Senior Principal Scientist Johnson & Johnson Innovative Medicine, United States
Disclosure(s):
Tae Eun Yang: No financial relationships to disclose
Objectives: The purpose of the exposure-response (E-R) analyses of guselkumab (a dual-acting IL-23p19 subunit inhibitor) in participants with moderately to severely active Crohn’s disease (CD) was to characterize the relationship between guselkumab exposure metrics and clinical efficacy outcomes following IV or SC induction and SC maintenance treatment, and to evaluate the impact of potentially influential covariates to inform whether different subgroups of participants might benefit from different dose regimens.
Methods: The landmark E-R analyses were based on integrated data from one Phase 2b dose-ranging study and three Phase 3 studies and performed at 2 pivotal timepoints during the clinical studies (ie, Week 12 [induction treatment assessment] and Week 48 [maintenance treatment assessment]). Three IV induction dose regimens of 200, 600, or 1200 mg every 4 weeks (q4w) ×3 doses were evaluated in GALAXI 1, while the lowest induction dose regimen (200 mg q4w ×3 doses) was evaluated in the confirmatory Phase 3 GALAXI studies (GALAXI 2 and GALAXI 3). A single SC induction dose regimen of 400 mg q4w ×3 doses was evaluated in GRAVITI. Two SC maintenance dose regimens (ie, 100 mg q8w and 200 mg q4w) were evaluated in both GALAXI and GRAVITI. Individual guselkumab exposure metrics were obtained via simulation using the final PopPK model and actual dose information. A logistic regression model was used to quantify the relationship between guselkumab exposure metrics and probability of achieving binary clinical endpoints. Covariate modeling was based on the stepwise forward addition and backward elimination approach. Covariates including baseline disease characteristics (ie, CDAI score, SES-CD score, disease duration, CRP, and fecal calprotectin), prior biologic failure status, prior conventional medication failure status, and clinical efficacy status at Week 12 were assessed. The E-R analyses were performed using NONMEM and R.
Results: In the induction E-R analyses, an apparent E-R trend was observed but there was no dose-response, suggesting the presence of potential confounding factors (ie, CL). Once this confounder was corrected for, guselkumab exposure did not show any relationship with induction responses. In the maintenance E-R analyses, the distribution of the steady-state trough concentrations on the E-R curve indicated that guselkumab exposure was associated with substantial efficacy for both maintenance dose regimens. Covariate analysis suggested that participants who did not achieve clinical remission or endoscopic response at Week 12, or those who had baseline SES-CD scores>12 may receive additional benefit from the 200 mg SC q4w dose regimen compared with the 100 mg SC q8w dose regimen. In addition, comparable efficacy outcomes were achieved following SC induction relative to IV induction for the same guselkumab concentration quartile subgroup at Week 12 and Week 48, which supports the use of the proposed SC induction treatment in CD.
Conclusions: Landmark E-R analyses successfully support the selection of guselkumab IV and SC induction regimens, and SC maintenance regimens in participants with moderately to severely active CD.
