Momentum building behind tau as Alzheimer’s target

After years of playing second fiddle to amyloid as a drug target in Alzheimer’s disease, there are signs of increasing interest in the development of tau protein-targeting drugs.

Earlier this month, Johnson & Johnson (J&J) subsidiary Janssen announced a three-year agreement to develop tau-based immunotherapies with Swiss company AC Immune, whose lead candidate ACI-35 is in phase Ib testing.

J&J’s involvement marks one of the first times that a big pharma company has made a public play in tau R&D. Most activity in the category is being driven by small companies developing drugs designed to block the protein, including TauRx Therapeutics, Zeltia subsidiary Noscira and AXON Neuroscience, although Biogen Idec and Eisai announced a joint programme involving a tau candidate last year.

Modified forms of tau protein are responsible for the characteristic tangles seen in the brains of patients with Alzheimer’s, while amyloid beta forms the plaques that have been the focus of much of the new drug development carried out to date.

There is a fair amount of research supporting the view that targeting modified tau is a promising way to slow down, and potentially even stop, progression of the disease, according to GlobalData analyst Kyle Nicholson.

With the failure of several amyloid-targeted therapies – including Eli Lilly’s solanezumab and Roche’s gantenerumab, as well as several others – “doubts are starting to arise over whether or not the removal of beta amyloid will affect a patient’s cognitive status,” said Nicholson.

“Given that tau-related pathology might occur before beta amyloid becomes implicated, a tau-based approach may have a greater chance of eliciting measurable effects earlier in the disease’s progression,” he added.

Janssen’s licensing of rights to ACI-35 – which stimulates an antibody response against phosphorylated tau – is the first vaccine-based drug targeting the protein, although a similar approach against amyloid was unsuccessfully tested by Elan some years ago.

That programme was abandoned after vaccinated patients developed brain inflammation, but researchers remain hopeful about the immunisation approach. AC Immune also has an amyloid-targeted vaccine called ACI-24 in early-stage testing.

It has also been suggested – given that tau and amyloid seem to exert effects in tandem, with plaques accelerating the formation of tangles – that a combination of both approaches could be the most promising.

At the moment, though, J&J has not made a play for ACI-24 although AC Immune says it will be looking for partners once it has data from an ongoing phase I/IIa trial in hand.

Despite its promise as a first-in-class agent, Nicholson believes ACI-35 will face competition from passive immunotherapies for Alzheimer’s disease as well as oral beta-secretase inhibitors, an amyloid-targeting class, which he expects to start reaching the market from 2018.

“We expect AstraZeneca/Eli Lilly’s AZD-3293 and Merck & Co’s MK-8931 to capture over 15 per cent of the global Alzheimer’s disease space by 2023,” he said.

“ACI-35 will therefore likely enter a highly competitive arena several years after the beta amyloid therapies have already taken a significant patient share.”


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