Background

Irsenontrine is a selective inhibitor of phosphodiesterase 9. PDE9 is an enzyme that breaks down cyclicGMP, cGMP, which serves as a second messenger in synaptic function and memory. E2027 is intended to boost brain cGMP levels to improve cognition.
 
No peer-reviewed preclinical studies of E2027 are formally published. In meeting presentations, Eisai scientists reported the drug is 1,000-fold selective for PDE9A over other PDE family members, with a 50 percent inhibitory concentration of 3.5 nM. In rats, single and multiple oral doses were claimed to increase cGMP concentrations in CSF and hippocampus, and to improve performance in tests of natural memory, as well as in a model of scopolamine-induced amnesia (Ando et al., 2017; Ando et al., 2018).

Eisai discovered E2027 and is developing it to treat dementia with Lewy bodies, a disease marked by α-synuclein deposits in brain neurons. Phosphodiesterase inhibition has been claimed to ameliorate α-synuclein toxicity in cell-based assays (Höllerhage et al., 2017).

Development of two prior PDE9A inhibitors for Alzheimer’s disease ended after they failed to improve symptoms in Phase 2 (see BI 409306 and Aug 2011 news).  

Findings

In 2015 and 2016, Eisai ran a Phase 1 trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of E2027 in 112 healthy adults. Part A of this four-part study gave single ascending doses of 10 to 1,200 mg to non-elderly volunteers, Part B examined the effect of food, Parts C and D tested single doses in healthy elderly and in non-elderly Japanese volunteers. Target engagement was determined by measuring cGMP concentrations in CSF. Results of the single-dose study were presented at the 2017 Alzheimer’s Association International Conference (Aug 2017 conference news). The drug was well-tolerated at all doses. It was absorbed quickly, reaching maximum blood levels in two to four hours. Blood levels were increased by food; pharmacokinetics were similar in different ethnicities. Single doses of 100 and 400 mg led to three- to fourfold increases in CSF cGMP.

From August 2016 to November 2017, a second Phase 1 trial evaluated multiple doses in 74 healthy older adults, who received 5 to 400 mg drug or placebo once daily for two weeks, or 50 mg daily for six weeks. Primary outcomes were PK measurements; secondary measures included CSF cGMP. According to trial results presented at the 2018 AAIC, all doses were well-tolerated (abstract). Blood levels of drug reached steady-state after seven days, with 3.5 percent of plasma concentration reaching the brain. The drug caused a dose-dependent increase in CSF cGMP, which was maximal at 50 mg and sustained over the six-week regimen. Results of the single- and multiple-dose studies, and a cardiac safety analysis, led to the choice of a 50 mg daily dose for Phase 2 (Landry et al., 2022; Landry et al., 2022).

A third Phase 1 study in 16 healthy volunteers showed no clinically significant interaction of E2027 with diltiazem, a calcium channel blocker commonly used to treat high blood pressure, angina, and some heart arrhythmias (see 2018 AAIC abstract). A fourth study tracked elimination of radioactively labeled drug in eight volunteers; it concluded in October 2019 but results have not been made public. 

In May 2018, a Phase 2 trial began enrolling 206 participants with dementia with Lewy bodies for 12 weeks of treatment with 50 mg E2027 daily, or placebo. The two primary outcomes are the Montreal Cognitive Assessment (MoCA) and the electronic Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBICPlus); secondary outcome measures include the Neuropsychiatric Inventory, MMSE, and Cognitive Fluctuations Inventory, and safety. The trial, at 74 locations in the U.S., Europe, and Japan, was completed in April 2020 with 326 participants. According to results presented at the CTAD 2022 conference in San Francisco, irsenontrine failed to change either primary endpoint, or any secondary endpoint. The study confirmed a pharmacodynamic effect, with the drug eliciting a 150 to 192 percent increase in CSF cGMP in a small substudy, consistent with Phase 1 results. Amyloid deposition is a common co-pathology in DLB, and a post hoc subgroup analysis of patients by amyloid status found a trend toward improvement on the MoCA and CIBICPlus in the subgroups of patients lacking amyloid, but not those with amyloid.

Also at CTAD, the company reported results of a 2021 study testing the effect of amyloid co-pathology on irsenontrine’s ability to raise CSF cGMP in 34 patients with dementia with Lewy bodies or Parkinson’s disease dementia, with or without amyloid pathology. In this open-label study, CSF cGMP increased by an average of 239 percent in all groups after nine weeks of 50 mg daily, with no difference between amyloid negative or positive groups

For details on E2027 trials, see clinicaltrials.gov.