IL-17A is a pertinent therapeutic target for moderate-to-severe hidradenitis suppurativa: Combined results from a pre-clinical and phase II proof-of-concept study

Abstract

Hidradenitis Suppurativa (HS) is a chronic, recurrent, inflammatory, follicular skin disease whose pathology is complex and not fully understood. The objective of this study was to elucidate the role of IL-17A in moderate-to-severe HS. Transcriptomic and histological analyses were conducted on ex vivo HS (n = 19; lesional and non-lesional) and healthy control (n = 8) skin biopsies. Further, a Phase II exploratory, randomized, double-blind, placebo-controlled study was carried out in moderate-to-severe HS patients. Patients were treated with either CJM112 300 mg (n = 33), a fully human anti-IL-17A IgG1/κ monoclonal antibody, or placebo (n = 33). The main outcome of the translational analyses was to identify IL-17A-producing cells and indications of IL-17A activity in HS lesional skin. The primary objective of the clinical study was to determine the efficacy of CJM112 in moderate-to-severe HS patients by HS-Physician Global Assessment (HS-PGA) responder rate at Week 16. Transcriptomic and histopathologic analyses revealed the presence of heterogeneous cell types in HS lesional skin; IL-17A gene signatures were increased in HS lesional vs non-lesional or healthy skin. High expression of IL-17A was localized to T cells, neutrophils, and mast cells, confirming the transcriptional data. Clinically, the proportion of Week 16 HS-PGA responders was significantly higher (p = 0.03) in the CJM112 group vs placebo (32.3% vs 12.5%). This study elucidated the role of the IL-17A pathway in HS pathogenesis and clinically validated the IL-17A pathway in moderate-to-severe HS patients in a proof-of-concept study using the anti-IL-17A-specific antibody CJM112.

Keywords: IL-17A; T cells; clinical trial; hidradenitis suppurativa; pathophysiology.

FIGURE 1

Transcriptional Analysis of Lesional HS Biopsies. (A) Dot plot showing the log₂ fold change between lesional HS vs healthy control for individual donors (one dot is one gene) of a cell type signature. The size is by log adjusted p‐value (the bigger the size, the lower the p‐value). (B) Median expression levels of defined T‐cell types and IL‐17A signalling pathways are visualized in the heat map. Each block depicts the color‐graded level of the expression in this particular RNA sample with blue showing the minimal and red the maximal level for the respective gene set. HS, hidradenitis suppurativa; IL, interleukin; RNA, ribonucleic acid; Th, T helper

FIGURE 2

Analysis and Comparison of HS and Psoriasis Lesional Biopsies. (A) Nanostring data analysis showing a correlation between PsO and HS expression levels of selected genes. The black line represents the linear regression, r ² (correlation coefficient) is 0.506, and b (slope of the line) is 0.93. (B) Boxplots demonstrating Robust Multichip Average (RMA) normalized data of key genes analysed using GeneSpring (11.5.1) Boxplots represent min, max, median, and upper and lower quartiles. CD, cluster of differentiation; CXCL, chemokine C‐X‐C motif ligand 1; DEF4BA, beta‐defensin 4A precursor; HS, hidradenitis suppurativa; IFN, interferon; IL, interleukin; LCN‐2, lipocalin 2; MPO, myeloperoxidase; PsO, psoriasis.; RMA, Robust Multichip Average; S100A7A, S100calcium‐binding protein A7A

FIGURE 3

Immunohistochemical Analysis of HS Skin Biopsies. (A) Representative image of HS lesional biopsy showing dermal inflammation with abscess formation and IL‐17A‐positive cells. (B) Dermal lesions containing numerous neutrophils (MPO) and macrophages (CD68) as well as clusters of T (CD3) and B cells (CD20). (C) Strong epidermal expression of BD‐2 and S100A7/psoriasin above the inflammatory dermal lesions. (D) Double immunofluorescence illustrating the presence of CD3+/IL‐17+ positive cells in the dermis. BD‐2, beta‐defensin 2; H&E, haematoxylin, and eosin; IL, interleukin; MPO, myeloperoxidase; S100A7, S100 calcium‐binding protein A7

FIGURE 4

HS‐PGA Responder Rate (primary endpoint data). Line graph demonstrating HS‐PGA responder rate from Baseline to Week 16 in CJM112 300 mg and placebo‐treated HS patients. *p < 0.05 statistically different from placebo. HS‐PGA, hidradenitis suppurativa Physician's Global Assessment

FIGURE 5

DLQI and hsCRP at Baseline Over Time to Week 16 in CJM112 300 mg and Placebo‐treated HS Patients. Line graphs demonstrating (A) mean change from Baseline in DLQI score, (B) mean hsCRP levels, and HiSCR responder rate from Baseline to Week 16 in CJM112 300 mg and placebo‐treated HS patients. Error bars represent standard deviation. *p < 0.05 statistically different from placebo. DLQI, Dermatology Life Quality Index; HiSCR, Hidradenitis Suppurativa Clinical Response; hsCRP, high sensitivity C‐reactive protein