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Randomized placebo-controlled crossover study to assess tolerability and pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator, in healthy elderly.
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  • Sebastiaan Kraaij,
  • Laura Borghans,
  • Erica Klaassen,
  • Pim Gal,
  • Jeroen van der Grond,
  • Ken Tripp,
  • Chris Winrow,
  • Chad Glasser,
  • Geert Jan Groeneveld
Sebastiaan Kraaij
Centre for Human Drug Research
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Laura Borghans
Centre for Human Drug Research
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Erica Klaassen
Centre for Human Drug Research
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Pim Gal
Centre for Human Drug Research
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Jeroen van der Grond
Leiden Universitair Medisch Centrum
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Ken Tripp
Cyclerion Therapeutics
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Chris Winrow
Cyclerion Therapeutics
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Chad Glasser
Cyclerion Therapeutics
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Geert Jan Groeneveld
Centre for Human Drug Research

Corresponding Author:[email protected]

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Aim Dysfunction of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) signalling is implicated in the pathophysiology of cognitive impairment and dementia. Zagociguat is a central nervous system-(CNS-) penetrant sGC stimulator designed to amplify NO-cGMP signalling in the CNS. This article reports on a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. Methods In this randomized crossover study, 24 healthy participants ≥65 years of age were planned to receive 15 mg zagociguat or placebo once daily for two 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms, and laboratory tests to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and CSF. Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement, and biomarkers in blood, cerebrospinal fluid, and brain. Results Twenty-four participants were enrolled and 12 participants completed both treatment periods, while 12 participants completed only one treatment period. Zagociguat was well tolerated and penetrated the blood-brain barrier. 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 systemic blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected, perhaps due to optimal CNS function in healthy participants. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.
13 Mar 2023Submitted to British Journal of Clinical Pharmacology
14 Mar 2023Submission Checks Completed
14 Mar 2023Assigned to Editor
15 Mar 2023Review(s) Completed, Editorial Evaluation Pending
26 Mar 2023Reviewer(s) Assigned
18 May 2023Editorial Decision: Revise Major
26 Jun 20231st Revision Received
26 Jun 2023Assigned to Editor
26 Jun 2023Submission Checks Completed
26 Jun 2023Review(s) Completed, Editorial Evaluation Pending
03 Jul 2023Reviewer(s) Assigned
13 Jul 2023Editorial Decision: Revise Minor
14 Jul 20232nd Revision Received
14 Jul 2023Assigned to Editor
14 Jul 2023Submission Checks Completed
14 Jul 2023Review(s) Completed, Editorial Evaluation Pending
17 Jul 2023Editorial Decision: Accept