Vericiguat: a QTc interval study in patients with coronary artery disease
Authors: Boettcher M.-F , Duengen H.-D , Corcea V , Donath F , Fuhr R , Gal P , Mikus G , Trenk D , Werner N , Pires P.V , Maschke C , Aliprantis A.O , Besche N , Becker C 
Published: October 2021

Background

Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with ejection fraction less than 45% who had a previous decompensation event. Guidelines on QT studies recommend evaluation of investigational drugs at supratherapeutic exposures in healthy volunteers. We anticipated that supratherapeutic doses of vericiguat would decrease blood pressure. We conducted an adjusted QT study using the therapeutic range of vericiguat in patients with coronary artery disease (CAD), who were expected to be more haemodynamically stable with fewer confounders (e.g., on the electrocardiogram) than a HF population.

Purpose

To assess the effect of vericiguat 10 mg once-daily on placebo-adjusted change from baseline of the Fridericia-corrected QT interval (QTcF) in patients with stable CAD.

Methods

This was a randomised, Phase Ib, placebo-controlled, double blind, double-dummy, multicentre study (NCT03504982). Test drug was vericiguat once-daily (up-titrated from 2.5 mg to 5 mg and then to 10 mg [treatments A, B, C] at 14-day intervals). The positive control was moxifloxacin 400 mg (single dose on Day 8 or Day 50 with placebo on other days [treatment D]; Figure). Patients were randomised to one of two sequences.

We evaluated QTcF interval prolongation potential of vericiguat at increasing doses up to 10 mg, steady state. We investigated the pharmacokinetics, safety and tolerability of vericiguat. A clinically meaningful effect was defined as a QTcF change from baseline &gt;10 ms relative to placebo. Assay sensitivity for moxifloxacin was confirmed by the lower limit of the 90% confidence interval (CI) of the time-matched, baseline-adjusted mean difference to placebo exceeding 5 ms at &gt;1 time point.

Results

A total of 74 patients (66 males and 8 females) with CAD, mean (standard deviation) age 63.4 (8.0) years, were included. Mean difference between vericiguat and placebo in QTcF change from baseline (≤7 h post-dose) was &lt;6 ms; no upper limit of the 90% CIs crossed the threshold of 10 ms. Lower limits of the two-sided 90% CI of the differences between moxifloxacin and placebo in QTcF change from baseline were &gt;5 ms at 3 of 4 time points (Table).

Peak plasma concentration (Cmax) of vericiguat following administration of vericiguat 10 mg was 322 μg/l and median time of maximum concentration (Tmax) was 4.5 h post-dose, in line with concentrations observed following administration of vericiguat 10 mg to patients with HF [1]. For moxifloxacin 400 mg, Cmax was 1960 μg/l and median Tmax was 3 h post-dose, in line with previously reported values [2]. Vericiguat up to 10 mg was generally safe and well tolerated.

Conclusion

This study supports the assessment that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. These data contribute to the overall safety profile of vericiguat for the treatment of patients with HF.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA QTc study design