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)

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 & 2.1,2 Previous results from a GUS PsA Phase-2 trial3 and Ustekinumab (UST, anti-IL12/23p40 MAb) PsA Phase-3 trials (PSUMMIT 1 & 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 & 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, & 24 and in 34 healthy controls matched for age, sex, and ethnicity. Serum proteins measured were acute phase reactants CRP & SAA (Meso Scale Discovery (MSD) Platform) and inflammatory cytokines/chemokines: Th17 effector cytokines IL-17A, IL-17F, & 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), & YKL-40 (Quantikine Immunoassay). Serum IL-17A, IL-17B, & CRP measured in the Phase-3 PSUMMIT trials of UST for PsA4 were included for comparison with GUS. Results: At baseline, serum levels of acute phase proteins CRP, SAA, & IL-6, and Th17-effector cytokines IL-17A & IL-17F were elevated in pts with PsA compared with healthy controls (p 0.25). Baseline CRP, SAA, IL-6, & YKL40 were significantly associated with baseline joint disease (Disease Activity Score 28-CRP, Spearman p 0.25). Baseline SAA, IL-6, IL-17A, & IL-17F were higher in pts with prior TNF inhibitor exposure than without (p GUS treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F, & 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 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 & Development, LLC, Keying Ma Employee of: Janssen Research & Development, LLC, Karen Leander, Employee of: Janssen Research & Development, LLC, Vani Lakshminarayanan Employee of: Janssen Research & Development, LLC, Carol Franks Employee of: Janssen Research & Development, LLC, Philip Cooper Employee of: Janssen Research & Development, LLC, Kristen Sweet Employee of: Janssen Research & Development, LLC