Amyloid hypothesis: down but not out in Alzheimer’s disease?

Despite a string of drug candidate failures, pharma continues to invest R&D dollars in amyloid-targeting therapies for Alzheimer’s disease (AD), and Novartis is the latest to announce a major programme in this area.

The clumping of amyloid beta in the brain to form plaques is one the hallmarks of AD, and the ‘amyloid hypothesis’ suggests they are a primary driver for the neurodegeneration seen in the disease.

That viewpoint was severely dented back in 2012, when two highly-anticipated amyloid-targeting antibodies – Pfizer’s bapineuzumab and Lilly’s solanezumab – both failed phase III trials, adding to a lengthening list of other compounds that had tried and failed to address the underlying progression of the disease.

Scientists working on amyloid refused to give up on the target however, suggesting the late-stage trials had failed because they enrolled patients whose AD was too advanced to respond to treatment. Using the drugs even before AD symptoms are evident could give a better result, they argued.

Taking this on board, various anti-amyloid drugs – including solanezumab and Roche/Genentech’s crenezumab and gantenerumab – started trials in people at risk of developing AD but without symptoms of the disease.

Hit it hard, and early

Novartis has now joined their ranks via an alliance with Banner Alzheimer’s Institute (BAI) that will test the combination of two amyloid-targeting drugs – an injectable vaccine stimulating an immune response to the amyloid beta protein itself and an oral beta secretase or BACE inhibitor, which blocks an enzyme involved in the conversion of a precursor protein into amyloid.

The trial – due to begin in early 2015 – will enrol around 1,300 cognitively-healthy people who are genetically at high risk of developing AD because they have inherited two copies of the apolipoprotein E epsilon 4 (APOE4) gene.

“There is a huge unmet need for treatments that prevent or delay the development of the disease and we are excited about taking research in Alzheimer’s to the next level,” said Novartis’ pharmaceutical division head David Epstein.

Novartis’ announcement comes shortly after scientists at Lilly have reported enticing evidence to support the role of combination therapy.

Researchers at the company, led by senior scientist Ron DeMattos, have found that the combination of an amyloid-targeting antibody called N3pG and Lilly’s BACE inhibitor LY2811376 slowed the progression of the disease in mice genetically-engineered to develop AD-like symptoms.

Each drug given on its own was able to clear around 50 per cent of the amyloid beta plaques, but the combination was much more effective, removing 86 per cent of them. Moreover, the study found that the drugs targeted different types of amyloid, with the BACE inhibitor removing diffuse deposits of the protein while the antibody zeroed in in dense or ‘cored’ plaques.

“These results may have a significant impact on the future of Alzheimer’s disease therapies,” DeMattoss told delegates at the Alzheimer’s Association International Conference (AAIC) in Copenhagen, Denmark, last weekend.

“They support the clinical rationale for using future testing of combination therapy against the amyloid beta protein in clinical practice,” he added.

Targacept disappointment

Of course, the natural progression of AD means that trials in healthy, at-risk patients will take years to complete, and in the meantime patients with the disease only have access to therapies such as cholinesterase inhibitors that provide short-term relief of cognitive symptoms.

Hopes that the therapy arsenal might be expanded in the near-term have just been dashed by Targacept’s decision to abandon development of its TC-1734 candidate for mild-to-moderate AD after a phase IIb trial found it was less effective than the generic cholinesterase inhibitor donepezil.

The alpha4beta2 blocker – which does not act on amyloid but targets neurotransmitters in the brain – was formerly partnered with AstraZeneca (AZ) but the latter returned rights to the project last year.



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