Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies

Abstract Aims Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. Methods The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs . plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. Results In rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg −1 ]) in cGMP levels in the CSF relative to vehicle ( P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs . placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. Conclusions BI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. ClinicalTrials.gov number (NCT04672954).