Pharma’s fixation on amyloid misguided, says TauRx chair

The pharma industry’s dogged determination to develop amyloid-targeting therapies for Alzheimer’s disease is a “road to nowhere”, according to the scientist behind a rival approach.

Claude Wischik, professor of old age psychiatry at the University of Aberdeen in Scotland, has been researching the role of tau protein in Alzheimer’s for nearly 30 years and is chairman for TauRx, which has just completed enrolment in a phase III trial of a tau-targeting drug in mild-to-moderate AD.

Despite an R&D spend of around $15bn, a total of 20 beta amyloid protein-targeting drugs have failed to show efficacy in phase II and III studies involving AD patients, and pharma companies are now embarking on massive studies to see whether earlier intervention – in pre-symptomatic, at-risk patients – will provide better results.

“I simply don’t believe earlier treatment is going to work,” Wischik tells pharmaphorum, adding that from a pharmacoeconomic perspective the approach is also unsustainable as patients would need to be treated for decades with drugs that could cost in the region of £30,000 a year.

Levels of tau in the brain – measured either post-mortem or using PET imaging techniques – have consistently been found to be more closely associated with cognitive decline in Alzheimer’s than levels of amyloid, he argues.

Tau tangles start to appear in the cortex between 20 and 30 years before symptoms of dementia develop and in fact the pathogenic process starts even earlier, when short lengths of tau protein – called oligomers – can be found in the brain.

The oligomers seem to act like ‘prions’, the infectious particles that are responsible for transmissible spongiform encephalopathies (TSEs) such as mad cow disease and Creutzfeld-Jakob disease (CJD) in humans.

“AD is an endogenously triggered prionosis of tau protein which transmits itself around the brain,” according to Wischik.

Meanwhile, further evidence of the importance of tau in memory decline has come from a study reported at the recent Alzheimer’s Association International Conference (AAIC) in Copenhagen.

Keith Johnson and colleagues from Massachusetts General Hospital in the US conducted a PET imaging study of cognitively-normal adults – average age 72 – who had undergone annual memory testing over the last three years.

They found a clear correlation between levels of tau in the areas of the brain important to memory and worsening scores on the memory testing, and suggested PET imaging could be deployed to “pick participants for prevention trials and treatment trials that target tau.”

TauRx will face the first major test of its treatment approach when data from pivotal trials of its lead tau-targeting drug LMTX emerges in around 2016.

LMTX achieved an 80 to 90 per cent reduction in the rate of progression of AD symptoms over 12 to 18 months in phase II studies – two or three times better than cholinesterase drugs such as donepezil and around four times the benefit reported for Eli Lilly’s anti-amyloid drug solanezumab at the same clinical development stage, says Wischik.

If that level of efficacy is reproduced in phase III testing, TauRx could be in a position to launch LMTX in 2017. Data from the first trial in mild-to-moderate AD is due in early 2016, while a second phase III trial in mild AD should report later that year. Data from a third trial in fronto-temporal dementia should also come in 2016.

“In the AD field, it appears that theory has the ability to triumph over clinical trial data,” writes Wischik in a recently published review article in the journal Biochemical Pharmacology

“The long debate about tau vs beta-amyloid… will ultimately be resolved where it began, in the clinic,” he concludes in the article.

Links

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

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