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Alzheimer’s Drug Verubecestat Clears Milestone in Human Clinical Trial

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Can we prevent and treat Alzheimer's in the next 10 years?

On Monday Pres. Barack Obama proclaimed November “National Alzheimer's Disease Awareness Month.” The administration’s ambitious goal is to prevent and treat Alzheimer's by 2025. Although there are currently no approved therapies that slow or stop progression of the disease, several approaches are showing promise.

In a study published today in Science Translational Medicine, a team from Merck Research Laboratories reports results of early human and animal trials of a drug called verubecestat, which targets the production of protein plaques associated with the disease. “It's a summary of the discovery and early-stage profiling of what we hope is going to be a new therapeutic for Alzheimer's,” says team leader Matthew Kennedy. “It represents well over a decade of investment in this project by many, many scientists.” Definitive conclusions will have to await the results of larger, ongoing phase III clinical trials to assess their efficacy, effectiveness and safety, but the results are promising, experts say.

Verubecestat is a so-called BACE1 inhibitor. BACE1 (for Beta-site Amyloid precursor protein Cleaving Enzyme 1, aka beta-secretase 1) is an enzyme involved in producing amyloid beta, a protein that clumps together, eventually forming the plaques surrounding neurons that are the disease's key hallmark. The amyloid hypothesis of Alzheimer's proposes that the accumulation of amyloid beta aggregates in the brain drives a cascade of biological events leading to neurodegeneration. By blocking BACE1, the hope is this approach could prevent the buildup of these clumps in the first place. But until now, development of these drugs has been hindered by problems finding molecules with the right characteristics, and concerns over theoretical and actual side effects.


The second trial could prove a crucial test, because a treatment that limits production of amyloid is likely to work best at the earliest stages of the disease. Plaques may start building two decades before symptoms appear, so by the time a diagnosis is given it may be too late for this approach to help. Researchers await results (expected in 2017 and 2019, respectively) eagerly. If participants show slowed decline of cognitive functions together with reduced amyloid, it would provide strong support for the hypothesis that the protein clumps cause Alzheimer's.

But BACE1 inhibitors are not the only game in town. Another approach is antibody therapies. One of these drugs, aducanumab, dramatically reduced amyloid in the brains of patients with mild stages of Alzheimer's in a small trial reported in the September issue of Nature. Some participants also showed slower cognitive decline, although this too awaits confirmation from a larger, ongoing clinical trial. “I'm also encouraged by the aducanumab data,” Selkoe says. “These are all good shots on goal.”

Researchers believe antibody therapies work by “mopping up” existing amyloid aggregates whereas BACE1 inhibitors prevent the protein from being produced, so the two could prove complementary, Vassar says. “There may be hope for healing the brain with such an approach,” he adds. “We can't bring back dead neurons but we might be able to heal the ones that are still alive.”

Reddit comment:

Early detection may be crucial, and we're not the greatest with catching alzheimers early.

“The big issue is: What will the long-term safety of these drugs be?” Vassar says. “People may have to take these drugs for the rest of their lives, the trials are two years at most; what happens beyond that, as people get older, we have no idea.”

Long term health effects are unknown and unknowable in humans without further study. It could have some real nasty issues attached with it. Short term toxicity seems to be good, which is why it got the go ahead for longer clinical trials. In particular, they're not entirely sure how well the rodent model represents human alzheimers, and are questioning if the effects/side effects will be the same as a result. That's just from the article mind you, I'm no expert on the field. There's still years of testing/data crunching before we see if this drug works properly in humans.

Tentatively hopeful outlook, no smash hit yet. Check back in a couple years.

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