Background

E2511 is Eisai’s positive allosteric modulator of the tropomyosin receptor kinase A. TrkA activation by nerve growth factor is required for the survival and function of cholinergic neurons. Loss of these neurons early in Alzheimer’s disease contributes to cognitive decline. This small molecule, taken in tablet form, aims to preserve cholinergic nerve function and improve cognition.

No preclinical work on E2511 is published. At meetings, the company has presented evidence that it binds TrkA, activates kinase activity, and boosts expression of genes involved in cholinergic function in neurons. Chronic administration in Tau P301S transgenic mice prevented loss of cholinergic neurons and increased the number of cholinergic synapses (Tomioka et al., 202; Tomioka et al., 2023).

Findings

In September 2020, a Phase 1 study began assessing safety, pharmacokinetics, and food effects of single ascending doses in 40 healthy adults and five elderly participants. Safety endpoints spanned adverse events, physical exams, clinical laboratory tests, vital signs, electrocardiograms and electroencephalograms. According to results presented at the 2023 AAIC, E2511 produced no dose-dependent or severe adverse events, or changes in safety parameters (abstract). The drug reached maximum blood concentrations after one hour, and had a half-life of 3.2 hours. Pharmacokinetics were linear with dose, and comparable in elderly and younger adults.

A multiple-ascending-dose trial began in December 2021. It enrolled 32 healthy, non-Japanese adults to receive 10, 20, 40, or 80 mg tablets once daily for 14 days. CSF was collected on day 13. An additional three cohorts totaling 15 Japanese adults received 20, 40, or 80 mg daily for two weeks. One group of older adults was given 40 mg per day.

According to results presented at the 2023 CTAD conference, no dose-related adverse events or safety signals were observed. One Japanese participant, treated with the highest dose, had a serious event of mania, and was withdrawn from the study. Blood pharmacokinetics were as expected from the previous trial, and similar between Japanese and non-Japanese participants. The drug entered the brain, achieving CSF-to-plasma ratios ranging from 15 to 32 percent, depending on dose. Proteomic analysis of CSF found that treatment resulted in changes in multiple axonal and synaptic markers, consistent with E2511’s presumed mechanism of action. The company is planning a Phase 1b dose-finding trial.

For details on E2511 trials, see clinicaltrials.gov.