Journal of Allergy and Clinical Immunology

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Presentation transcript:

Journal of Allergy and Clinical Immunology GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis Emma Guttman-Yassky, MD, PhD, Ana B. Pavel, PhD, Lisa Zhou, BA, Yeriel D. Estrada, BS, Ning Zhang, MD, Hui Xu, MS, Xiangyu Peng, MS, Huei-Chi Wen, MD, PhD, Panayiota Govas, MD, MScMed, Girish Gudi, PhD, Vinu CA, MPharm, MSc, Hui Fang, PhD, Yacine Salhi, PhD, Jonathan Back, PhD, Venkateshwar Reddy, PhD, Robert Bissonnette, MD, Catherine Maari, MD, Fred Grossman, DO, FAPA, Gerhard Wolff, MD, PhD Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2018.11.053 Copyright © 2019 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 1 GBR 830 inhibition of OX40-OX40L binding. Binding of OX40L to the OX40 receptor on T cells potentiates inflammatory responses, chronicity, and loss of tolerance. Inhibition of OX40L/OX40 binding by GBR 830 attenuates these effects. APC, Antigen-presenting cell. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 2 Study design and subject disposition. *Includes subjects who did not receive GBR 830 (n = 2). aExcludes subjects from the randomized population (GBR 830, n = 2) who did not receive 1 or more partial or full dose of study treatment. bExcludes subjects from the ITT population (GBR 830, n = 17; placebo, n = 5) who did not receive both doses of study drug and have 1 or more postbaseline skin biopsy specimens (day 29 or day 71). Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 3 Immunohistochemistry images of OX40 target from representative GBR 830–treated and placebo-treated subjects. A and B, Immunohistochemistry staining of OX40 (Fig 3, A) and OX40L (Fig 3, B) at baseline and after treatment (day 29 and day 71). Protein expression is shown in red staining, and images in each line were taken from the same subject. C and D, Mean fold change (FCH) from baseline in OX40 expression (Fig 3, C) and OX40L (Fig 3, D) expression. Symbols under bar graphs indicate statistical differences between posttreatment versus pretreatment within each treatment arm. Symbols above bar graphs indicate significant differences between GBR 830–treated versus placebo-treated subjects for FCH. +P < .1 (trend), *P < .05, and ***P < .001. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 4 Immunohistochemistry images for representative drug and placebo subjects at baseline and after treatment (A-C) and quantification of epidermal proliferation markers (D-F). Hematoxylin and eosin (H&E) (Fig 4, A), K16 (Fig 4, B), and Ki67 (Fig 4, C) staining show epidermal hyperplasia. Images for both drug and placebo panels were taken from a representative subject for each. Mean fold change (FCH) from baseline is shown for epidermal thickness (Fig 4, D), K16 mRNA expression measured by using RT-PCR (Fig 4, E), and Ki67 protein expression measured by using immunohistochemistry (Fig 4, F). Symbols under bar graphs indicate statistical differences between posttreatment versus pretreatment within each treatment arm. Symbols above bar graphs indicate significant differences between GBR 830–treated versus placebo-treated subjects for FCH. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 5 Changes in quantitative RT-PCR mRNA expressions after treatment. Significant reductions in mRNA expression of representative inflammatory markers of TH1 (A and B), TH2 (C-F), and TH17/TH22 (G-J) pathways were observed in subjects treated with GBR 830 compared with baseline and also placebo-treated subjects. Symbols under bar graphs indicate statistical differences between posttreatment versus pretreatment within each treatment arm. Symbols above bar graphs indicate significant differences between GBR 830–treated and placebo-treated subjects for fold change (FCH). +P < .1 (trend), *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig 6 Percentage change in EASI score from baseline through day 85 in the ITT population (A) and subjects with severe symptoms with SCORAD scores of greater than 50 (B). Yellow stars indicate intravenous administration. Significance for GBR 830 versus placebo treatment: +P < .1 (trend), *P < .05, and **P < .01. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions

Fig E1 TH2 and TH17/TH22 markers did not change in GBR 830–treated subjects compared with placebo-treated subjects. FCH, Fold change. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology DOI: (10.1016/j.jaci.2018.11.053) Copyright © 2019 The Authors Terms and Conditions