Scientific journey to the first FDA-approved drug for eosinophilic esophagitis
When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formu...
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Veröffentlicht in: | Journal of allergy and clinical immunology 2022-12, Vol.150 (6), p.1325-1332 |
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description | When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus. |
doi_str_mv | 10.1016/j.jaci.2022.09.027 |
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Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.</description><identifier>ISSN: 0091-6749</identifier><identifier>ISSN: 1097-6825</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2022.09.027</identifier><identifier>PMID: 36209816</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cytokines ; Discovery ; dupilumab ; eosinophils ; esophagitis ; FDA ; Humans ; IL-13 ; IL-4 ; IL-5 ; Mice ; Pharmaceutical Preparations ; United States ; United States Food and Drug Administration</subject><ispartof>Journal of allergy and clinical immunology, 2022-12, Vol.150 (6), p.1325-1332</ispartof><rights>2022 American Academy of Allergy, Asthma & Immunology</rights><rights>Copyright © 2022 American Academy of Allergy, Asthma & Immunology. 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All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-a8009e2621bdfd84bf0245a2edef86cdf55470cd5fe0c92cce4751c734a7243d3</citedby><cites>FETCH-LOGICAL-c521t-a8009e2621bdfd84bf0245a2edef86cdf55470cd5fe0c92cce4751c734a7243d3</cites><orcidid>0000-0001-9790-6332</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jaci.2022.09.027$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36209816$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rothenberg, Marc E.</creatorcontrib><title>Scientific journey to the first FDA-approved drug for eosinophilic esophagitis</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.</description><subject>Animals</subject><subject>Cytokines</subject><subject>Discovery</subject><subject>dupilumab</subject><subject>eosinophils</subject><subject>esophagitis</subject><subject>FDA</subject><subject>Humans</subject><subject>IL-13</subject><subject>IL-4</subject><subject>IL-5</subject><subject>Mice</subject><subject>Pharmaceutical Preparations</subject><subject>United States</subject><subject>United States Food and Drug Administration</subject><issn>0091-6749</issn><issn>1097-6825</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u3CAUhVGVqpmmfYEuKi-zsQvX2BgpihTlp60UtYu2a8TAZQbLYxywR8rbh9GkUbrpChDnHA73I-QToxWjrP3SV702vgIKUFFZURBvyIpRKcq2g-aErCiVrGwFl6fkfUo9zee6k-_Iad0ClR1rV-THL-NxnL3zpujDEkd8LOZQzFssnI9pLu5urko9TTHs0RY2LpvChVhgSH4M09YP2Ycp7_TGzz59IG-dHhJ-fF7PyJ-729_X38r7n1-_X1_dl6YBNpe6y1UQWmBr62zH144CbzSgRde1xrqm4YIa2zikRoIxyEXDjKi5FsBrW5-Ry2PutKx3aE3-QtSDmqLf6fiogvbq35vRb9Um7JUUHJiQOeD8OSCGhwXTrHY-GRwGPWJYkgIBNe9yzS5L4Sg1MaQU0b08w6g6gFC9OoBQBxCKSpVBZNPn1wVfLH8nnwUXRwHmMe09RpUOJAxaH9HMygb_v_wn5Jmb7A</recordid><startdate>20221201</startdate><enddate>20221201</enddate><creator>Rothenberg, Marc E.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9790-6332</orcidid></search><sort><creationdate>20221201</creationdate><title>Scientific journey to the first FDA-approved drug for eosinophilic esophagitis</title><author>Rothenberg, Marc E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-a8009e2621bdfd84bf0245a2edef86cdf55470cd5fe0c92cce4751c734a7243d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Cytokines</topic><topic>Discovery</topic><topic>dupilumab</topic><topic>eosinophils</topic><topic>esophagitis</topic><topic>FDA</topic><topic>Humans</topic><topic>IL-13</topic><topic>IL-4</topic><topic>IL-5</topic><topic>Mice</topic><topic>Pharmaceutical Preparations</topic><topic>United States</topic><topic>United States Food and Drug Administration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rothenberg, Marc E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rothenberg, Marc E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Scientific journey to the first FDA-approved drug for eosinophilic esophagitis</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2022-12-01</date><risdate>2022</risdate><volume>150</volume><issue>6</issue><spage>1325</spage><epage>1332</epage><pages>1325-1332</pages><issn>0091-6749</issn><issn>1097-6825</issn><eissn>1097-6825</eissn><abstract>When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36209816</pmid><doi>10.1016/j.jaci.2022.09.027</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9790-6332</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cytokines Discovery dupilumab eosinophils esophagitis FDA Humans IL-13 IL-4 IL-5 Mice Pharmaceutical Preparations United States United States Food and Drug Administration |
title | Scientific journey to the first FDA-approved drug for eosinophilic esophagitis |
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