P52 Efficacy of guselkumab in bionaive psoriatic arthritis patients with severe disease activity: <i>post hoc</i> analysis of Phase 3, randomized, double-blind, placebo-controlled study

Abstract The efficacy and safety of guselkumab, a fully human IL-23p19-subunit inhibitor, has been established in DISCOVER-1 and -2 studies. This post hoc analysis evaluates guselkumab efficacy through Week (W)100 in Bionaive psoriatic arthritis (PsA) patients with severe disease activity (DA) based on a range of composite and patient-reported outcomes. In DISCOVER-2, Bionaive adults with active PsA (≥5 swollen and ≥5 tender joints, CRP ≥0.6 mg/dL) received (1:1:1) guselkumab 100 mg every 4W (Q4W); guselkumab 100 mg at W0, W4, Q8W; or placebo with crossover to guselkumab Q4W at W24. Severe DA was defined by clinical DA Index for PsA (cDAPSA &amp;gt;27), PsA DA Score (PASDAS ≥5.4), and patient global assessment (PtGA ≥80 mm) criteria. Least square mean (LSM) changes from baseline were estimated with mixed models for repeated measures, adjusted for treatment group, baseline outcome levels, and study stratification factors (baseline csDMARD use, high-sensitivity serum CRP). Among 739 DISCOVER-2 patients, 648 (88%), 639 (86%), and 218 (29%) met cDAPSA (mean = 49.5), PASDAS (mean = 6.8), and PtGA (mean = 89.0) criteria for severe DA. Baseline characteristics and treatment groups were generally consistent across severe DA cohorts, except guselkumab Q4W group had a higher proportion of males and dactylitis than placebo. In multivariate analyses, irrespective of the severe DA cohort, significantly greater improvements were observed in guselkumab-treated patients vs. placebo in all evaluated endpoints (largest effect observed in severe PtGA cohort). Guselkumab showed clinically meaningful improvements at W2 for cDAPSA (guselkumab Q4W: −5.9; Q8W: −7.2; placebo: −5.0) and W8 for PASDAS (guselkumab Q4W: −1.5; Q8W: −1.5; placebo: −0.9) and PtGA (guselkumab Q4W: −30.0; Q8W: −32.1; placebo: −17.4). The LSM differences between guselkumab Q4W/Q8W and placebo were enhanced through W24 across severe DA cohorts, at which time further improvements with guselkumab occurred, resulting in significant (P &amp;lt; 0.001) differences of −9.8/−9.0 for cDAPSA, −1.1/−1.1 for PASDAS, and −24.0/−20.2 for PtGA. Further improvements were observed through 2 years of guselkumab treatment in all evaluated outcomes (LSM difference from BL: ΔcDAPSA, ∼−36; ΔPASDAS, ∼−3.6; ΔPtGA, ∼−56) representing ∼73%, ∼53%, and ∼63% improvements in joint DA, PsA activity across domains, and patient-reported overall DA. Guselkumab demonstrated rapid (W2 for joint and W8 for overall DA) and clinically meaningful improvements in DA in Bionaive PsA patients with severe DA in a range of joint-focused and multi-domain outcomes; these improvements were further enhanced by W24 and sustained through 2 years. Overall, findings support the use of guselkumab in PsA patients with severe DA.