(M-096) Simultaneous PASI Exposure Response Analysis of Ustekinumab in Subjects with Psoriasis and Psoriatic Arthritis

Yingyi Li – Johnson and Johnson Innovative Medicine; Yu Kyoung Cho – Johnson and Johnson Innovative Medicine; Wangda Zhou – Johnson and Johnson Innovative Medicine; Yuan Xiong – Johnson and Johnson Innovative Medicine; Mahesh Samtani – Johnson and Johnson Innovative Medicine

Objectives: Psoriasis (PsO) is a chronic inflammatory skin disease driven by immune mediators like TNFα, IFNγ, IL-17, and IL-23. Psoriatic Arthritis (PsA) is a chronic inflammatory arthritis that develops in up to 30% of patients with PsO.1 Furthermore, over 90% of PsA patients initially experience arthritis in the context of pre-existing PsO.2 Ustekinumab (Stelara), a monoclonal antibody which neutralizes the biological effects of human interleukin (IL)-12 and IL-23, is approved to treat PsO and PsA. Ustekinumab can inhibit bioactivity of human IL-12 and IL-23 by preventing these cytokines from binding to their receptors on the surface of immune cells. The simultaneous exposure response (E/R) analysis was performed to characterize an important endpoint (PASI) exposure relationship between two indications using PsO and PsA patients’ data.

Methods: The data used in E/R models with PsO population was obtained from two Phase III studies (C0743T09 and C0743T08) in subjects with PsO. The data used in E/R models with PsA population was obtained from Phase III studies in subjects with PsA (CNTO1275PSA3001 and CNTO1275PSA3002). Across these clinical studies, ustekinumab doses of 45 or 90 mg were administered subcutaneously initially and 4 weeks later, followed by 45 or 90 mg doses every 12 weeks. The individual post-hoc pharmacokinetic (PK) parameters and PK exposures were simulated based on previously developed population PK model in PsO and PsA. A landmark E/R model analysis was performed separately using PASI score at week 24 with average concentration at steady state (Cavg,ss) in PsO or PsA. Ustekinumab PsO and PsA data was then combined into one dataset to perform covariate screening analysis. Baseline PASI was tested in the covariate analysis.

Results: The previously developed population PK model was used to simulate individual post-hoc PK parameters and PK exposures. The landmark E/R analysis using PASI data at week 24 with Cavg,ss in PsO estimated EC50 as 0.607 µg/mL, while in PsA EC50 was 0.605 µg/mL. The separate E/R analysis suggested that EC50 was similar in both populations. By using a combined dataset of PsO and PsA, the covariate analysis determined that baseline PASI was significant covariate on Emax. The result indicated that EC50 showed no difference between two populations. The overlaid E/R plots in PsO vs PsA population suggested that the PASI E/R curve shared are similar sigmoidal trend while PASI response rate in PsO had higher Emax.

Conclusions: The simultaneous E/R analysis using combined datasets of PsO and PsA suggests that indication was not a covariate on EC50 and showed no difference between two populations. The observed maximum PASI response rate was higher in patients with PsO compared to those with PsA, and the landmark E/R model included covariate of baseline PASI on Emax is able to characterize this disparity.

Citations: Citations:
1. FitzGerald O, Ogdie A, Chandran V, Coates LC, Kavanaugh A, Tillett W, et al. Psoriatic arthritis. Nat Rev Dis Primers. (2021) 7:59.
2. Pennington SR, FitzGerald O. Early origins of psoriatic arthritis: clinical, genetic and molecular biomarkers of progression from psoriasis to psoriatic arthritis. Front Med (Lausanne). (2021) 8:723944.

Keywords: Keywords: Exposure-Response Analysis, Psoriasis, Psoriatic Arthritis