To evaluate the safety, tolerability and pharmacokinetic profile of single and multiple ascending doses of CVN293 in healthy volunteers.

CVN293 is a novel, investigational, small molecule inhibitor of the two-pore domain potassium channel KCNK13. Selectively expressed in microglia, KCNK13 has demonstrated the potential to mediate the potassium efflux required for activation of the NLRP3 inflammasome, which is thought to be involved in downstream inflammation associated with neurodegeneration. Through inhibition of KCNK13 and microglial proinflammatory processes, CVN293 has the potential to dampen neuroinflammation.

This Phase 1 single/multiple ascending dose (SAD/MAD) study investigated the safety, tolerability and pharmacokinetics of orally administered CVN293 in healthy subjects. Following a randomized, double-blind and placebo-controlled design, subjects received either CVN293 or placebo with SAD cohorts receiving single doses up to 1000mg (all fasted; 150mg also tested under fed conditions). MAD cohorts received repeated doses over 14 days, up to 750mg (375mg twice daily).

CVN293 was generally well-tolerated following single and 14-day multiple dosing, with all subjects completing the treatment period. There were no severe or dose-limiting adverse events (AEs), treatment-related discontinuations, or clinically meaningful changes in vital signs or laboratory parameters.  All related AEs were considered mild.  In the SAD and MAD phases, CVN293 plasma exposure increased in a generally dose proportional manner.  CSF sampling demonstrated that CVN293 achieved exposures at least equivalent to plasma free fraction implying good and predictable CNS exposure.