OP0229 GUSELKUMAB INDUCES SUSTAINED REDUCTION IN ACUTE PHASE PROTEINS AND TH17 EFFECTOR CYTOKINES IN ACTIVE PSORIATIC ARTHRITIS IN TWO PHASE-3 CLINICAL TRIALS (DISCOVER-1 AND DISCOVER-2)
Authors: S. Siebert, I. Mcinnes, M. J. Loza, K. MA, K. Leander, V. Lakshminarayanan, C. Franks, P. Cooper, K. Sweet
Journal: Annals of the Rheumatic Diseases (2020)

Background: Guselkumab (GUS), an IL-23 inhibitor monoclonal antibody (Mab) that specifically binds to the IL-23p19 subunit, demonstrated efficacy compared to placebo (PBO) in reducing skin and musculoskeletal signs and symptoms in patients (pts) with active psoriatic arthritis (PsA) in two phase-3 studies, DISCOVER 1 &amp; 2. 1,2 Previous results from a GUS PsA Phase-2 trial 3 and Ustekinumab (UST, anti-IL12/23p40 MAb) PsA Phase-3 trials (PSUMMIT 1 &amp; 2) 4 showed associations of baseline IL-17A, IL-17F, and CRP with baseline disease characteristics, and associations of GUS-induced cytokine reductions with clinical responses. Objectives: To investigate plausible cytokine expression in PsA and alterations after exposure to GUS therapy. Methods: In DISCOVER 1 &amp; 2, pts were treated with GUS 100 mg at Wk 0, 4, then every 8Wks (q8w); GUS 100mg q4w; or matching PBO. 21 serum biomarkers were measured in a random subset of 300 PsA pts from the DISCOVER program at Weeks (Wks) 0, 4, &amp; 24 and in 34 healthy controls matched for age, sex, and ethnicity. Serum proteins measured were acute phase reactants CRP &amp; SAA (Meso Scale Discovery (MSD) Platform) and inflammatory cytokines/chemokines: Th17 effector cytokines IL-17A, IL-17F, &amp; IL-22 (Single Molecule Counting Erenna® Immunoassay Platform) and soluble ICAM-1, soluble VCAM-1, IL-6, CXCL-8, IL-10, IL-13, IL-12p70, CCL22, IFN-γ, CCL2, CCL4, TNFα, IL-1β, IL-2, IL-4 (MSD), &amp; YKL-40 (Quantikine Immunoassay). Serum IL-17A, IL-17B, &amp; CRP measured in the Phase-3 PSUMMIT trials of UST for PsA 4 were included for comparison with GUS. Results: At baseline, serum levels of acute phase proteins CRP, SAA, &amp; IL-6, and Th17-effector cytokines IL-17A &amp; IL-17F were elevated in pts with PsA compared with healthy controls (p&lt;0.05, geometric mean ≥ 40% higher, FIG 1). There was no significant dysregulation in the other cytokines measured in PsA pts compared to healthy controls. Baseline IL-17A, IL-17F, IL-22, &amp; CCL22 were significantly associated with baseline psoriasis disease activity (Body Surface Area &amp; Psoriatic Area and Severity Index, Spearman Signed Rank p&lt;0.05, r&gt;0.25). Baseline CRP, SAA, IL-6, &amp; YKL40 were significantly associated with baseline joint disease (Disease Activity Score 28-CRP, Spearman p&lt;0.05, r&gt;0.25). Baseline SAA, IL-6, IL-17A, &amp; IL-17F were higher in pts with prior TNF inhibitor exposure than without (p&lt;0.05, geometric mean ≥ 40% higher), although pts with PsA both with and without prior TNF inhibitor had higher levels than the healthy control set. GUS treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F, &amp; IL-22 that were significantly greater than PBO as early as Week 4 (FIG 1). These protein levels continued to decrease through Wk 24 in GUS-treated pts with both dosing regimens (p&lt;0.05, geometric mean decrease from baseline ≥ 33%). Further, Wk 24 IL-17A &amp; IL-17F levels for pts treated with either dose of GUS were not significantly different from healthy controls, suggesting a normalization of peripheral effector cytokines associated with the IL-23/Th17 axis following treatment with GUS. Effects on IL-17A/IL-17F were greater in GUS treated pts than UST treated pts, while CRP levels were similar in both programs (FIG 2). Conclusion: Comprising a strong pharmacodynamic effect, GUS treatment reduced serum protein levels of acute phase and Th17-effector cytokines (whose elevations at baseline were associated with PsA disease characteristics) and achieved comparable levels to those in healthy controls. In pts with PsA, reductions of IL-17A and IL-17F by GUS were of greater magnitude than those by UST. References: [1]Deodhar et al. ACR 2019, abs #807. Arth Rheumatol. 2019;71 S10: 1386 [2]Mease et al. ACR 2019, abs #L13. Arth Rheumatol. 2019;71 S10:5247 [3]Siebert et al. EULAR 2019, abs #479. Ann Rheum Dis. 2019;78 S2:293 [4]Siebert et al. Arth Rheumatol. 2019;71:1660 Acknowledgments: None Disclosure of Interests: Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Matthew J Loza Employee of: Janssen Research &amp; Development, LLC, Keying Ma Employee of: Janssen Research &amp; Development, LLC, Karen Leander, Employee of: Janssen Research &amp; Development, LLC, Vani Lakshminarayanan Employee of: Janssen Research &amp; Development, LLC, Carol Franks Employee of: Janssen Research &amp; Development, LLC, Philip Cooper Employee of: Janssen Research &amp; Development, LLC, Kristen Sweet Employee of: Janssen Research &amp; Development, LLC