P2‐240: PF‐04447943, a novel PDE9A inhibitor, increases cGMP levels in cerebrospinal fluid: Translation from non‐clinical species to healthy human volunteers

PDE9A is a cGMP-specific phosphodiesterase widely expressed in the mammalian central nervous system. PDE9A inhibitors are hypothesized to regulate cGMP signaling pathways involved in synaptic plasticity and, therefore, such inhibitors are proposed as a novel approach to remediate the synaptic dysfunction at the core of Alzheimer's disease (AD). PF-04447943 is a novel, selective PDE9A inhibitor being evaluated for the treatment of AD. Here we examine the effect of PDE9 inhibition on cerebrospinal fluid (CSF) cGMP in rats and monkeys and evaluate its potential as a biomarker in humans. Systemically administered PDE9 inhibitors were used to examine the effect of PDE9 inhibition on CSF cGMP in rats and monkeys. Following administration of a single dose of PDE9 inhibitor in rats and monkeys, plasma and CSF were collected and analyzed for drug and cGMP (CSF only). Pharmacokinetic/pharmacodynamic analyses, performed using both drug concentration data in plasma (and/or CSF) and CSF cGMP, were used to predict human exposures associated with potential modulation of CSF cGMP. After safety and tolerability of single-dose PF-04447943 was established in healthy volunteers, a separate cohort of healthy volunteers was dosed to measure the effect of PF-04447943 on CSF cGMP. cGMP was increased in rats, monkeys and humans following drug administration. In rats, PF-04447943 was rapidly distributed to CSF and had similar Tmax values for plasma and CSF drug levels, and CSF cGMP. Maximal increases in CSF cGMP were over 2-fold (change from baseline). In the monkey model, a delay in the increase of CSF cGMP as compared to maximal CSF drug concentrations was observed. In healthy volunteers, PF-04447943 was rapidly absorbed but showed a lag in distribution to CSF and mild hysteresis in the CSF cGMP response, similar to that observed in the monkey. At 6 hours post-dose, CSF cGMP had increased over 3-fold, greater than predicted from the rat model. In humans, PF-04447943 caused a significant increase in CSF cGMP levels, which was slightly greater than predicted from rat models. Based on these findings, PF-04447943 is a functional PDE9A inhibitor in humans with potential as a therapeutic agent for the treatment of AD.