(T-083) Exposure-Response Analysis of Guselkumab in Induction Studies in Adults with Moderately to Severely Active Ulcerative Colitis in the QUASAR Program

Jafar Sadik Shail – Johnson & Johnson Innovative Medicine; Yu Kyoung Cho – Johnson & Johnson Innovative Medicine; Yuan Xiong – Johnson and Johnson Innovative Medicine; Jie Shao – Johnson and Johnson Innovative Medicine; Zhenhua Xu – Johnson and Johnson Innovative Medicine; An Vermeulen – Johnson and Johnson Innovative Medicine; Mahesh Samtani – Johnson and Johnson Innovative Medicine

Objectives: The exposure-response (E-R) analyses were performed using pooled efficacy endpoints and guselkumab exposure data from a Phase 2b induction dose-ranging study (IS-1) and a Phase 3 confirmatory induction study (IS-2) of guselkumab, a dual acting IL-23p19 subunit inhibitor, in adult participants with moderately to severely active ulcerative colitis (UC). The main objective of this analysis was to characterize the relationship between guselkumab exposure metrics and clinical efficacy measures following intravenous (IV) administration in adult participants with moderately to severely active UC.

Methods: Landmark E-R analyses were performed for the pooled efficacy endpoints at the end of the induction period, Week I-12 from IS-1 and IS-2 studies. In the induction period, a total of 1,013 participants were included, with 385 participants treated with placebo, 521 participants treated with 200 mg IV q4w guselkumab, and 107 participants treated with 400 mg IV q4w guselkumab. The 4 key efficacy endpoints (ie, clinical remission, clinical response, endoscopic healing, histologic endoscopic mucosal healing) were evaluated in relation to predicted exposure metrics (Ctrough, week12 and Cave, week0-12).

Results: Initial exploratory E-R analysis suggested apparent positive E-R relationships between systemic guselkumab exposures (Ctrough, week12 and Cave, week0-12) and efficacy endpoints at Week I-12. Further graphical and model-based analyses showed that the apparent positive E-R relationship could be explained by intrinsic disposition characteristics (clearance (CL) or half-life (t1/2)) of guselkumab. After accounting for CL or t1/2 no clear positive E-R relationships remained across all 4 efficacy endpoints at Week I-12 . These findings are consistent with the observed lack of dose-response relationship of guselkumab during IV induction.

Conclusions: The lack of E-R, consistent with the observed lack of dose-response relationship, supports the use of the lower efficacious dose of 200 mg IV for induction. The E-R findings are consistent with literature where a similar phenomenon of apparent positive E-R relationships explained by intrinsic disposition characteristics of a drug has been reported for other monoclonal antibodies used in the treatment of Inflammatory Bowel Disease (IBD) such as vedolizumab[1].

Citations: Osterman MT, Rosario M, Lasch K, Barocas M, et al. Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimization. Aliment Pharmacol Ther. 2019;49(4):408-418.

Keywords: Guselkumab, Induction E-R, UC