E. Marostica (1), N. Snelder (1), M. Jensen (2), M. Lobmeyer (2), W. Smith (3), C. Bethune (4), S. Bhanot (4), E. Morgan (4), R. Yu (4), Y. Wang (4), R. Geary (4), S. Willmann (2)
(1) LAP&P Consultants BV, Leiden, The Netherlands, (2) Bayer AG, Wuppertal, Germany, (3) Bayer, Whippany, NJ, USA, (4) Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA
Introduction/Objectives: Antisense oligonucleotide (ASO) is a synthetized string of nucleic acids that binds to mRNA produced by a particular gene thereby preventing its translation to the specific protein known to be causative of a specific disease.
FXI-ASO (BAY 2306001, ISIS 416858) is a 20-mer second generation 2’-MOE chimeric antisense oligonucleotide inhibitor of Factor XI (FXI) that has been clinically studied in healthy volunteers (HVs) and in phase 2 studies with patients undergoing total knee arthroplasty (TKA) as well as end-stage renal disease (ESRD) patients on hemodialysis. In these studies, doses of unconjugated FXI-ASO ranging between 50 mg and 300 mg were administered as either single-dose (SD) or multiple-dose (MD).
BAY 2976217 (former name: ION-957943) is a generation 2.0 triantennary N-acetyl galactosamine (GalNAc) conjugated 2`-MOE chimeric antisense oligonucleotide inhibitor of FXI. It shares the same RNA nucleic acid sequence as the unconjugated FXI-ASO. The GalNAc conjugation facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake and thereby enhances drug delivery to the hepatocyte which is the target cell type for inhibition of FXI synthesis. BAY 2976217 has demonstrated dose-dependent reduction of FXI antigen and activity in a recent phase 1 study (doses ranging from 40 mg to 120 mg SD or 10 mg to 80 mg MD).
The objective of the analysis was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for the unconjugated FXI-ASO and BAY 2976217 that allows to bridge the dose-exposure-FXI relationship from the unconjugated FXI-ASO to the GalNAc-conjugated BAY 2976217 and facilitates extrapolation of the reduction of FXI levels in ESRD patients after repeated doses of BAY 2976217, based on PK/PD data previously collected for the unconjugated FXI-ASO.
Methods: A previously developed PK/PD model by Yu et al. [1] to describe PK and FXI activity of the unconjugated FXI-ASO in HVs after subcutaneous administration was used as a starting point. This model was further developed and extended by integrating unconjugated FXI-ASO data from ESRD patients as well as BAY 2976217 data from HVs after ascending single and multiple subcutaneous doses.
In the extended model, subcutaneous absorption was described by parallel zero- and first-order processes. A covariate analysis was performed to investigate differences between HVs and ESRD patients in PK based on the unconjugated FXI-ASO data.
The indirect response model with inhibitory effect on the generation of FXI that was initially developed by Yu et al. [1] was extended with an effect compartment to account for the delay between plasma concentration and effect. The indirect response model was simultaneously fitted to unconjugated FXI-ASO and BAY 2976217 FXI activity data. Differences between HVs and ESRD patients in PD were explored.
To support extrapolation of FXI levels in ESRD patients receiving BAY 2976217, simulations of PK and FXI activity (with inter-individual variability) were performed with the final PK/PD model.
Results: FXI activity reduction after unconjugated FXI-ASO and BAY 2976217 could be described by an indirect response model with inhibitory effect on the generation of FXI via an effect compartment. A factor of approximately 1/3 on the effect site elimination rate constant was estimated for ESRD patients who showed higher plasma concentrations and lower extent of FXI reduction as compared to HVs.
Overall, PK and PD parameters were estimated with good precision and the extended population PK/PD model could adequately describe the central trend and the inter-individual variability for plasma concentration as well as FXI activity across dose groups and studies for both ASOs. By carrying forth the effect of ESRD on PK and PD to BAY 2976217 and assuming no influence of ESRD on the activity of ASGPR-mediated hepatic uptake, the population PK/PD model was used to extrapolate what doses and dosing regimens of BAY 2976217 will lead to reduction of FXI activity levels at steady-state in ESRD patients as compared to the unconjugated FXI-ASO. Overall, the model estimated an increase in potency by a factor of 20 for BAY 2976217 compared to the unconjugated FXI-ASO in ESRD patients.
Conclusions: Under the assumption that the ASGPR-mediated hepatic uptake is not altered in ESRD patients compared to healthy subjects, the developed model could be used to extrapolate clinical dose and time course of plasma drug exposure as well as FXI activity of BAY 2976217 in ESRD patients based on PK/PD data previously collected for the unconjugated FXI-ASO.
References:
[1] Yu R.Z. et al., Population pharmacokinetic/pharmacodynamic (PK/PD) modelling for a second generation antisense oligonucleotide (ISIS-FXIRx), targeting factor XI, in healthy subjects, ASCPT Annual Meeting (2015)
Reference: PAGE () Abstr 9474 [www.page-meeting.org/?abstract=9474]
Poster: Drug/Disease Modelling - Other Topics