Understanding Irsenontrine’s Role Among Neurodegenerative Disorders: Michael Irizarry, MD, PhD

WATCH TIME: 4 minutes

"We know that the drug has a very strong pharmacodynamic effect, it does increase cyclic GMP in the cerebrospinal fluid, and it does it over a sustained period of time. What we don’t know is what condition will benefit the most by doing that."

There are currently no FDA approved disease-modifying therapies available for dementia with Lewy bodies (DLB), and only a handful for Parkinson disease dementia (PDD). A previously conducted phase 2 study assessing Eisai’s irsenontrine suggested that the agent could be more effective in improving cognition in patients with DLB without amyloid copathology, thus prompting the need for a new analysis. The trial included 34 individuals with 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.

Presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, the study looked at change in cyclic guanosine monophosphate (cGMP) as the primary end point, with an increase of more than 50% 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.

To learn more about the findings, NeurologyLive^® sat down with study investigator Michael Irizarry, MD, PhD. Irizarry, senior VP of clinical research and deputy chief clinical officer of the neurology business group at Eisai, provided perspective on the study and irsenontrine’s inability to differentiate based on presence or absence of amyloid copathology. Additionally, he detailed the benefits this drug might bring as a novel phosphodiesterase 9 inhibitor, and whether it may be used in other neurodegenerative disorders instead.

Click here for more coverage of CTAD 2022.

REFERENCE
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.