Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis

Lawrence F. Eichenfield; Thomas Bieber; Lisa A. Beck; Eric L. Simpson; Diamant Thaçi; Marjolein de Bruin-Weller; Mette Deleuran; Jonathan I. Silverberg; Carlos Ferrandiz; Regina Fölster-Holst; Zhen Chen; Neil M.H. Graham; Gianluca Pirozzi; Bolanle Akinlade; George D. Yancopoulos; Marius Ardeleanu

doi:10.1007/s40257-019-00445-7

Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis

Lawrence F. Eichenfield^*, Thomas Bieber, Lisa A. Beck, Eric L. Simpson, Diamant Thaçi, Marjolein de Bruin-Weller, Mette Deleuran, Jonathan I. Silverberg, Carlos Ferrandiz, Regina Fölster-Holst, Zhen Chen, Neil M.H. Graham, Gianluca Pirozzi, Bolanle Akinlade, George D. Yancopoulos, Marius Ardeleanu

^*Corresponding author for this work

Dermatology

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

138 Scopus citations

Abstract

Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

Original language	English (US)
Pages (from-to)	443-456
Number of pages	14
Journal	American Journal of Clinical Dermatology
Volume	20
Issue number	3
DOIs	https://doi.org/10.1007/s40257-019-00445-7
State	Published - Jun 1 2019

Funding

The authors thank the patients and their families for their participation in these studies; their colleagues for their support; and Linda Williams (Regeneron Pharmaceuticals, Inc.) and El-Bdaoui Haddad (Sanofi Genzyme) for their contributions. Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification. Submit requests to https://errs.regeneron.com/external. Funding This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. The study sponsors participated in the study design collection, analysis, and interpretation of data; writing of the report; and the decision to submit the article for publication. Medical writing/ editorial assistance was provided by Vicki Schwartz, PhD, and Manuela Pigors, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Conflict of interest L. F. Eichenfield has received honoraria for consulting services from Almirall, Celgene, Dermira, Dermavant, Eli Lilly and Company, Forté Pharma, Galderma, L’Oréal, Incyte, MatriSys, Menlo Therapeutics, Otsuka, Novan, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, and Valeant/Ortho Dermatologics; and study support (to institution) from Celgene, Dermira, Dermavant, Eli Lilly and Company, Galderma, Incyte, Medimetriks, Pfizer, Regen-eron Pharmaceuticals, Inc., Sanofi Genzyme, and Valeant. T. Bieber is a speaker for Almirall, Anacor, Astellas, Celgene, Chugai, Galderma, Janssen-Cilag, L’Oréal, Novartis, Oxagen, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi. L. A. Beck has received honoraria as a consultant and research grants as principal investigator for clinical trials from AbbVie, Pfizer, Realm Therapeutics, and Regeneron Pharmaceuticals, Inc.; has received honoraria as a consultant from AbbVie, Astra-Zeneca, Allakos, Boehringer-Ingelheim, Celgene, Eli Lilly and Company, GSK, Leo Pharma, Novan, Novartis, Realm Therapeutics, Regeneron, Sanofi, and UCB; and is a stockholder in Medtronic and Pfizer. E. L. Simpson has received honoraria for consulting services from AbbVie, Anacor, Celgene, Dermira Pharmaceutical Co., Eli Lilly and Company, Galderma, Genentech, Inc., GSK, LEO Pharma, Menlo Therapeutics, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, and Valeant Pharmaceutical Co.; and has received study support from Anacor, Eli Lilly and Company, GSK, MedImmune, Novartis, Regeneron Pharmaceuticals, Inc., Roivant Sciences, Tioga Pharmaceuticals, Inc., and Vanda Pharmaceuticals, Inc. D. Thaçi has received research support from AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Celgene, Dignity, Eli Lilly and Company, GSK, Jans-sen-Cilag, LEO Pharma, MSD, Novartis, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sandoz, and Sanofi; received honoraria and is an independent advisor for AbbVie, Celgene, Janssen, La Roche-Posay, LEO Pharma, Medac, Novartis, Pfizer, Inc., Sun Pharma, and UCB; received honoraria and is a consultant for AbbVie, Celgene, Dignity, Galápagos, Novartis, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sanofi, and UCB; and received honoraria and is an advisory board member for AbbVie, Amgen, Celgene, Eli Lilly and Company, GSK, Janssen, LEO Pharma, Mundipharma, Novartis, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, and UCB. M. de Bruin-Weller is a principal investigator, advisory board member, and consultant for Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and a principal investigator and advisory board member for AbbVie. M. Deleuran has received research support, consulting/advisory board agreements, and/or honoraria for lecturing from AbbVie, Eli Lilly and Company, LEO Pharma, Meda, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi. J. I. Silverberg has received honoraria for advisory board participation, as a speaker, and for consultancy from AbbVie, Eli Lilly and Company, Galderma, GSK, Kiniksa, LEO Pharma, Menlo Thera- peutics, Pfizer, Realm Therapeutics, Regeneron Pharmaceuticals, Inc., Roivant, and Sanofi; and research grants from GSK, Regeneron Pharmaceuticals, Inc., and Sanofi. C. Ferrandiz is a principal investigator in clinical trials for AbbVie, Sanofi, LEO Pharma; and an advisory board participant for Sanofi. R. Fölster-Holst is an investigator for studies, speaker, and consultant for Astellas, Almirall Hermal, Beiersdorf, Johnson & Johnson, La Roche-Posay, LEO Pharma, Neubourg Skin Care GmbH, Novartis, Pierre Fabre, Procter & Gamble, and Regener-on Pharmaceuticals, Inc. Z. Chen, N.M.H. Graham, B. Akinlade, G.D. Yancopoulos, and M. Ardeleanu are employees of and shareholders in Regeneron Pharmaceuticals, Inc. G. Pirozzi is an employee of and may hold stock and/or stock options in Sanofi.

