Magnus Åstrand 1, Peter J Greasley 2, Iain MacPhee 3, Anis Khan 1, Michael McCarthy 4
1 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca (Gothenbourg, Sweden), 2 Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca (Gothenburg, Sweden), 3 Late-Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca (Cambridge, UK), 4 Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca (Gaithersburg, United States of America)
Objectives
APOL1-mediated kidney disease (AMKD) is associated with toxic gain of function variants in people of African ancestry with the high-risk APOL1 genotypes (G1 and/or G2). APOL1 protein is part of the innate immune system but not considered essential. Opemalirsen (previously known as AZD2373) is an antisense oligonucleotide (ASO) targeting the APOL1 mRNA. It is currently being evaluated as a potential treatment for AMKD. The aim of this work was to characterize APOL1 protein lowering effect in plasma and to characterize the APOL1 protein dose response of opemalirsen using modeling and thereby guide dose selection for a dose ranging study in patients with AMKD.
Methods
Two randomized, placebo-controlled Phase 1 trials in healthy male volunteers of West African ancestry were included in the assessment. In the Single Ascending Dose (SAD) study NCT04269031, 31 participants received opemalirsen at 10, 30, 75, or 150 mg or placebo. In Multiple Ascending Dose (MAD) NCT05351047 study, 24 participants received weekly doses 20, 50, or 150 mg or placebo for 6 weeks. Administration route was subcutaneous. Plasma APOL1 protein levels were quantified based on samples taken at 11
and 12 scheduled timepoints up to 10 and 13 weeks after first dose in the SAD and MAD study respectively. ASOs such as opemalirsen often shows a rapid distribution phase and high maximum concentration in plasma while the site-of-action concentration in tissue often have longer terminal elimination half-life and much lower peak to trough ratio after repeated dosing. A kinetic-pharmacodynamic (KPD) model was therefore chosen to describe the time and dose dependent APOL1 plasma protein reduction. The model comprised a one-compartment kinetic component combined with a turnover model component with zero order input to describe the time course of APOL1 protein levels in plasma. The hypothetical drug concentration was used to drive the reduction of APOL1 protein via reduction of the input rate according to an inhibitory emax model.
Results
The KPD model adequately described the APOL1 protein levels over time and across doses based on diagnostic plots confirming the quality and robustness of the final model. The model identified a clear dose dependent APOL1 protein reduction after repeated dosing. Exposure from a single dose appeared too short to provide clear APOL1 reduction. The model predicts additional APOL1 reduction for longer treatment duration compared to the 6 weeks treatment in the MAD study. Reductions of 36 and 64% are predicted at steady state for 50 and 150mg once weekly opemalirsen doses.
Conclusions
A KPD model for APOL1 was built on SAD and MAD data. The model predicts dose-dependent plasma APOL1 reductions that are hypothesized to result in clinical meaningful reductions in human Urine Albumin-to-Creatinine Ratio based on transgenic mice data.
Reference: PAGE 34 (2026) Abstr 12318 [www.page-meeting.org/?abstract=12318]
Poster: Drug/Disease Modelling - Other Topics