Amyloid Copathology Not a Factor in Pharmacodynamic Effect of Irsenontrine in Dementia With Lewy Bodies, Parkinson Disease Dementia


Over a 12-week treatment period, irsenontrine was well tolerated across both amyloid positive and negative patients, with no significant difference in pharmacodynamic responses or change in central nervous system biomarkers.

Michael Irizarry, PhD, senior VP of clinical research and deputy chief clinical officer of the neurology business group at Eisai

Michael Irizarry, PhD

Findings from a study assessing Eisai’s novel phosphodiesterase 9 (PDE9) inhibitor irsenontrine (E207) showed robust change in cellular cyclic guanosine monophosphate (cGMP) in patients with dementia with Lewy bodies (DLB) or Parkinson disease dementia (PDD); however, this effect did not differentiate based on the presence or absence of amyloid copathology.1

Previous phase 2 findings suggested that irsenontrine could be more effective for cognition in patients with DLB without amyloid copathology, thus prompting the need for a new analysis. Presented at the 2022 Clinical Trials on Alzheimer Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, the study included 34 individuals who met diagnostic criteria for DLB or PDD who were assigned to 4 groups: DLB amyloid positive (n = 11), DLB amyloid negative (n = 10), PDD amyloid positive (n = 3), and PDD amyloid negative (n = 10) using the plasma PrecivityAD amyloid-ß 42/40 ratio.

Investigator Michael Irizarry, PhD, senior VP of clinical research and deputy chief clinical officer of the neurology business group at Eisai, and colleagues, followed patients who were treated with 50 mg irsenontine daily for 12 weeks. Each individual underwent a lumbar puncture at baseline and 9 weeks with change on cerebrospinal fluid cGMP as the primary outcome. Additionally, patients were evaluated on a variety of other clinical assessments, as well as biomarker analyses that looked at apolipoprotein e4 status, plasma and CSF Aß42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), total tau, and neurogranin.

Any increase of more than 50% in CSF cGMP between amyloid negative and positive individuals was considered pharmacologically relevant. All told, there was a robust increase in CSF levels of cGMP, averaging a 239% increase from baseline that was consistent in each diagnostic cohort. When observing amyloid status through Aß 42/40, there was a least square mean increase at week 9 of 230% and 250% in the DLB amyloid negative (n = 7) vs positive (n = 10) groups, respectively. For PDD, the LS mean increases were 187% and 363%, respectively, for amyloid negative (n = 8) and positive (n = 3) patients.

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Between the 4 groups, the treatment effects at week 12 on electronic Montreal Cognitive Assessment (eMOCA) were inconsistent. Specifically, DLB amyloid negative and positive patients saw changes of –0.4 (standard deviation [SD], 2.7) and –1.9 (SD, 4.0), respectively, while those in the PDD groups saw changes of 1.8 (SD, 3.3) and –4.7 (SD, 3.5). When amyloid status was defined by CSF Aß42/40, subgroup assignment and CSF cGMP resulted were still consistent across diagnostic cohorts.

At week 9, LS mean changes in CSF cGMP following treatment with Irsenontine were 274% vs 225%, respectively, for the DLB amyloid negative (n = 6) and positive groups (n = 11), and 212% vs 466%, respectively, for the PDD amyloid negative (n = 10) vs positive (n = 1) groups. Overall, the treatment was well tolerated with the majority of treatment-emergent adverse events being mild or moderate. Notably, central nervous system biomarkers remained unchanged over the observed 9 weeks of treatment.

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1. Sachdev P, Pinner K, Devins T, et al. The effects of the novel phosphodiesterase 9 (PDE9) inhibitor E2027 (irsenontrine) on CSF cGMP, additional CSF and plasma biomarkers and clinical outcomes in amyloid positive and amyloid negative patients with dementia with lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Presented at: CTAD Conference 2022; November 29-December 2; San Francisco, CA. Abstract P48.
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