THU0052 USTEKINUMAB AND GUSELKUMAB TREATMENT RESULTS IN DIFFERENCES IN SERUM IL17A, IL17F AND CRP LEVELS IN PSORIATIC ARTHRITIS PATIENTS: A COMPARISON FROM USTEKINUMAB PH3 AND GUSELKUMAB PH2 PROGRAMS

Abstract

Background: Ustekinumab (UST) is a monoclonal antibody (mAb) that binds the p40 epitope which is shared by IL12 and IL23, whereas guselkumab (GUS) is a mAb that selectively binds the p19 subunit of IL23. In recent studies, both UST (Phase 3 programs)1 and GUS (Phase 2 program)2 have demonstrated a reduction in musculoskeletal clinical signs and symptoms and improvement of psoriatic lesions in patients with active psoriatic arthritis (PsA), implicating the IL12/23 pathway in disease pathogenesis. Objectives: To explore the post-treatment pharmacodynamic changes of IL17A, IL17F, and CRP with GUS and UST in the context of PsA. Methods: Serum protein levels of IL17A, IL17F, and CRP were measured in 142 subjects and 38 matched healthy controls from the GUS Ph2 study2 at Weeks 0, 4, and 16. In the UST Ph3 studies1, biomarkers were assayed at Weeks 0, 4, and 24 as follows: IL17A (n=474), IL17F (n=237), CRP (n=927). IL17A and IL17F were assayed using Single Molecule CountingTM Human Immunoassay Kits (formerly Singulex). CRP was measured using CardioPhase hsCRP assay (UST studies) or Meso Scale Discovery Platform (GUS study). Results: At baseline, the Th17 effector cytokines IL17A and IL17F were elevated in the serum of PsA subjects in the GUS Ph2 cohort compared to healthy controls. IL17A and IL17F levels significantly correlated with affected skin body surface area, but not swollen or tender joint scores, in both studies. While none of the baseline levels of evaluated cytokines were associated with American College of Rheumatology (ACR) or Psoriasis Area Severity Index (PASI) clinical responses to UST, baseline IL17F levels were modestly associated with ACR20 response to GUS at week 24. Both UST and GUS treatment resulted in pharmacodynamic decreases in IL17A, IL17F, and CRP levels, with GUS treatment restoring IL17A and IL17F levels to that of healthy controls by week 16. Consistent with being a component of ACR scores, CRP changes were significantly associated with ACR20 responses to both UST and GUS treatment. Weeks 4 and 16 changes in IL17F with GUS treatment were significantly associated with ACR20 response at week 24. Week 24 PASI75 response to GUS was significantly associated with week 4 changes in IL17A, with a similar trend observed at Week 16. Conclusion: These results underscore the relevance of the IL23/Th17 pathway in PsA, with GUS treatment providing a stronger suppression of the pathway than UST treatment. The significant associations of changes in IL17A and IL17F levels with GUS treatment with PASI75 and ACR20 response, respectively, support the importance of the IL23/Th17 pathway for both skin and joint pathologies. The associations of reduction in CRP levels with both UST and GUS treatment also reinforce the role of acute phase inflammation in joint pathology.