POS0195 GUSELKUMAB TREATMENT MODULATES CORE PSORIATIC ARTHRITIS GENE EXPRESSION IN TWO PHASE 3 CLINICAL TRIALS (DISCOVER-1 AND -2)

Background: Guselkumab (GUS), an interleukin-23 p19-subunit monoclonal antibody, demonstrated efficacy compared with placebo (PBO) in reducing signs and symptoms of psoriatic arthritis (PsA) the phase 3 DISCOVER-1 & 2 studies. 1,2 Objectives: To evaluate gene expression blood PsA patients (pts) -2 studies impact GUS on these genes. Methods: Pts were treated 100 mg every 4 weeks (Q4W); at W0, W4, then Q8W; or matching PBO. Whole transcriptome profiling by RNA-sequencing was performed using Novaseq platform samples obtained from a subset 673 pts baseline across DISCOVER studies, as well 21 demographically (age, sex, ethnicity) matched healthy controls procured independently clinical program. A subgroup (N=227) also had serial (W0/W4/W24) evaluated; selected based having characteristics (demographics, disease activity, medication use) representative overall cross-study population. Significance differentially expressed genes (DEGs) between defined false discovery rate (FDR) <0.05 log-linear model edgeR. Top significance |logFC| >1. For cell type analysis, that changed treatment tested for enrichment Cibersort. Gene scores calculated Set Variation Analysis (GSVA). Results: define genes, we active vs. control whole transcriptomes detected 355 upregulated 314 downregulated (top shown Table 1), here core Upregulated largely related to neutrophils, monocytes, macrophages, extracellular matrix, whereas T cells. The significantly decreased increased PBO W4 W24 (Fig 1). Upon stratification Psoriasis Area Severity Index 75% response American College Rheumatology 20% response, changes W0 statistically significant among responders, but not non-responders, (data shown). We second differential analysis comparing both arms change arm over time. At found many DEGs none These included B-, T-, NK-, plasma cells (increased GUS) eosinophils, macrophages (decreased GUS), suggestive partial normalization immune composition blood. Conclusion: Using profiling, controls, suggesting dysregulation profiles PsA. majority disease-associated modulated GUS, directionality toward transcriptomic signatures. References: [1]Deodhar et al. Lancet. 2020;395:1115. [2]Mease P 2020;395:1126. 1. derived transcriptomes. Downregulated logFC logCPM FDR ADGRG7 5.92 -0.90 0.02101 AK8 -1.36 -1.06 1.61E-07 ADAMTS2 4.06 0.82 0.006466 FTCD -1.48 -1.74 1.67E-05 PGF 3.21 -0.68 GPR15 -1.54 1.81 PCSK9 -2.96 0.023872 CHRM3 -2.62 9.6E-08 OLAH 2.76 0.75 0.004539 RFPL4AL1 -1.69 -3.34 0.009738 MAOA 2.55 -0.26 0.005463 SPACA3 -1.85 -3.23 0.000216 SLC2A14 2.30 0.59 0.022594 VANGL2 -1.95 -1.79 MMP1 2.25 -1.16 0.004745 RFPL4A -2.04 -1.28 DAAM2 2.12 4.31 0.024628 GLYATL2 -2.77 -2.78 1.93E-15 BCAR1 -3.13 -2.58 6.24E-26 Bold indicates positive change. CPM = counts per million. Disclosure Interests: Stefan Siebert Consultant of: AbbVie, Janssen, Novartis, UCB, Grant/research support from: Amgen (previously Celgene), Bristol Myers Squibb, Boehringer Ingelheim, GSK, Kristen Sweet Shareholder Johnson Johnson, Employee Janssen Research Development LLC, Christopher T. Ritchlin Amgen, Gilead, Eli Lilly, Pfizer, Elizabeth C Hsia Alexa Kollmeier Xie L Xu Qingxuan Song Michelle Miron LLC