Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes
American Journal of Cardiovascular Drugs, vol. 23, pp. 145–155
Abstract
Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. ClinicalTrials.gov number, NCT03504982. Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.
Authors 14
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Affiliation as printed
Clinical Pharmacology, Bayer AG, Wuppertal, Germany
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Internal Medicine, Cardiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
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Affiliation as printed
Department of Cardiac Surgery, PMSI Clinical Republican Hospital "T. Mosneaga", Chisinau, Republic of Moldova
Department of Cardiac Surgery, PMSI Clinical Republican Hospital “T. Mosneaga”, Chisinau, Republic of Moldova
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Affiliation as printed
SocraTec R&D GmbH, Erfurt, Germany
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Affiliation as printed
Early Phase Clinical Unit, Parexel, Berlin, Germany
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Pim Gal Aachen Centre for Human Drug Research (CHDR) Clinical Pharmacology and Toxicology Department
Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research, Leiden, The Netherlands
Clinical Pharmacology and Toxicology Department, Leiden University Medical Center, Leiden, The Netherlands
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University Hospital Heidelberg
Affiliation as printed
Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany
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University of Freiburg · University Medical Center Freiburg · Universitäts-Herzzentrum Freiburg-Bad Krozingen
Affiliation as printed
Department University Heart Center Campus Bad Krozingen, Clinics of Cardiology and Angiology-Clinical Pharmacology, University Medical Center Freiburg, Freiburg, Germany
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University of Bonn · University Hospital Bonn
Affiliation as printed
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
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Affiliation as printed
Research and Development, Bayer AG, Wuppertal, Germany
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Affiliation as printed
Study Management, Bayer AG, Wuppertal, Germany
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Merck & Co., Inc., Rahway, NJ, USA (United States) · Flagship Pioneering (United States)
Affiliation as printed
Pioneering Medicines, Flagship Pioneering, Boston, Massachusetts, USA
Translational Medicine, Merck & Co., Inc., Rahway, New Jersey, USA
Pioneering Medicines, Flagship Pioneering, Boston, USA
Translational Medicine, Merck & Co., Inc., Rahway, USA
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Affiliation as printed
Chrestos Concept GmbH & Co. KG, Essen, Germany
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Corina Becker corresponding
Affiliation as printed
Clinical Pharmacology, Bayer AG, Wuppertal, Germany. corina.becker@bayer.com
Clinical Pharmacology, Bayer AG, Wuppertal, Germany
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