Contributions
Abstract: P730
Type: Poster
Abstract Category: Therapy - disease modifying - Tools for detecting therapeutic response
Background: Ofatumumab is an anti-CD20 human monoclonal antibody that depletes B cells and has demonstrated dose-dependent efficacy in MS patients during Phase 2 studies. Novartis is currently initiating Phase 3 clinical trials in relapsing MS. The efficacy of anti-CD20 therapy in MS is hypothesised to be directly related to how strongly it depletes circulating B cells. Thus, understanding the dose-response relationship between ofatumumab dose level administered and B cell dynamics is key for selecting a treatment regimen providing optimal efficacy with favourable safety.
Objective: To develop a population dose-response model for B cell count under ofatumumab treatment as a function of time and patient-specific characteristics and to evaluate the predictive properties of this model.
Data and methods: 231 patients from the Phase 2 MIRROR study in RRMS patients were dosed subcutaneously with either with placebo, 3 mg q12w, 30 mg q12w, 60 mg q12w, or 60 mg q4w. The treatment duration was 24 weeks, with treatment follow-up until Week 48. B cell counts were assessed at screening and every 4 weeks until the end of the study, and in a follow-up phase observing B cell recovery after treatment stop. Due to target-mediated drug disposition, pharmacokinetic (PK) samples were mostly below limit of quantification except at the highest dose. Therefore, we fitted a K-PD model where a dosing compartment drives a turnover response in B cells. We used nonlinear mixed effects methods to estimate the K-PD model parameter means and inter-patient variability.
Results: Predictive checks showed that the K-PD model adequately captured B cell depletion and repletion dynamics vs. dosing and demonstrated good predictive properties.
Conclusion: The dose-response model well-described B cell dynamics, and could be used to compare performance of ofatumumab dosing regimens.
Disclosure: This abstract is supported by Novartis Pharma AG, Basel, Switzerland
All authors are employees of Novartis.
Abstract: P730
Type: Poster
Abstract Category: Therapy - disease modifying - Tools for detecting therapeutic response
Background: Ofatumumab is an anti-CD20 human monoclonal antibody that depletes B cells and has demonstrated dose-dependent efficacy in MS patients during Phase 2 studies. Novartis is currently initiating Phase 3 clinical trials in relapsing MS. The efficacy of anti-CD20 therapy in MS is hypothesised to be directly related to how strongly it depletes circulating B cells. Thus, understanding the dose-response relationship between ofatumumab dose level administered and B cell dynamics is key for selecting a treatment regimen providing optimal efficacy with favourable safety.
Objective: To develop a population dose-response model for B cell count under ofatumumab treatment as a function of time and patient-specific characteristics and to evaluate the predictive properties of this model.
Data and methods: 231 patients from the Phase 2 MIRROR study in RRMS patients were dosed subcutaneously with either with placebo, 3 mg q12w, 30 mg q12w, 60 mg q12w, or 60 mg q4w. The treatment duration was 24 weeks, with treatment follow-up until Week 48. B cell counts were assessed at screening and every 4 weeks until the end of the study, and in a follow-up phase observing B cell recovery after treatment stop. Due to target-mediated drug disposition, pharmacokinetic (PK) samples were mostly below limit of quantification except at the highest dose. Therefore, we fitted a K-PD model where a dosing compartment drives a turnover response in B cells. We used nonlinear mixed effects methods to estimate the K-PD model parameter means and inter-patient variability.
Results: Predictive checks showed that the K-PD model adequately captured B cell depletion and repletion dynamics vs. dosing and demonstrated good predictive properties.
Conclusion: The dose-response model well-described B cell dynamics, and could be used to compare performance of ofatumumab dosing regimens.
Disclosure: This abstract is supported by Novartis Pharma AG, Basel, Switzerland
All authors are employees of Novartis.