Exposure-Response Analysis of Guselkumab in the Maintenance Phase in Adults with Moderately to Severely Active Ulcerative Colitis

Objectives: QUASAR study was a Phase 2b/3, randomized, double-blind, placebo controlled, parallel group, multicenter study to evaluate the safety and efficacy of guselkumab, an IL-23p19 subunit inhibitor, in adult participants with moderately to severely active ulcerative colitis (UC). The exposure-response (E-R) analyses were performed using efficacy endpoints and guselkumab exposure data from a QUASAR Phase 3 maintenance study of guselkumab. The main objective of this analysis was to characterize the relationships between guselkumab exposure metrics and clinical efficacy measures at Maintenance Week 44 (M-44) following intravenous (IV) and subcutaneous (SC) administration in adult participants with moderately to severely active UC and identify subpopulations who can potentially benefit from a higher guselkumab maintenance dose.

Methods: Landmark E-R analyses were performed for efficacy endpoints at Week M-44 for maintenance in the QUASAR study. A total of 568 randomized participants who were guselkumab IV induction responders were included, with 190 participants treated with placebo, 188 participants treated with 100 mg guselkumab SC q8w, and 190 participants treated with 200 mg guselkumab SC q4w. The 4 key efficacy endpoints (ie, clinical remission, clinical response, endoscopic healing, histologic endoscopic mucosal healing) were evaluated in relation to predicted exposure metrics (maintenance Ctrough, week44 and Cave, week36-44). Covariates were tested for the landmark E-R analyses.

Results: There were consistent positive E-R relationships for all 4 selected key efficacy endpoints at Week M-44 in participants who received guselkumab 200 mg SC q4w or 100 mg SC q8w. For all 4 efficacy endpoints at Week M-44, Ctrough, week44 was a better predictor for the E-R relationships than Cave, week36-44. Covariate analysis demonstrated that the extent of UC disease was an influential factor on the Emax across all 4 selected key efficacy endpoints at Week M-44. Moreover, clinical remission status at maintenance baseline was an influential factor for clinical remission at Week M-44. Endoscopic healing status at maintenance baseline and fecal calprotectin at maintenance baseline were also significant covariates for endoscopic healing at Week M-44.

Conclusions: E-R modeling analyses demonstrated that higher guselkumab exposure is expected to result in a greater probability of achieving all 4 clinical efficacy endpoints at M-44 in the overall population. Particularly, the subpopulation with extensive disease exhibits a greater guselkumab treatment effect from 200 mg SC q4w relative to 100 mg SC q8w.