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Novel BACE inhibitor shows promise in Alzheimer’s disease

Pearl Toh
03 Aug 2018

The novel oral BACE* inhibitor elenbecestat showed an acceptable safety profile and was generally well tolerated in patients with mild cognitive impairment (MCI)-to-moderate Alzheimer’s disease (AD), with additional benefit of reducing amyloid load in the brain, a new study finds.

Elenbecestat inhibits the cleavage of amyloid precursor protein into amyloid beta (Aβ) peptides 40 and 42, accumulation of which represents the hallmark of AD pathology. Elenbecestat has been shown to suppress Aβ 40 and 42 productions in the brain, plasma, and cerebrospinal fluid in previous studies.

“Clinical assessments suggest elenbecestat may have attenuating effects on cognitive decline in MCI-to-moderate AD subjects,” the investigators stated.

In the phase II, multicentre, double-blind study, 70 patients with AD and were tested positive for amyloid plaque deposit on the PET scan were randomized to placebo or elenbecestat (5, 15, or 50 mg once daily). During the study, patients who received elenbecestat 5 mg and 15 mg with at least 3 months remaining were switched to the elenbecestat 50-mg arm and were referred to as the “50-mg total arm” (n=38) hereafter, who were exposed to elenbecestat 50 mg per day for a mean duration of about 11 months. [AAIC 2018, abstract 27524]

At 18 months, treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation occurred at similar rates in both the 50-mg total arm and the placebo arm. According to the researchers, the most common AEs reported in the 50-mg total arm were upper respiratory infection, contact dermatitis, diarrhoea, headache, and fall. There were no deaths or discontinuation due to liver toxicity observed.

Exploratory analyses in patients who underwent longitudinal amyloid PET assessment revealed that amyloid load was significantly reduced with elenbecestat 50-mg total vs placebo, regardless of whether they were labelled with florbetaben (n=50; difference, -5.8 percent; p=0.013) or florbetapir (n=7; difference, -13.6 percent; p=0.014) for PET imaging.

Furthermore, there was a trend towards slower decline in clinical symptoms with elenbecestat than with placebo, as assessed using CDR-SB** (n=41; difference, -0.5; p=0.55), although the difference was not statistically different between groups. In a subgroup of patients with florbetaben PET SUVR*** values between 1.4–1.9 at baseline, patients in the 50-mg total group showed 72 percent less decline in CDR-SB compared with placebo.

According to the investigators, this is the first study to show that a BACE inhibitor significantly reduced Aβ in the brain with a potential to delay clinical symptom decline in exploratory analyses.

Also safe in Japanese subgroup

The safety profile of elenbecestat was further supported by findings of another phase II study, which randomized 16 healthy Japanese adults 1:1 to elenbecestat 50 mg or a matching placebo for 14 days. [AAIC 2018, abstract 24768]

The researchers found that the pharmacokinetics of elenbecestat and its metabolites (M1, M2, and M5) in the Japanese participants was similar to that of non-Japanese subjects shown in previous studies. No TEAEs or clinically important effect on vital signs or ECG findings related to elenbecestat were reported.

“These results supported the inclusion of Japanese subjects in the ongoing phase III studies of elenbecestat without dose adjustment,” said the researchers.

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Most Read Articles
Jairia Dela Cruz, 03 May 2018
Acute coronary syndrome (ACS) patients with diabetes mellitus, as well as high-risk nondiabetic patients, appear to obtain significant cardioprotection from the addition of ezetimibe to simvastatin, and this benefit is achieved without compromising safety, according to an exploratory analysis of data from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Pearl Toh, 28 Aug 2017
Taking long-chain omega-3 fatty acids (LC-OM3) supplements, mainly EPA* and DHA** omega-3s, was associated with a modest but significant reduction in cardiac death risk, according to a meta-analysis of randomized controlled trials (RCTs).
Dr. Lau Hui Ling, 01 Aug 2017
Oral contraceptive selection should be individualized for each patient to yield maximum benefit.
18 Apr 2016
Copper intrauterine device exhibited superior efficacy to injectable progestin contraception in women attending termination of pregnancy services in South Africa, according to a pragmatic, open-label, parallel arm, randomised controlled trial.