Effects of the novel phosphodiesterase 9 inhibitor irsenontrine on CSF proteomics profile in Aβ

backgroundIrsenontrine (E2027) is a potent and selective PDE9 inhibitor that increases cellular cGMP, essential for glutamatergic synaptic function, and was investigated as symptomatic treatment for dementia with Lewy bodies (DLB). A recent Phase 2 study suggested differences in clinical responses in irsenontrine-treated DLB patients depending on amyloid (Aβ) co-pathology. In this post-hoc CSF proteomic sub-study, we evaluated how protein levels and biological pathways changed from baseline in DLB participants with and without amyloid co-pathology (Aβ+ and Aβ−). We hypothesized that the treatment with irsenontrine affects specific protein pathways, which is attenuated in Aβ+ DLB patients.

methodsThe CSF proteome was measured using proximity extension assay (PEA) proteomics in all available paired baseline and week 9 CSF samples from a trial with irsenontrine. This included 9 Aβ+ and 6 Aβ− DLB patients (CSF Lumipulse Aβ42/40 cut-off 0.057) with a mean ± sd age of 76 ± 6 years and 67% were male. We determined the treatment effect stratified by amyloid status using paired Wilcoxon tests on the protein levels (p < 0.05) and individual pathway enrichment KEGG pathway z-scores (p < 0.05).

resultsFollowing irsenontrine treatment, CSF protein level changes were present in both groups (DLB Aβ− 10 up; 32 down; DLB Aβ+ 16 up; 27 down). More pathways were affected in DLB Aβ− (5 pathways), compared to DLB Aβ+ (3 pathways), and several of these were related to the mechanism of action, including the upregulation of the Pantothenate and CoA biosynthesis pathway (upregulated in Aβ+ and Aβ−), and downregulation in the GABAergic synapse pathway (DLB Aβ− only).

conclusionThis global proteomics analysis in this DLB clinical trial suggests that, despite the small number of treated participants, there were changes in CSF proteins related to the mechanism of action, as indicated by the upregulation of pantothenate and CoA biosynthesis pathway, which relates to glutamate metabolism. In addition, more pathways that were associated with the mechanism of irsenontrine were affected in the DLB Aβ− vs. Aβ+ group, supporting differential effects based on presence or absence of amyloid co-pathology. TRIAL REGISTRATION INFORMATION: The clinical trial was registered at clinicaltrials.gov with NCT03467152 at March 16th 2018. Patient enrollment started on the 4th of May 2018. Trial protocol and statistical analysis plan can be accessed on clinicaltrials.gov.