POS0308 EFFECT OF GUSELKUMAB ON SERUM BIOMARKERS IN PSORIATIC ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE OR INTOLERANCE TO TUMOR NECROSIS FACTOR INHIBITORS: RESULTS FROM THE COSMOS STUDY

Abstract

BackgroundGuselkumab (GUS), a selective IL-23 inhibitor, is efficacious in treating bio-naïve and TNFi-experienced active PsA patients (pts).1.2 In the COSMOS study of active PsA pts with lack of efficacy/intolerance, i.e., inadequate response (IR), to 1-2 TNFi, GUS demonstrated significantly greater response rates and mean improvements in PsA signs and symptoms vs. placebo (PBO) at Week (W) 24.3ObjectivesEvaluate baseline (BL) serum levels of pro-inflammatory biomarkers (CRP, serum amyloid A [SAA], TNFα, IFNɣ, IL-6, IL-10, IL-17F, IL-17A, IL-22) and their relationship to BL disease activity, GUS treatment (tx), and clinical response in COSMOS TNFi-IR pts.MethodsTNFi-IR pts ≥18 yrs with active PsA (≥3 swollen & ≥3 tender joint counts [SJC/TJC]) were randomized 2:1 to GUS 100 mg every 8 W (Q8W) through W44 or PBO with early escape (W16) or crossover (W24) to GUS Q8W. Samples for serum biomarker analyses, collected at W0, 4, 16, 24, and 48 from consenting pts, were compared with healthy controls (HC; independent of COSMOS). Associations between early biomarker changes and BL disease activity, GUS tx, and clinical response at W24 were assessed.ResultsAmong 285 COSMOS pts, 50/95 PBO and 100/190 GUS pts had available biomarker data. BL characteristics of the biomarker cohort were similar to the overall COSMOS population and well balanced across tx arms. At BL, levels of TNFα, IFNɣ, IL-6, IL-10, IL-17A, IL-17F, and IL-22 were significantly upregulated in TNFi-IR pts vs. HC (Table 1). IL-6, CRP, and SAA levels were associated with BL joint disease severity per Disease Activity Score (DAS) 28-CRP (but not with SJC [0-66]/TJC [0-68]). IL-17A and IL-17F levels were associated with BL PASI score. Through W24, significant decreases from BL in levels of CRP, SAA, IL-6, IL-17A, IL-17F, and IL-22 were seen in GUS-, but not PBO-tx pts. Reductions in IL-17A, IL-17F and IL-22 with GUS were significant by W4, decreased further by W16, and were sustained through W24 and W48. In GUS-tx pts, serum levels of IL-17F (from W16) and IL-22 (from W4) were not significantly different vs. HC. At W48, reductions in these same markers were seen in PBO-tx pts who crossed over to GUS at W16/24 (Figure 1; IL-17A, IL-17F, & IL-22 data shown). In these TNFi-IR pts, GUS-tx pts achieving ACR20 at W24 exhibited higher IL-22 and IFNɣ levels at BL than nonresponders (NR). All other biomarkers evaluated were not significantly associated with ACR20 response to GUS. In the subset of pts with IGA of psoriasis assessed, BL IL-6 and SAA levels were upregulated in W24 IGA 0/1 responders (R) vs. NR in the GUS arm. ACR20 and IGA 0/1 R at W24 exhibited an early greater reduction in IL-6 expression (at W4) than did respective NR in the GUS arm. No BL biomarkers were associated with ACR50 or PASI75 responses to GUS at W24.Table 1.Select Serum Biomarkers at BL in TNFi-IR pts vs. HC▫Biomarker, pg/mLHC N=24TNFi-IR N=150Fold differencep-valueCRP22.1 (1.5)22.8 (2.2)1.60.2895SAA21.7 (1.2)22.8 (2.4)2.10.0794IL-60.07 (1.1)0.98 (1.7)1.90.0314*IL-10-2.3 (1.1)-1.7 (1.0)1.50.0272*IL-17A-2.1 (1.3)-0.3 (1.5)3.3<0.0001*IL-17F0.05 (1.1)1.3 (1.5)2.40.0007*IL-221.9 (1.1)3.1 (1.3)2.40.0002*TNFα0.5 (0.75)1.4 (1.1)1.80.0002*IFNɣ2.4 (0.84)2.9 (1.3)1.50.0259*Data are mean (SD); *p<0.05 and |fold difference| >1.4; ▫adjusted for confounding factors age & sex.ConclusionGUS-tx TNFi-IR pts showed response-specific associations with BL biomarkers (IL-22, IFNɣ, IL-6, and SAA). GUS resulted in decreased levels of elevated CRP, SAA, IL-6, IL-17A, IL-17F, and IL-22, while no significant change was observed with PBO tx. Reductions in these biomarkers were evident as early as W4 and approximated levels seen in HC from W16 onward (W4 for IL-22), suggesting apparent normalization of effector cytokines associated with the IL-23/Th17 axis following GUS tx.