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World's No. 1 killer provides model for tackling surge in Alzheimer's cases

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World's No. 1 killer provides model for tackling surge in Alzheimer's cases

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This is the fourth story in an S&P Global Market Intelligence series focusing on Alzheimer's disease. The healthcare news team is examining promising therapies and the failures that have riddled the drug pipeline along the way.

The approach to tackling heart disease holds lessons for addressing the rising specter of Alzheimer's disease, experts say.

Early diagnosis coupled with a healthy lifestyle and the prescription of statins has managed to cut the number of deaths in the developed world. While cardiovascular disease is still the world's No. 1 killer, accounting for 17.9 million deaths in 2016, more than three-quarters of the deaths took place in low to middle-income countries where there are no healthcare systems in place to detect and help prevent heart attacks and strokes, according to the World Health Organization.

Like heart disease, Alzheimer's presents physicians and researchers with a biological quandary. With patients, biotech executives and investors dispirited by a spate of recent setbacks in Alzheimers' research — including crenezumab, a monoclonal antibody being developed by Roche Holding AG there is hope that a spate of new approaches that have proven successful in heart disease may yet yield promise. Those include disease stratification, where patients are grouped according to their risk of disease or response to therapy by using diagnostic tools, and the use of precision medicine, a more tailored approach with targeted therapies.

"Nobody, nobody doubts or questions our approach to cardiovascular disease, where we actually give statins in the prevention of disease. Everybody accepts there is a biomarker, which is cholesterol, and you give statins if you have an enhanced risk of cardiovascular disease," said Andrea Pfeifer, CEO of AC Immune SA, the Swiss biotechnology company that discovered crenezumab.

"So why can we not translate this result into an Alzheimer's setting?"

There are 11 million people living with Alzheimer's disease in Europe, and this is forecast to rise to 14 million by 2030. The economic cost of the disease — characterized by increasing forgetfulness, confusion and agitation — is expected to increase by 43% to over €250 billion by 2030 from 2008, according to the European Federation of Pharmaceutical Industries and Association. This is equivalent to the GDP of Finland. Globally, a new case is diagnosed every three seconds, equating to 9.9 million new cases of dementia each year, bringing the total expected by 2050 to 131.5 million people.

"It's a huge unmet need and there's nothing there. ... Pharma are all looking for it, they're all hunting aggressively for new targets in neurodegeneration at earlier stages where it's less visible," said Giovanni Mariggi, London-based partner at Medicxi, a life sciences investment firm. "So I don't think one should say CNS and neurodegeneration has been abandoned: It's the opposite – there's a lot of people looking for something."

Abeta failures

Roche halted two Phase 3 studies of crenezumab in people with early sporadic Alzheimer's disease after the investigational molecule targeting abeta amyloid proteins failed to meet its primary endpoint. This setback, along with Biogen Inc. and Eisai Co. Ltd.'s decision to stop the development of aducanumab on March 21, increased the negative tone surrounding research focused on the so-called amyloid approach, which targets the build-up of plaques that lead to brain cell death.

"Right now I believe it's not a problem with the molecule, it's a problem with the class," Pfeifer said. "I think the class, being Abeta, we need to look into earlier in a preventative setting."

Halle, Germany-based Probiodrug AG is doing just that. In developing PQ912, a small molecule glutaminyl cyclase inhibitor which is able to penetrate the blood-brain barrier, the Euronext-listed biotech attracted the attention of the U.S. National Institutes of Health and won a $15 million grant to partially fund a phase 2 trial on March 20.

"One of the big advantages is the fact that they're developing a small molecule. ... But more specifically to the mechanism of action: theirs is unique," said Brigitte de Lima, analyst at Goetz Partners Securities, which is house broker to Probiodrug. "All the other approaches have focused on targeting the actual plaques, whereas what they do is inhibiting an enzyme which appears to have no other physiological function other than making toxic bits which then aggregate to form plaques - It's almost like a catalytic effect."

Biomarkers, inflammation, abeta and tau?

Together with prevention — a possible statin-like approach to Alzheimer's which would require biomarkers and imaging of the brain — Pfeifer believes that a combination approach which tackles both abeta and tau, a tangle of proteins which accumulate within the brain, might yield more positive results than just pursuing one of these two proteins. As the progression of tau is much slower, it is easier to track disease and thus is an important second target for Alzheimer's which AC Immune — along with its partners Roche and its Genentech unit, Johnson & Johnson's Janssen business and Eli Lilly and Co. — is increasingly focused on.

"It has become increasingly clear that pathological tau more closely correlates with the progression of the disease, as well as cognitive improvements in models of disease," Pfeifer said.

Furthermore, inflammation plays a clear but as yet ill-defined role in neurodegenerative diseases including Parkinson's and Alzheimer's, and the outcome of an ongoing trial of crenezumab in a Colombian sub-population of people at risk of developing familial Alzheimer's will be closely observed for any hints, Pfeifer said. Called the Alzheimer's Prevention Initiative, the trial is being carried out in collaboration with the Banner Institute and funded by the National Institute on Aging and is expected to finish in 2022. The issue of patient heterogeneity in Alzheimer's is also increasingly under the spotlight and an ongoing trial in a group of Down syndrome adults, a homogenous genetic population at risk of early onset Alzheimer's, might provide further clarity.

Value of data sharing

In the continuing absence of a disease-modifying treatment for Alzheimer's, the greater collaboration and sharing of knowledge observed between companies and researchers in the field of neurodegeneration — compared with those working in the inflammation or oncology space — provides some grounds for optimism, Probiodrug CEO Ulrich Dauer said.

"There are a lot of promising approaches. ... We know it's a complex disease, it has multiple components. I am not discouraged by these failures, because I think they are really not differentiated enough and they are based on a very simplified picture of the disease pathology," Dauer said in an interview.

Pfeifer believes that precision medicine, driven by more sensitive diagnostics, will allow us to select the appropriate patient populations to develop effective single and combination therapies.

"I think as a big pharma biotech company, as a society, as investors — I don't think you can just overlook or forget about Alzheimer's," Pfeifer said. "We really have to work together in a different way to tackle what became the biggest healthcare challenge of the century.

"I thought after cancer, nothing can be more complicated. But I was wrong."

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