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Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis

2020; Elsevier BV; Volume: 147; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2020.04.055

1097-6825

Benjamin Ungar, Ana B. Pavel, Randall Li, Grace W. Kimmel, John K Nia, Peter W. Hashim, Hee Jin Kim, Margot Chima, Anjali S. Vekaria, Yeriel Estrada, Hui Xu, Xiangyu Peng, Giselle Singer, Danielle Baum, Yasaman Mansouri, Mark Taliercio, Emma Guttman‐Yassky,

Asthma and respiratory diseases

Atopic dermatitis (AD) affects 3% to 10% of adults.1Sacotte R. Silverberg J.I. Epidemiology of adult atopic dermatitis.Clin Dermatol. 2018; 36: 595-605Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Recently, the increased understanding of AD pathogenesis has led to development of new treatments, including dupilumab, the first US Food and Drug Administration–approved biologic for moderate-to-severe AD. Although TH2 skewing is common across all AD subtypes, as suggested by the efficacy of dupilumab across populations with AD, it is a highly heterogeneous disease with diverse subtypes characterized by varying immune activation, perhaps requiring additional therapeutic approaches.2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar,3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar Recent studies have shown increased TH17 skewing in several AD subtypes, including intrinsic,3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar Asian,2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar and pediatric AD,4Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and have also shown that TH17-related markers are significantly correlated with AD severity.2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 4Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar An Asian patient with AD demonstrated clinical and tissue improvement with secukinumab, a selective IL-17A inhibitor.5Noda S. Hashim P.W. Khattri S. Shroff A. Guttman-Yassky E. Successful use of secukinumab in an Asian patient with severe refractory atopic dermatitis.J Invest Dermatol. 2016; 136: S40Abstract Full Text Full Text PDF Google Scholar However, controlled trials with IL-17 antagonists in patients with moderate-to-severe AD (including TH17-high subtypes) are lacking. Currently, anti–IL-17 therapies have been US Food and Drug Administration–approved for psoriasis and the IL-17 axis is known to play a role in epidermal hyperplasia.6Hawkes J.E. Chan T.C. Krueger J.G. Psoriasis pathogenesis and the development of novel targeted immune therapies.J Allergy Clin Immunol. 2017; 140: 645-653Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar Furthermore, IL-17 is increasingly being recognized as playing a role in other autoimmune diseases such as rheumatoid arthritis and ankylosing spondylitis, in which IL-17 treatments have also shown efficacy.7Eyerich K. Dimartino V. Cavani A. IL-17 and IL-22 in immunity: driving protection and pathology.Eur J Immunol. 2017; 47: 607-614Crossref PubMed Scopus (150) Google Scholar Additionally, through evaluation of patients with primary IL-17A deficiency, its protective role against Candida infections has been elucidated.8Levy R. Okada S. Beziat V. Moriya K. Liu C. Chai L.Y. et al.Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency.Proc Natl Acad Sci U S A. 2016; 113: E8277-E8285Crossref PubMed Scopus (77) Google Scholar We thus conducted a randomized, double-blind, placebo-controlled phase 2, investigator-initiated study (NCT02594098) that was begun following our publication on intrinsic and extrinsic AD.3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar We aimed to investigate the efficacy and safety of secukinumab versus placebo in 41 subjects with moderate-to-severe AD (27 of whom received secukinumab and 14 of whom received placebo), including by evaluating intrinsic AD (defined by an IgE level of 2.0 and a false discovery rate of <0.05). Overall, minimal changes in the lesional profiles of both the secukinumab-treated and placebo groups were noted at week 16 (see Fig E4 and Table E4 in this article’s Online Repository at www.jacionline.org). Among a previously defined immune gene subset,9Guttman-Yassky E. Bissonnette R. Ungar B. Suarez-Farinas M. Ardeleanu M. Esaki H. et al.Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.J Allergy Clin Immunol. 2019; 143: 155-172Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar a few inflammatory markers were significantly downregulated compared with baseline in the secukinumab-treated patients with intrinsic AD, with only a few markers trending toward significance in the patients with extrinsic AD. Despite the TH17/IL-23 blockade by secukinumab, TH17/IL-23–related markers (eg, PI3/Elafin, IL-12/23p40, S100A8/12, and CXCL1, IL-19) did not show significant changes with secukinumab versus with placebo, even in patients with intrinsic AD, as even greater downregulation was seen in the placebo group (Fig 2 and see Table E4). Correspondingly, few significantly downregulated genes were observed in other inflammatory pathways (see Table E4). To confirm and expand our RNA sequencing findings, we also performed RT-PCR on key AD-related immune and barrier markers (see Figs E5 and E6 in this article’s Online Repository at www.jacionline.org). Overall, the RT-PCR data mirrored the RNA sequencing results. Notably, no genes were significantly downregulated at week 16 versus at baseline in the secukinumab-treated group, but multiple markers were significantly downregulated in the placebo-treated group at either week 4 or week16 (eg, IL-17A, IL-17F, IL-19 [P < .05]). As this study was designed to evaluate secukinumab in patients with intrinsic versus extrinsic AD, we also performed comparisons between these populations, detecting no clinical or molecular significant changes among them (see Fig E7 and E8 and Table E3 and E5 in this article’s Online Repository at www.jacionline.org). Details are available in the Online Repository. Because higher TH17 activation was previously demonstrated in Asian patients with AD,2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar we also conducted a post hoc analysis of Asian patients. Similarly, no significant changes were found between secukinumab treatment and placebo (see Fig E9 and Tables E3 and E6 in this article’s Online Repository at www.jacionline.org). Adverse events were uncommon, with similar rates seen between treatment arms. A total of 3 adverse events occurred, all in secukinumab-treated patients: orbital cellulitis, upper respiratory infection, and streptococcal pharyngitis (Table E7 in this article’s Online Repository at www.jacionline.org). No Candida or Staphylococcus infections occurred. Although all AD subtypes share TH2 activation,4Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar the disease shows vast clinical and molecular heterogeneity. Furthermore, specific TH2 targeting with dupilumab clears only approximately one-third of patients. Thus, additional targeted therapies are needed to resolve AD in all subtypes and to further dissect the contribution of individual cytokine pathways to disease pathogenesis. For example, TH22 targeting is effective only in patients with high IL-22 expression. As certain populations of patients with AD (including those with intrinsic AD3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar and Asian patients with AD2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) show increased TH17 activation, we hypothesized that IL-17 targeting may have some benefit in selected populations. It is possible that TH17 activation in some patients with AD occurs in response to increased microbial burden. Our data, which integrate clinical assessments with extensive cellular and genomic biomarkers in skin, show (independent of the measure) that IL-17 is not a valid therapeutic target in patients with AD, including in subsets of patients with higher TH17 activation, such as those with intrinsic AD3Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar and Asian patients with AD.2Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar Our outcomes clearly reject the hypothesis that IL-17A is a solo pathogenic contributor to AD. Nevertheless, specific targeting approaches against the cytokines IL-17, IL-23, IL-22, and /IFN-γ may still be needed in conjunction with TH2-targeting strategies to fully resolve AD in the majority of patients. 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