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2 Dec 2014

AZ and Lilly to proceed with BACE inhibitor trial in Alzheimer’s

Early trials show promise for the BACE inhibitor AZD3293

AstraZeneca (AZ) and Eli Lilly have started a large-scale trial of their candidate drug for Alzheimer’s disease that should generate results in mid-2019.
The first patients are now being enrolled in the phase II/III study of AZD3293, an oral beta secretase cleaving enzyme (BACE) inhibitor that has been shown in early-stage trials to reduce levels of beta amyloid in the cerebrospinal fluid of Alzheimer’s patients and healthy volunteers.
AZ and Lilly formed an alliance to develop AZD3293 (also known as LY3314814) back in September, with AZ drawing on Lilly’s earlier experience with the emerging drug class. Lilly had problems with an earlier BACE inhibitor candidate – called LY2886721 – after liver abnormalities were seen in patients taking the drug in trials, forcing it to abandon the compound in 2013.
BACE is an enzyme involved in the conversion of amyloid precursor protein (APP) into amyloid beta, preventing the formation of amyloid plaques that are a hallmark of Alzheimer’s disease.
Earlier trials of amyloid-targeting therapies such as Lilly’s solanezumab and Pfizer’s bapineuzumab proved disappointing, but researchers speculate that giving drugs earlier in the course of the disease could improve their efficacy in slowing cognitive and memory decline.
The phase II/III trial of AZD3293, called AMARANTH, will enrol 1,500 patients with early Alzheimer’s disease – those with mild cognitive impairment or mild Alzheimer’s related dementia. The drug will be compared to placebo over a two-year treatment period.
The trial will include two biomarker groups, one subject to positron emission tomography (PET) scanning at enrolment and over the course of the study, another that will use lumbar puncture for CSF sampling.
“We believe that BACE inhibitors have the potential to target one of the key drivers of this devastating disease,” said Samantha Budd, head of translational science in AZ’s neuroscience R&D unit.
“Together with Lilly, we have unique expertise that will allow us to evaluate the potential of AZD3293,” she added. Previously, AZ has suggested that AZD3293 could become a $5bn-a-year product if it proves successful in trials, although it acknowledges it is a high-risk project.
There are a number of other BACE inhibitors coming through the clinical pipeline for Alzheimer’s disease, notably Merck & Co’s MK-8931 – which is now in phase III testing – as well as Eisai/Biogen Idec’s E2609 and a candidate from Novartis that is due to start a combination trial next year. Roche was forced to discontinue its own BACE inhibitor at the end of last year.

BACE inhibitors as potential therapeutics for Alzheimer’s disease.

Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer’s disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer’s disease.

Ref: Recent Pat CNS Drug Discov. 2007 Nov;2(3):188-99.

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