Joanna Parkinson 1, Magnus Ã…strand 1, Anis Khan 2, Ahmad Ebrahimi 1, Corina Dota 1, Jasia King 1
1 AstraZeneca (Gothenburg, Sweden), 2 AstraZeneca (Gaithersburg, USA)
Objectives
Opemalirsen (previously known as AZD2373) is an antisense oligonucleotide (ASO) targeting the APOL1 mRNA. It is currently explored as a potential treatment for APOL1 mediated kidney disease. The aim of this work was to assess the risk of QT-interval prolongation with opemalirsen using concentration-QTc (C-QTc) modeling.
Methods
Two randomized, placebo-controlled Phase 1 trials in healthy male volunteers were included in the assessment. The studies were pooled to increase the sample size for the C-QTc modeling. 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 20, 50, or 150 mg or placebo weekly for 6 weeks. Administration route was subcutaneous. Digital ECG (dECG) recordings were taken at scheduled timepoints preceding PK sampling, and time-matched opemalirsen concentrations were obtained across all arms. A prespecified linear mixed-effects model [1] was applied with ΔQTcF (change from baseline QTcF) as the dependent variable, time-matched opemalirsen concentration as the independent variable, and baseline QTcF, nominal time, and treatment arm as factors. Model adequacy was evaluated via goodness-of-fit plots. Heterogeneity was assessed, since data were pooled from multiple studies.
Results
Opemalirsen did not have an effect on heart rate, there was no evidence of hysteresis in ΔQTcF and no indication of non-linearity in the C-QTcF relationship, hence all assumptions for using pre-specified linear mixed-effect model were met. The model adequately described the concentration-ΔQTcF relationship with a small and non-significant slope of -0.0009 ms/ng/mL (95% CI: -0.0019, 0.0000). The diagnostic plots confirmed the quality and robustness of the final model. At the highest geometric mean Cmax of 4,274.77 ng/mL (achieved in the MAD study), the estimated ΔΔQTcF was -1.83 ms with a 90% CI of -5.63 to 1.96 ms. Across the evaluated opemalirsen concentration range, the upper bound of the 90% CI for mean ΔΔQTcF remained below the regulatory threshold of 10 ms. Heterogeneity assessment indicated no bias between SAD and MAD studies, thus supporting pooling of the data.
Conclusions
No clinically relevant QTcF prolongation was observed within the studied exposure range of opemalirsen. ASOs are currently held to the same regulatory standards as small molecules for evaluating QT effects, despite their low proarrhythmic risk [2] and this assessment contributes to the growing body of evidence that ASOs are unlikely to cause QT prolongation. In addition, the modeling presented here provides a practical example on how to conduct C-QTc modeling assessment for pooled studies.
References:
References
[1] Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397
[2] Yusheng Qu, Kim A. Henderson, Tod A. Harper Jr, Hugo M. Vargas. Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities? 2024. Clinical Pharmacology & Therapeutics 116(1)
Reference: PAGE 34 (2026) Abstr 12317 [www.page-meeting.org/?abstract=12317]
Poster: Drug/Disease Modelling - Safety