Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose,

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Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial James G. Krueger, MD, PhD, Laura K. Ferris, MD, Alan Menter, MD, Frank Wagner, MD, Alexander White, MD, Sudha Visvanathan, PhD, Bojan Lalovic, PhD, Stella Aslanyan, MD, Elaine E.L. Wang, MD, David Hall, PhD, Alan Solinger, MD, Steven Padula, MD, Paul Scholl, MB BChir Journal of Allergy and Clinical Immunology Volume 136, Issue 1, Pages 116-124.e7 (July 2015) DOI: 10.1016/j.jaci.2015.01.018 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Mean PASI percentage improvement from baseline over 24 weeks. Mean improvements in PASI scores for patients receiving intravenous (IV) or subcutaneous (SC) BI 655066 are shown. For the intravenous BI 655066 group, there were 24 subjects to week 12 and 23 subjects thereafter; a patient originally allocated to the 5 mg/kg BI 655066 group was lost to follow-up because of relocation, and discontinued after week 12. For the BI 655066 subcutaneous group, there were 15 subjects throughout. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Representative photographs of PASI improvements with BI 655066 in a male (A) and female (B) patient from baseline (left panel) and week 12 (right panel). Fig 2, A, Single dose of 0.25 mg/kg BI 655066 administered subcutaneously. PASI scores were 39, 22, 9, 1.5, 0, and 0 at baseline and weeks 2, 4, 8, 12, and 24, respectively. Fig 2, B, Single dose of 1 mg/kg BI 655066 administered subcutaneously. PASI scores were 12.80, 9.5, 1.2, 1, 0.6, and 0 at baseline and weeks 2, 4, 8, 12, and 24, respectively. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Changes in expression of genes/proteins in key pathophysiologic pathways in psoriatic lesion development and maintenance after administration of a single dose of BI 655066. A, Representative skin biopsy specimens from a single patient treated with subcutaneous BI 655066 at a dose of 0.25 mg/kg (baseline and week 8) stained for specific markers, including K16 and Ki67, S100A7, neutrophil gelatinase lipocalin, β-defensin 2, DC-LAMP, CD11c, and CD3. B, Heat map showing FC expression (change from baseline to week 8) in a subset of 60 genes (significantly increased in lesional vs nonlesional skin) from a published RNA-seq analysis in patients with moderate-to-severe psoriasis15 that are overall normalized by treatment with BI 655066 (purple) versus placebo (green). The scale shows log2 FC in expression of each gene, with red representing FC increase and blue representing FC decrease. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Changes in expression of genes/proteins in key pathophysiologic pathways in psoriatic lesion development and maintenance after administration of a single dose of BI 655066. A, Representative skin biopsy specimens from a single patient treated with subcutaneous BI 655066 at a dose of 0.25 mg/kg (baseline and week 8) stained for specific markers, including K16 and Ki67, S100A7, neutrophil gelatinase lipocalin, β-defensin 2, DC-LAMP, CD11c, and CD3. B, Heat map showing FC expression (change from baseline to week 8) in a subset of 60 genes (significantly increased in lesional vs nonlesional skin) from a published RNA-seq analysis in patients with moderate-to-severe psoriasis15 that are overall normalized by treatment with BI 655066 (purple) versus placebo (green). The scale shows log2 FC in expression of each gene, with red representing FC increase and blue representing FC decrease. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Correlation plot of log FC in expression of IL-23/IL-17 axis–associated genes by means of RNA-seq versus TaqMan PCR after treatment with BI 655066 (adjusted for placebo response). RNA-seq and TaqMan PCR data calculated as follows: [logFC(BI 655066 treated (Week 8 − baseline)) − logFC(Placebo treated (Week 8 − Baseline))]. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Patient disposition. aReasons for not meeting the inclusion criteria included viral hepatitis, other comorbidities, history of alcohol abuse, exclusionary laboratory results, inadequate response to prior biologics, or not meeting the age limit. bOne patient was originally randomized into the group receiving 1 mg/kg BI 655066 administered subcutaneously but received 0.25 mg/kg BI 655066. cPatient lost to follow-up because of relocation was originally allocated to the 5 mg/kg BI 655066 group and discontinued after week 12. dOne patient originally assigned to receive 1 mg/kg BI 655066 administered subcutaneously inadvertently received the 0.25 mg/kg dose. eOne patient was directly assigned to the group receiving 1 mg/kg BI 655066 administered subcutaneously to maintain 6 patients in the group. IV, Intravenous; SC, subcutaneous. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 BI 655066 dose response. Intravenous and subcutaneous bioavailability-normalized BI 655066 doses versus individual percentage change from baseline PASI score (AUEC). Data were calculated as described in the Results section in this article's Online Repository and depicted as black (intravenous [IV]) or gray (subcutaneous [SC]) triangles. A line of best fit of an Emax dose-response relationship (dashed line) is overlaid. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Overall decrease in FC expression of a cluster of 79 genes using RNA-seq (baseline to week 8). Heat map showing overall decreases in FC expression (change from baseline to week 8) in a cluster of 79 genes from RNA-seq analysis after treatment with BI 655066 (purple) versus placebo (green), with each column representing individual patients. The scale shows log2 FCs in expression of each of the 79 genes, with red representing FC increase and blue representing FC decrease. Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Correlation plot of the cluster means of the 79 genes (from Fig E1) for each patient versus PASI scores at week 8, showing a significant correlation between reductions in expression of this gene cluster in BI 655066–treated patients and lower PASI scores (BI 655066 [purple dots] vs placebo [green dots]). The decrease in expression of this subset of 79 genes after BI 655066 treatment was significantly correlated with PASI scores at week 8 (r = 0.73, P = 2 × 10−6). Journal of Allergy and Clinical Immunology 2015 136, 116-124.e7DOI: (10.1016/j.jaci.2015.01.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions