Randomized placebo‐controlled crossover study to assess tolerability and pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator, in healthy elderly
British Journal of Clinical Pharmacology, vol. 89, pp. 3606–3617
Abstract
AIMS: Dysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. METHODS: In this randomized crossover study, 24 healthy participants aged ≥65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. RESULTS: Twenty-four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well-tolerated and penetrated the blood-brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. CONCLUSION: Zagociguat was well-tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.
Authors 9
-
Sebastiaan J. W. van Kraaij Aachen Centre for Human Drug Research Leiden the Netherlands Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
-
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research Leiden The Netherlands
-
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research Leiden The Netherlands
-
Pim Gal Aachen Centre for Human Drug Research Leiden the Netherlands Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
-
Jeroen van der Grond Aachen Department of Radiology Leiden University Medical Center Leiden The Netherlands Department of Radiology Leiden University Medical Centre Leiden the Netherlands
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Radiology Leiden University Medical Centre Leiden The Netherlands
Department of Radiology Leiden University Medical Centre Leiden The Netherlands
-
Affiliation as printed
Cyclerion Therapeutics Cambridge Massachusetts USA
Cyclerion Therapeutics Cambridge Massachusetts USA
-
Affiliation as printed
Cyclerion Therapeutics Cambridge Massachusetts USA
Cyclerion Therapeutics Cambridge Massachusetts USA
-
Affiliation as printed
Cyclerion Therapeutics Cambridge Massachusetts USA
Cyclerion Therapeutics Cambridge Massachusetts USA
-
Geert Jan Groeneveld corresponding Aachen Centre for Human Drug Research Leiden the Netherlands Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research Leiden The Netherlands
Department of Surgery Department of Neurology Leiden University Medical Centre Leiden The Netherlands
Cited by 5 stored of 5
5 results
No patents citing this paper on Lens.org (checked 2026-10-11).