Drugs in Clinical Pipeline: E2609

E2609 is a novel, small molecule, BACE1 inhibitor that has been shown in nonclinical studies to inhibit the production of Aβ40 and Aβ42 in brain, reducing Aβ in cerebrospinal fluid (CSF) and plasma after oral dosing. Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key enzyme responsible for the production of Aβ peptides.

Amyloid beta (Aβ) deposition in the brain is thought to be one of the causes of Alzheimer's disease. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. E2609 may reduce the overall amount of amyloid beta by inhibiting BACE.

A single oral administration of E2609 in non-human primates significantly reduced plasma Aβ1-40 and Aβ1-42 levels equally, with an estimated plasma IC₅₀(unbound) of 1.3 nM, concordant with the potency of the cell-based assay. E2609 reached a rapid equilibrium between plasma and CSF with near identical t_max, and had a moderate to high CNS penetration. A single oral administration of E2609 led to an equal reduction of both CSF Aβ1-40 and Aβ1-42 levels. At effective doses, a peak reduction of up to ~90% was observed in CSF that was sustained for 24 hours or more. The pharmacodynamic parameters for CSF Aβ lowering (plasma IC₅₀, plasma IC₅₀(unbound) and k_out) were estimated as 35.0 nM, 9.7 nM, and 0.148 hr-1 for Aβ1-40, and 33.2 nM, 9.2 nM, and 0.148 hr -1 for Aβ1-42, respectively [1].

This novel compound was discovered at Eisai through a collaborative partnership between centres in Britain, Japan and the United States (US). In March 2014, Eisai and Biogen Idec signed a collaboration agreement to jointly develop E2609.

Common Name: E2609
Synonyms:  E2609; E 2609; E-2609
IUPAC Name: -
CAS Number: -
Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor
Indication: Alzheimer's disease; Treatment of Dementia
Development Stage: Phase II
Company: Eisai/Biogen

The E2609 story got a lot of interest since the 2012 AAIC conference in Vancouver, Canada, where Eisai presented data to suggest that E2609 lowers Aβ concentration in the brain, CSF, and plasma of rats and guinea pigs, and that it lowers CSF and plasma Aβ in non-human primates. These Phase I study results confirmed E2609 'Proof of Mechanism' for preventing amyloid beta production by BACE inhibition in humans.

The two E2609 Phase I studies presented at the AAIC 2012 comprised a single oral ascending dose study (SAD, Study A001-001) and a 14-day multiple oral ascending dose study (MAD, Study A001-002). The SAD study showed a reduction in plasma amyloid beta levels, whilst the MAD study showed a statistically significant reduction of cerebrospinal fluid (CSF) amyloid beta levels.

SAD Study

This was a single-center, randomized, double-blind, placebo-controlled study in 8 cohorts of healthy adult subjects aged 30 to 55 and 1 cohort of healthy elderly subjects aged 65 to 85 [2]. Each cohort comprised 8 subjects, with 6 randomized to a single dose of E2609 and 2 to placebo. Healthy young subjects received single doses of 5, 10, 25, 50, 100, 200, 400 or 800 mg. Healthy elderly subjects received a single dose of 50 mg. Subjects were dosed after fasting overnight. Blood samples were collected predose and at multiple time points up to 144 h postdose to measure plasma concentrations of E2609 and Aβ peptides. Safety and tolerability were assessed by adverse events (AE), vital signs, electrocardiograms, and clinical laboratory blood tests. The maximum dose-dependent reduction of plasma amyloid beta (1-X) relative to baseline was 52% at 5 mg, and 92% at 800 mg. E2609 showed acceptable tolerability across all doses, and the most common adverse events included headache and dizziness.

MAD Study

MAD study was a randomised, double-blind, placebo-controlled, multiple ascending dose study conducted in 50 healthy adult volunteers [3]. Subjects were divided into five cohorts, with each cohort receiving E2609 doses of between 25 mg and 400 mg per day for 14 days. The study measured amyloid beta levels both in plasma and CSF. Preliminary interim analysis results showed that E2609 demonstrated a clear reduction in plasma amyloid beta (1-X) levels and a dose-dependent reduction in CSF amyloid Beta(1-X) in subjects who received daily doses of between 25 mg and 200 mg. The percentage decrease in CSF amyloid Beta(1-x) after 14 days dosing compared to baseline was statistically significant, with E2609 demonstrating a 46.2%, 61.9%, 73.8% and 79.9% difference in percentage decrease compared to placebo in the 25 mg, 50 mg, 100 mg and 200 mg cohorts, respectively. No clinically significant safety concerns were observed following repeated oral dosing of up to 200 mg. Several cases of orolabial herpes relapse were observed in the 200 mg cohort, however, while being evaluated, the significance of these cases is unknown as the blind remains unbroken on the safety data.

References:

1. Lucas, F.; et. al. Novel BACE1 inhibitor, E2609, lowers Aβ levels in the cerebrospinal fluid and plasma in nonhuman primates. Alzheimer's and Dementia 2012, 8(4), P224.

2. Lai, R.; et. al. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimer's and Dementia 2012, 8(4), P96.

3. Albala, B.; et. al. CSF amyloid lowering in human volunteers after 14 days’ oral administration of the novel BACE1 inhibitor E2609. Alzheimer's and Dementia 2012, 8(4), S743.

4. ClinicalTrials.gov Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild Dementia Due to Alzheimer's Disease. NCT02322021 (retrieved 24-04-2015)

5. ClinicalTrials.gov Evaluation of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of E2609 in Healthy Subjects. NCT01511783 (retrieved 24-04-2015)

6. ClinicalTrials.gov An Study to Determine the Bioavailability of E2609 Tablets Compared to Capsules and the Effect of Food on Absorption. NCT01716897 (retrieved 24-04-2015)