A phase I, randomized, proof‐of‐clinical‐mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers

Abstract

BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

“…On the basis of the potency of BI 409306 against the rat PDE9 enzyme, a 50% increase in CSF cGMP was achieved at a CSF BI 409306 exposure of approximately 40% of the IC 50 against PDE9. This is roughly in line with data from a clinical study measuring cGMP increase in CSF after oral treatment with BI 409306 in healthy male volunteers (Boland et al, 2017).…”

“…This suggests that cGMP levels in CSF might be a suitable biomarker for central inhibition of PDE9A in human patients. In support of this, a phase I proof-ofmechanism study of BI 409306 (25-, 50-, 100-, or 200-mg single dose) in healthy males demonstrated dose-dependent increases in CSF cGMP that reflected plasma and CSF drug exposure (Boland et al, 2017). Overall, these studies support the utility of CSF cGMP levels as a translatable biomarker of functional target engagement between animal and human studies.…”

“…In support of this hypothesis, preclinical studies have shown that inhibition of PDE9A can increase cGMP levels in the rat brain, enhance LTP, and improve memory function in rodent cognition tasks (van der Staay et al, 2008;Hutson et al, 2011;Kleiman et al, 2012;Kroker et al, 2012Kroker et al, , 2014. In addition, a dose-dependent increase in cGMP levels in cerebrospinal fluid (CSF) of healthy volunteers has been demonstrated following a single oral administration of the PDE9A inhibitor BI 409306 (Boland et al, 2017). BI 409306 is a novel, potent, and selective PDE9A inhibitor in clinical development (Moschetti et al, 2016;Boland et al, 2017;Brown et al, 2019;Frölich et al, 2019).…”

“…In addition, a dose-dependent increase in cGMP levels in cerebrospinal fluid (CSF) of healthy volunteers has been demonstrated following a single oral administration of the PDE9A inhibitor BI 409306 (Boland et al, 2017). BI 409306 is a novel, potent, and selective PDE9A inhibitor in clinical development (Moschetti et al, 2016;Boland et al, 2017;Brown et al, 2019;Frölich et al, 2019). The current study aimed to assess the in vitro potency and selectivity of BI 409306 and to evaluate its functional target engagement in vivo through measurements of cGMP levels in brain tissue and CSF.…”

A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia

“…In these studies, the most frequent adverse events (AEs) were visual symptoms such as photopsia (flashing light), photophobia (increased sensitivity to light), chromatopsia (change in color perception), and blurred vision. These AEs occurred shortly after administration and were resolved within 1–2 h. In a proof-of-mechanism study conducted in healthy male volunteers, BI 409306 administered orally as a single dose crossed the blood–brain barrier and triggered a dose- and concentration-dependent increase in cGMP in the CSF [ 14 ].…”