1 research outputs found
Firstâinâhuman trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNSâpenetrant soluble guanylyl cyclase stimulator
Abstract Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.3, 1, 3, 10, 20, 30, and 50âmg were administered once to healthy participants in a singleâascendingâdose phase; then zagociguat 2, 5, 10, and 15âmg was administered q.d. for 14âdays in a multipleâascendingâdose phase; and, finally, zagociguat 10âmg was administered once in both fed and fasted state in a foodâinteraction phase. Safety of zagociguat was evaluated by monitoring treatmentâemergent adverse events, suicide risk, vital signs, electrocardiography, and laboratory tests. Pharmacokinetics of zagociguat were assessed through blood, urine, and cerebrospinal fluid sampling. Pharmacodynamic effects of zagociguat were evaluated with central nervous system (CNS) tests and pharmacoâelectroencephalography. Zagociguat was wellâtolerated across all doses evaluated. Zagociguat exposures increased in a doseâproportional manner. Median time to maximum concentration ranged from 0.8 to 5âh and mean terminal halfâlife from 52.8 to 67.1âh. CNS penetration of the compound was confirmed by cerebrospinal fluid sampling. Zagociguat induced up to 6.1âmmHg reduction in mean systolic and up to 7.5âmmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic (PD) effects on neurocognitive function were observed. Zagociguat was wellâtolerated, CNSâpenetrant, and demonstrated PD activity consistent with other sGC stimulators. The results of this study support further development of zagociguat