Randomized placebo-controlled crossover study to assess tolerability and
pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator,
in healthy elderly.
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.