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Failures in Alzheimer's research spur new approaches to drug development

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Failures in Alzheimer's research spur new approaches to drug development

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This is the final story wrapping up a series focusing
on Alzheimer's disease. The healthcare news team
examined promising therapies and the failures that
have riddled the drug pipeline along the way.

The Alzheimer's disease drug pipeline is riddled with failures, but pharma companies are vying for what would be a massive reward, as an estimated 74.7 million individuals worldwide will develop the disorder by 2030.

The net present value of potential Alzheimer's treatments ranges from $538 million to about $8 billion, according to market intelligence firm Evaluate.

Such estimates underscore why drugmakers like Cambridge, Mass.-based Biogen Inc. and Japan's Eisai Co. Ltd., which recently saw the end of prominent clinical trials in Alzheimer's, have not yet given up, whether through partnerships with other developers or by digging up alternate product candidates in their arsenal. Others, like Spain's Grifols SA, are testing already marketed drugs for Alzheimer's.

Meanwhile, in research and development of novel agents, Probiodrug AG, AC Immune SA and Anavex Life Sciences Corp. are among the smaller biotechs leading the pack.

The heir apparent

Despite Biogen's and Eisai's high-profile trial failure in early Alzheimer's, the effectiveness of amyloid-targeting therapies in presymptomatic Alzheimer's disease has yet to be determined, said Laurie Ryan, the U.S. National Institute on Aging's dementias of aging branch chief. Researchers and analysts discussed the drugs' potential in presymptomatic patients with S&P Global Market Intelligence in the first of a series of stories on Alzheimer's disease research.

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Ryan emphasized the importance of timing, as "the disease looks different over time. The bottom line is, things change, amyloid goes up and then plateaus."

In the second story in the series, Giovanna Lalli, head of scientific affairs at the U.K. Dementia Research Institute at University College London, walked through the science underpinning Alzheimer's research.

"Dementia is a very complex world and we still do not understand much about the basic mechanism so it's not only toxic accumulation of abeta amyloid," Lalli said. "It's clear that abeta amyloid is a feature and of course tau also," she said, referring to the amyloid and tau proteins misfold and form abnormal tangles in the brains of Alzheimer's patients.

With the failures of amyloid treatments in trials, some researchers have zeroed in on tau, the focus of the third story in the series. Approaches to tau include small molecule, antibody, antisense oligonucleotide, vaccine and gene therapy drug candidates.

"Tau is [amyloid beta's] heir apparent in the AD pathogenesis arena," Stifel analyst Paul Matteis wrote on April 3, noting that tau may better correlate with Alzheimer's symptoms and progression.

New frontiers

Anavex CEO Christopher Missling said that the complexity of the disease's many-fold abnormalities may indicate that targeting just one of them is not sufficient.

"Instead of picking selectively, why don't we let the body decide?" Missling said in an interview. "Each patient is different … so how can you customize the treatment?"

Missling pointed to the sigma-1 receptor protein, which activates homeostasis in the body and reduces imbalances that appear in multiple changes in the body related to Alzheimer's.

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The NIA's Ryan said recent advancements have also shown that other disease elements besides amyloid and tau can track Alzheimer's disease, such as markers for inflammation in the brain and communication between neurons.

Infectious or inflammatory components in conditions that occur at the same time as Alzheimer's, such as cardiovascular disease, may also play a role in disease development, according to NIA director Richard Hodes.

One of the NIA's later-stage sponsored trials, the Systolic Blood Pressure Intervention trial, is therefore evaluating whether lowering blood pressure can positively impact cognitive function and risk of dementia.

The prevention-focused approach to tackling heart disease holds lessons for curbing Alzheimer's disease, experts told Market Intelligence in the fourth story in the series. Researchers are searching for ways to detect Alzheimer's even earlier, as the disease can have a 20-year asymptomatic period, Sharon Fekrat, a professor of ophthalmology and surgery at Duke University told the U.S. Senate in April.

Meanwhile, some companies are trying to develop therapies for symptoms of Alzheimer's. The fifth story in the series relates the efforts of Biohaven Pharmaceutical Holding Co. Ltd.'s efforts to develop its drug candidate, troriluzole, to ease the well-known memory loss and confusion associated with Alzheimer's disease.

Eyeing precision medicine

Not everyone with Alzheimer's developed the disease in the same way. The NIA calls the disease an "aggregate of neuropathologic changes," meaning the patient population is diverse and wide.

Anavex's Missling compared the central nervous system field to that of oncology, which now often checks patients' genomic backgrounds before entering clinical trials for precision medicines that target specific genetic or molecular markers. Doing the same for the varied Alzheimer's patient population could identify the most effective treatments, Missling said.

"[Alzheimer's] is also a syndrome, so it's not a single process; there are different pathways to having the same Alzheimer's disease dementia pathology, so some may be more metabolic, some more genetic, autosomal or familial AD," NIA's Ryan said. "[Alzheimer's] will require ultimately precision medicine or combinations of therapies."

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