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ACoP 2021: General Pharmacometrics e.g. popPK, PKPD, E-R, trial simulation, C-QT
Nastya Kassir

Exposure-Response Analysis of Etrolizumab in Patients with Moderately-to-severely Active Ulcerative Colitis

Objectives: Etrolizumab is an IgG1-humanised monoclonal antibody that specifically targets the β7 subunit of α4β7 and αEβ7 integrins, and has been evaluated for the treatment of ulcerative colitis (UC). Phase III trials in patients with moderately-to-severely active UC were performed and included induction and/or maintenance phases. Patients were previously treated with tumor necrosis factor inhibitors (TNF-exposed: HICKORY) or naïve (TNF-naïve: HIBISCUS I/II and LAUREL). Exposure-response (ER) analyses were performed to characterize the relationships between exposure and efficacy endpoints and to assess and adjust for covariate effects.

Methods: The ER analyses were separately performed for clinical outcomes. In all studies and phases, etrolizumab was administered subcutaneously at 105 mg every 4 weeks. Clinical outcomes were assessed at the end of induction for HIBISCUS I/II and HICKORY and at the end of maintenance for HICKORY and LAUREL.[1] Clinical outcomes used in the ER analyses included Mayo Clinic Score (MCS)-defined remission (primary outcome), endoscopic improvement, remission using the modified MCS and clinical response (induction only). Trough concentration at week 4 (Ctrough,wk4) was selected as the exposure metric. ER modeling was conducted using logistic regression. Model fitting was performed by first fitting a univariate base model with exposure as the only covariate. The impact of covariates on clinical outcomes was examined in a full covariate model, including all pre-specified covariates (i.e., baseline fecal calprotectin, MCS, C-reactive protein, albumin, and smoking status).

Results: The exposure metric, Ctrough,wk4 of induction, was selected based on the pharmacokinetic behavior of etrolizumab and aimed to minimize the probability of confounding given that clearance was known to decrease over time based on the population pharmacokinetic analysis. Linear models with a single intercept for placebo and active treatments adequately described the data for all 14 analyses. Etrolizumab exposure-response slope was significant (p<0.05) for 12/14 analyses except for remission and remission using the modified MCS for the maintenance phase in TNF-naïve patients. The ER relationships for induction outcomes were more apparent than those for maintenance outcomes. MCS at baseline was the only statistically significant covariate to impact the induction outcomes with limited influence on the ER relationship. Lower MCS at baseline (< 9) increased the probability of achieving MCS-defined remission, endoscopic improvement, and modified MCS remission at the end of induction. No significant covariates were identified for maintenance outcomes.

Conclusions: There was a statistically significant positive ER relationship for most of the clinical outcomes tested, reflecting a better treatment effect in UC patients with higher exposure. The single dose level tested in the Phase III UC clinical trials was a potential limitation in assessing the true ER relationship due to a potentially confounding effect on exposure of clinical improvement and favorable outcome.

[1] (HIBISCUS I (NCT02163759), HIBISCUS II (NCT02171429), LAUREL (NCT02165215), HICKORY (NCT02100696))

  • Nastya Kassir, Genentech (Presenting Author)
  • Rui Zhu, Genentech (CoAuthor)
  • Anita Moein, Genentech (CoAuthor)
  • Jurgen Langenhorst, Pharmetheus AB (CoAuthor)
  • Jakob Ribbing, Pharmetheus AB (CoAuthor)
  • Rong Zhang, Genentech (CoAuthor)
  • Meina Tang, Genentech (CoAuthor)
  • Young S. Oh, Genentech (CoAuthor)
  • Wenhui Zhang, Genentech (CoAuthor)

Reference: ACoP12 (2021) PMX-82 []
General Pharmacometrics e.g. popPK, PKPD, E-R, trial simulation, C-QT