P273 Ustekinumab and guselkumab treatment results in differences in serum IL-17A, IL-17F and CRP levels in PsA patients: a comparison from ustekinumab Phase 3 and guselkumab Phase 2 programmes
Authors: Siebert Stefan , Loza Matthew J , Song Qingxuan , Gorecki Patricia C , McInnes Iain B , Sweet Kristen 
Published: April 2020

Abstract

Background
Ustekinumab (UST) is a monoclonal antibody (mAb) that binds the p40 epitope which is shared by IL-12 and IL-23, whereas guselkumab (GUS) is a mAb that selectively binds the p19 subunit of IL-23. In recent studies, both UST (Phase 3 programs) and GUS (Phase 2 program) have demonstrated a reduction in musculoskeletal clinical signs and symptoms and improvement of psoriatic lesions in patients with active psoriatic arthritis (PsA), implicating the IL-12/23 pathway in disease pathogenesis. This analysis explored the post-treatment pharmacodynamic changes of IL-17A, IL-17F, and CRP with GUS and UST in the context of PsA.

Methods
Serum protein levels of IL-17A, IL-17F, and CRP were measured in 142 subjects and 38 matched healthy controls from the GUS Phase 2 study at Week (W)0, W4, and W16. In the UST Phase 3 studies, biomarkers were assayed at W0, W4, and W24 as follows: IL-17A (n = 474), IL-17F (n = 237), CRP (n = 927). IL-17A and IL-17F 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 IL-17A and IL-17F were elevated in the serum of PsA subjects in the GUS Phase 2 cohort compared to healthy controls. IL-17A and IL-17F 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 IL-17F levels were modestly associated with ACR20 response to GUS at Week 24. Both UST and GUS treatment resulted in pharmacodynamic decreases in IL-17A, IL-17F, and CRP levels, with GUS treatment restoring IL-17A and IL-17F levels to that of healthy controls by W16. Consistent with being a component of ACR scores, CRP changes were significantly associated with ACR20 responses to both UST and GUS treatment. W4 and W16 changes in IL-17F with GUS treatment were significantly associated with ACR20 response at W24. W24 PASI75 response to GUS was significantly associated with W4 changes in IL-17A, with a similar trend observed at W16.

Conclusion
These results underscore the relevance of the IL-23/Th17 pathway in PsA, with GUS treatment providing a stronger suppression of the pathway than UST treatment. The significant associations of changes in IL-17A and IL-17F levels with GUS treatment with PASI75 and ACR20 response, respectively, support the importance of the IL-23/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.

Disclosures
S. Siebert: Other; S.S. has been a study investigator for Janssen. M.J. Loza: Other; M.L. is a Janssen employee. Q. Song: Other; Q.S. is a Janssen employee. P.C. Gorecki: Other; P.G. is a Janssen employee. I.B. McInnes: Other; I.M. has been a study investigator for Janssen. K. Sweet: Other; K.S. is a Janssen employee.