OP0166 Comparative evaluation of cellular and molecular changes associated with response to selective il-23 blockade vs dual il-12/23 blockade in psoriasis skin
Authors: K. Li, K. Campbell, S. Garcet, C. Brodmerkel, J. Krueger
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Emerging clinical data indicate that selective blockade of interleukin 23 (IL-23) can achieve greater efficacy compared to dual blockade of IL-12/23 in patients with moderate-to-severe psoriasis (PsO).<sup><sup>1</sup></sup> Ustekinumab (UST) targets the p40 subunit common to IL-12 and IL-23, whereas guselkumab (GUS) specifically targets the IL-23-specific p19 subunit. While differences in antibody potency may explain therapeutic differences between UST and GUS, we explored cellular and molecular changes in the skin of PsO patients treated with UST or GUS to understand the mechanism underlying selective IL-23p19 inhibition. <h3>Methods</h3> UST data were derived from the ACCEPT study (NCT00454584, n=85), in which PsO patients received either 45 mg or 90 mg of UST at weeks (wks) 0 and 4, and GUS data were from the first-in-human study (NCT00925574, n=24) that tested single subcutaneous doses of GUS. Skin biopsies were collected at baseline (BL), and wks 1 and 12 post-treatment from each study to evaluate 1) histologic improvement via epithelial thickness, T cells (CD3), and myeloid DCs (CD11c) counts and 2) molecular response to drug via microarray. Biopsies from healthy subjects served as controls. GUS 100 mg and 300 mg groups were combined to increase analytic power. The IC<sub>50</sub> of each drug was evaluated by cell-based bioassays. <h3>Results</h3> The two cohorts are comparable in BL demographics, disease characteristics, skin histopathology, PsO lesional molecular expression profiles, and significantly enriched canonical pathways. Blockade of IL-23 with GUS resulted in a significantly greater reduction in CD3 and CD11c counts in the skin at wk12 relative to BL when compared to UST blockade (&gt;90% vs~70%). In pts who achieved &gt;50% improvement in PASI score, GUS (n=9) showed a larger impact on the PsO transcriptomic profile than UST 90 mg (n=12) by wk1 and greater enhancement was achieved by wk12. GUS neutralised 74% of the PsO disease profile by &gt;80%, while UST resolved only 21% at wk12. Expression of PsO disease markers such as defensin Beta 4A and lipocalin 2 were fully resolved by GUS beyond the level observed in non-lesional skin of PsO pts, while UST only resolved these markers by 32% and 63%, respectively. <i>In vitro</i>, GUS showed higher potency (2–14 fold) than UST in inhibiting IL-23 activity, which may contribute to stronger neutralisation of PsO disease markers by GUS. <h3>Conclusions</h3> In conclusion, this comparative study demonstrates that GUS inhibits psoriasis-associated pathology and resolves the skin transcriptomic PsO disease profile more strongly than UST. <h3>Reference</h3> [1] Langley RG, Tsai TF, Flavin S, Song M, Randazzo B, Wasfi Y, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: Results of the randomized, double-blind, Phase 3 NAVIGATE trial. Br J Dermatol2017Jun 21. doi:10.1111/bjd.15750 <h3>Disclosure of Interest</h3> K. Li Shareholder of: Johnson and Johnson, LLC, Employee of: Janssen Research and Development, LLC, K. Campbell Shareholder of: Johnson and Johnson, LLC, Employee of: Janssen Research and Development, LLC, S. Garcet Grant/research support from: Janssen Research and Development, LLC, C. Brodmerkel Shareholder of: Johnson and Johnson, LLC, Employee of: Janssen Research and Development, LLC, J. Krueger Grant/research support from: Janssen Research and Development, LLC