LAUSR

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 50 mg were administered once to healthy participants in a single-ascending-dose phase; then zagociguat 2, 5, 10 and 15 mg was administered QD for 14 days in a multiple-ascending-dose phase; and finally, zagociguat 10 mg was administered once in both fed and fasted state in a food-interaction phase. Safety of zagociguat was evaluated by monitoring treatment-emergent 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 tests and pharmaco-electroencephalography. Zagociguat was well tolerated across all doses evaluated. Zagociguat exposures increased in a dose-proportional manner. Median Tmax ranged from 0.8 h to 5 h and mean T1/2 from 52.8 h to 67.1 h. CNS penetration of the compound was confirmed by CSF sampling. Zagociguat induced up to 6.1 mmHg reduction in mean systolic and up to 7.5 mmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic effects on neurocognitive function were observed. Zagociguat was well tolerated, CNS-penetrant and demonstrated pharmacodynamic activity consistent with other sGC stimulators. The results of this study support further development of zagociguat.