Joanna Parkinson1, Ahmad Ebrahimi2, Christer Gottfridsson2, Corina Dota2, Dinko Rekic3
1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, 2Cardiovascular Safety Center of Excellence and SKGs, Global Patient Safety, Oncology R&D, AstraZeneca, 3Alexion, AstraZeneca, Rare Disease
Objectives All drugs with systemic bioavailability require assessment of the QT interval, which represents ventricular depolarization and repolarization activity of the heart by electrocardiogram (ECG) in clinical trials [1]. This is conducted to evaluate the risk of QT prolongation and the occurrence of rare but potentially fatal ventricular arrhythmia, Torsade de Pointes. Historically, clinical QT assessment has been performed in dedicated thorough QT/QTc (TQT) studies, which can be expensive and complex. In December 2015, the E14 Q&As (R3) was approved by the ICH Assembly and the revised Question #5.1 generated harmonized guidance on how concentration response modelling could be used as primary analysis method for regulatory decision making [2]. Since then, AstraZeneca (AZ) evaluated innovative ways to implement this new regulatory guidance in assessing the risk of QT-prolongation in a patient-centric and cost-effective way. Methods As pioneers in this industry-wide transformation, AZ swiftly adapted to the new regulatory landscape, instituting a structured framework for project teams to apply these methodologies effectively [3]. Our prompt response not only positioned us as front-runners in adopting this approach but also facilitated its consistent application across our entire portfolio: currently all clinical QT assessments in AstraZeneca are conducted using C-QTc modelling approach. This applies to assessments using high-quality ECG data from early studies as well as using C-QTc modelling as a primary analysis method in dedicated TQT studies. Results The result is a substantial reduction in both cost and time in our drug development processes, reinforcing our commitment to excellence and innovation in cardiac safety evaluation. Since 2021, AstraZeneca submitted 5 successful TQT-substitutes (1 ASO and 4 small-molecules [4-7]), where C-QTc assessment was conducted using early clinical data from phase 1 studies (single and/or multiple ascending dose studies; in case of an oncology drug, also including dose expansion), thus avoiding the need to run a dedicated QT study. All submissions were based on single study data, which ranged in size from 40 to 180 participants. Studies were mainly done in healthy volunteers, except for an oncology drug, where patients with advanced solid malignancies were included [4]. Using ECG data collected from early studies instead of dedicated TQT study reduced the cost of clinical QT assessment by up to 98%. In case of drugs for which sufficient early clinical data were not available (e.g. drugs, where phase 1 studies were completed prior to implementation of ICH Q&A 5.1 and high-quality ECG data was not collected), we designed lean TQT studies, with C-QTc modelling as primary analysis. This allowed us to reduce the size of such studies by at least 50%: typical TQT study with sample size of 50-60 subjects was replaced with 24 subjects for a cross-over design [8]. Since 2021, AZ has performed 2 TQT studies, both with C-QTc analysis as primary analysis method [8, 9]. Conclusions The swift adaptation to the new regulatory opportunity allowed AZ to excel in using model-based QT assessment in drug development. This not only largely reduced the cost of clinical QT assessment (up to 98%) and saved time but also avoided unnecessary exposure of healthy volunteers to the drug (by avoiding dedicated TQT studies).
[1] E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Guidance for Industry. 2005 [2] E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Questions and Answers (R3) Guidance for Industry. 2015 [3] PAGE 32 (2024) Abstr 10873 [www.page-meeting.org/?abstract=10873] [4] Voronova V, Cullberg M, Delff P, Parkinson J, Dota C, Schiavon G, et al. Concentration-QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations. Br J Clin Pharmacol. 2022;88(2):858–64 [5] Rekic D, Azarov I, Knöchel J, Sokolov V, Nilsson C, Wernevik L, et al. AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval. Br J Clin Pharmacol. 2022;88(11):4839–4 [6] Parkinson J, Sundell J., Rekic D, Nelander K, Ericsson H, Ebrahimi A, Dota C, Sunnåker M. The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong QT interval at expected therapeutic doses. Pharmacology Research & Perspectives 2024;12:e1184 [7] Sundell J., Rekic D., Melin J., Johansson S., Ebrahimi A., Dota C., Parkinson J. Concentration–QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval. CPT Pharmacometrics Syst Pharmacol. 2024;00:1–10 [8] Parkinson J, Dota C, Källgren C, Gottfridsson C, Bjursell M, Perl S, K?rnicke T, Rekic D, Johansson S. Verinurad does not prolong QTc interval: a thorough QT study using concentration–QTc modelling. Br J Clin Pharmacol. 2022;1–9 [9] NCT06194032
Reference: PAGE 33 (2025) Abstr 11617 [www.page-meeting.org/?abstract=11617]
Poster: Drug/Disease Modelling - Safety