson and Graham, {Neil M.H.} and Gianluca Pirozzi and Yancopoulos, {George D.} and Jennifer, {Jennifer D.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2019",

month = jan,

doi = "10.1016/j.jaci.2018.08.022",

language = "English (US)",

volume = "143",

pages = "155--172",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "1",

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Guttman-Yassky, E, Bissonnette, R, Ungar, B, Suárez-Fariñas, M, Ardeleanu, M, Esaki, H, Suprun, M, Estrada, Y, Xu, H, Peng, X, Silverberg, JI, Menter, A, Krueger, JG, Zhang, R, Chaudhry, U, Swanson, B, Graham, NMH, Pirozzi, G, Yancopoulos, GD & Jennifer, JD 2019, 'Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis', Journal of Allergy and Clinical Immunology, vol. 143, no. 1, pp. 155-172. https://doi.org/10.1016/j.jaci.2018.08.022

TY - JOUR

T1 - Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

AU - Guttman-Yassky, Emma

AU - Bissonnette, Robert

AU - Ungar, Benjamin

AU - Suárez-Fariñas, Mayte

AU - Ardeleanu, Marius

AU - Esaki, Hitokazu

AU - Suprun, Maria

AU - Estrada, Yeriel

AU - Xu, Hui

AU - Peng, Xiangyu

AU - Silverberg, Jonathan I.

AU - Menter, Alan

AU - Krueger, James G.

AU - Zhang, Rick

AU - Chaudhry, Usman

AU - Swanson, Brian

AU - Graham, Neil M.H.

AU - Pirozzi, Gianluca

AU - Yancopoulos, George D.

AU - Jennifer, Jennifer D.

PY - 2019/1

Y1 - 2019/1

N2 - Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

AB - Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

KW - Atopic dermatitis

KW - IL-4 receptor α inhibition

KW - dupilumab

KW - epidermal pathology

KW - gene expression

KW - skin

KW - transcriptome

KW - type 2 inflammation

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Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

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