Ivan Azarov (1), Dinko Rekić (2), Victor Sokolov (1), Jane Knöchel (2), Kirill Zhudenkov (1), Catarina Nilsson (2), Kirill Peskov (1), Linda Wernevik (3), David Han (4), Tina Rydén-Bergsten (2), Ahmad Ebrahimi (5), Corina Dota (5), and Björn Carlsson (3)
(1) M&S Decisions LLC, Moscow, Russia, (2) Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden, (3) Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden, (4) PAREXEL, Glendale, Los Angeles, CA, USA, (5) Cardiovascular Safety Center of Excellence, Global Patient Safety, Oncology R&D, AZ Gothenburg, Sweden
Objectives:
AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted, N-acetylgalactosamine (GalNAc)-conjugated anti-sense oligonucleotide specifically inhibiting PCSK9 expression in the liver. Monthly subcutaneous administration of AZD8233 may therefore provide an important and potential best in class treatment option for patients with uncontrolled hypercholesterolemia [1]. A phase I single ascending dose clinical trial has been conducted for the assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, including the evaluation of the risk of QT interval prolongation of AZD8233 (NCT03593785). The aim of this work was to investigate the exposure-response relationship between AZD8233 concentration and heart rate-corrected QT interval in healthy male volunteers to assess potential effects of the treatment on the QTc interval.
Methods:
NCT03593785 study consisted of two parts. Part 1 was a randomized, single-blind, placebo-controlled study in healthy male subjects with elevated low-density lipoprotein-cholesterol (LDL-C) levels to assess the safety, tolerability, PK, and PD of AZD8233 following single 4 mg, 12 mg, 20 mg, 30 mg, 60 mg, 90 mg, and 120 mg dose. Part 2 was a randomized, single-blind, placebo-controlled study in healthy male Chinese and Japanese subjects with elevated LDL-C levels to assess the safety, tolerability, PK, and PD of AZD8233 in these populations, following a single 90 mg dose. Each cohort randomized 6 subjects to active treatment and 2 subjects to matching placebo. A total of 73 male healthy subjects were randomized into this study. The total of 1094 time-matched PK and digital ECG data points were used in the analysis.
Concentration-QTc relationship was studied using a linear mixed-effects modelling approach [2] with baseline-adjusted Fridericia-corrected QT interval (ΔQTcF) as a dependent variable [3-4]. The prespecified linear model included the following fixed effects: the intercept in the absence of a treatment effect, the slope of the assumed linear association between concentration and ΔQTcF, the fixed effects associated with treatment, nominal time and the difference between the individual baseline QTcF and the baseline averaged across all subjects. Random effects were applied for the intercept and the concentration-effect slope. The analysis was performed by utilizing “lme4” package [5] (lme4 1.1-21) in R Statistics, version 3.5.1.
Results:
Exploratory data analysis of the time-matched PK-ECG data showed that AZD8233 has no significant effect on heart rate and the Fridericia formula was deemed the appropriate method for the QT correction. There was no evidence of hysteresis and no evidence of non-linearity in the relationship between AZD8233 concentration and QTcF effect. The prespecified linear mixed effect model described the data well, as judged by goodness-of-fit plots.
PK data in study D7990C00001 indicated an approximate 1.7-fold higher Cmax in Asian versus non-Asian cohorts. Therefore, assuming a therapeutic dose of 60 mg, the highest clinically relevant scenario was defined as 1.7-fold the expected Cmax following a 60 mg dose, which corresponded to the plasma concentration of 1.39 µg/mL. Estimated placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at this concentration (1.39 µg/mL) was -2.2 ms (90% CI: -4.11, -0.28). Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10 ms regulatory threshold [3] at all observed concentrations following doses ranging from 4 to 120 mg.
Conclusions:
The clinical study NCT03593785, conducted in healthy volunteers, and further concentration-QTc analysis of time matched PK and ECG samples shows that AZD8233 does not prolong QT-interval since the upper bound of the two-sided 90% confidence interval for the QTcF effect was estimate as -0.28 ms at the highest clinically relevant scenario (below 10 ms regulatory threshold). This study contributes to the growing body of evidence in support of evaluating future ASOs in a similar manner to other non-small molecule therapeutics, and maybe influencing the regulatory framework.
References:
[1] Gennemark P, Walter K, Clemmensen N, et al. An oral antisense oligonucleotide for PCSK9 inhibition. Science Translational Medicine, 2021;13(593):eabe9117.
[2] Garnett, C., Bonate, P. L., Dang, et al. Scientific white paper on concentration-QTc modeling. Journal of pharmacokinetics and pharmacodynamics, 2018, 45(3), 383-397.
[3] ICH E14 Guideline. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non‐antiarrhythmic drugs: E14. 2005.
[4] ICH E14 Guideline. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Q&A (R3). 2015.
[5] Bates, D., Mächler, M., Bolker, et al. Fitting linear mixed-effects models using lme4. arXiv preprint arXiv:1406.5823, 2014.
Reference: PAGE 30 (2022) Abstr 10107 [www.page-meeting.org/?abstract=10107]
Poster: Drug/Disease Modelling - Endocrine