ASJC Scopus subject areas

Dermatology

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10.1007/s40257-019-00445-7

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Eichenfield, L. F., Bieber, T., Beck, L. A., Simpson, E. L., Thaçi, D., de Bruin-Weller, M., Deleuran, M., Silverberg, J. I., Ferrandiz, C., Fölster-Holst, R., Chen, Z., Graham, N. M. H., Pirozzi, G., Akinlade, B., Yancopoulos, G. D., & Ardeleanu, M. (2019). Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis. American Journal of Clinical Dermatology, 20(3), 443-456. https://doi.org/10.1007/s40257-019-00445-7

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title = "Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis",

abstract = "Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.",

author = "Eichenfield, {Lawrence F.} and Thomas Bieber and Beck, {Lisa A.} and Simpson, {Eric L.} and Diamant Tha{\c c}i and {de Bruin-Weller}, Marjolein and Mette Deleuran and Silverberg, {Jonathan I.} and Carlos Ferrandiz and Regina F{\"o}lster-Holst and Zhen Chen and Graham, {Neil M.H.} and Gianluca Pirozzi and Bolanle Akinlade and Yancopoulos, {George D.} and Marius Ardeleanu",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = jun,

day = "1",

doi = "10.1007/s40257-019-00445-7",

language = "English (US)",

volume = "20",

pages = "443--456",

journal = "American Journal of Clinical Dermatology",

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Eichenfield, LF, Bieber, T, Beck, LA, Simpson, EL, Thaçi, D, de Bruin-Weller, M, Deleuran, M, Silverberg, JI, Ferrandiz, C, Fölster-Holst, R, Chen, Z, Graham, NMH, Pirozzi, G, Akinlade, B, Yancopoulos, GD & Ardeleanu, M 2019, 'Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis', American Journal of Clinical Dermatology, vol. 20, no. 3, pp. 443-456. https://doi.org/10.1007/s40257-019-00445-7

TY - JOUR

T1 - Infections in Dupilumab Clinical Trials in Atopic Dermatitis

T2 - A Comprehensive Pooled Analysis

AU - Eichenfield, Lawrence F.

AU - Bieber, Thomas

AU - Beck, Lisa A.

AU - Simpson, Eric L.

AU - Thaçi, Diamant

AU - de Bruin-Weller, Marjolein

AU - Deleuran, Mette

AU - Silverberg, Jonathan I.

AU - Ferrandiz, Carlos

AU - Fölster-Holst, Regina

AU - Chen, Zhen

AU - Graham, Neil M.H.

AU - Pirozzi, Gianluca

AU - Akinlade, Bolanle

AU - Yancopoulos, George D.

AU - Ardeleanu, Marius

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

AB - Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

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EP - 456

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JF - American Journal of Clinical Dermatology

IS - 3

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Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis

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