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Why coming up with a drug for Alzheimer's is so devilishly hard

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The first days of 2018 have been a bleak reminder of how tough it is to develop drugs for some of the world's most frightening diseases, which rob people of their memories, abilities and personalities.

In the span of one week, pharma giant Pfizer announced it was ending its internal efforts to develop new drugs for Alzheimer's and Parkinson's disease. Axovant Sciences announced that its experimental drug, which late last year failed an Alzheimer's trial, had also failed to treat a different form of dementia. A day later, a leading medical journal published an account of yet another experimental drug that failed to prevent cognitive decline in people with mild to moderate Alzheimer's disease.

These setbacks pile on to an already depressing situation: more than 400 failed clinical trials since the last Alzheimer's drug - which only treats the symptoms of the disease, temporarily - was approved more than a decade ago.

"If you think it's been a bad week, it's been a bad 14 years. It's 14 years since the last new drug was approved by the FDA and the string of failures this week is nothing new and not unexpected," said David Bennett, director of the Rush Alzheimer's Disease Center in Chicago. "I view Pfizer getting out of the Alzheimer's business as not a good thing for the field, but that doesn't mean that I have a strong recommendation for what Pfizer should do in its next trial."

Alzheimer's is a formidable foe for a number of reasons. The brain isn't easy to access, and much about how it works remains mysterious, even as scientific knowledge has moved forward. Doctors can't take easy, repeat biopsies to see whether a drug is working.

Trials are long and expensive: It has become increasingly clear that it is necessary to treat patients early in the disease, and then wait to see if the disease is prevented or slowed.

Patients, though they are affected in heartbreaking ways, typically are unable to act as advocates for more funding or research when they are in the throes of the disease - unlike cancer or AIDS patients.

That doesn't mean pharmaceutical companies and researchers are giving up. Dennis Selkoe, a professor of neurology at Brigham and Women's Hospital in Boston, who has served as the head of the external neuroscience advisory board for Pfizer, said part of the reason for the long string of failures is that in their desperation to find a drug, companies conducted trials that weren't optimal - not targeting people early enough in the disease, or not using the best possible drugs.

"When the world says, 'Man, it's terrible - Alzheimer's has gotten nowhere,' I don't think it's a lack of knowledge about the disease mechanism. It's because we've chosen weak drugs that don't do much. And we've tried them when people already have significant impairment," Selkoe said.

The failures have helped inform research. Trials increasingly test drugs earlier, when they are more likely to have an effect. Improved imaging technology has helped researchers to peer into the brain. Growing knowledge of the disease, which is characterized by the buildup of amyloid beta protein and tangles called tau, has helped guide the development of smarter drugs.

An experimental drug called aducanumab from the Massachusetts-based biotech company, Biogen, is being tested in late stage trials, after showing success in reducing amyloid in early trials. Selkoe said he enrolls his own patients in this trial and is hopeful that if it shows good results, it could spur more companies to develop drugs in this space. Selkoe has no financial relationship with Biogen.

But the long list of failures may make companies hesitant to fund research when they have limited resources and more promising drug development programs in other disease areas.

Pfizer will maintain a venture fund of undisclosed size to invest in neuroscience research.

"After years of research and investment and putting our strong and focused efforts into advancing neuroscience therapies, we recognized our ongoing efforts were not going to deliver the impactful medical advances for patients that we had aspired to achieve," Pfizer spokeswoman Neha Wadhwa said in a statement. "This was a difficult decision and it is not lost on us that there is a tremendous need for new therapies in this therapeutic area."

Part of the difficulty is that people with Alzheimer's disease often suffer from other brain pathologies - that also make major contributions to their cognitive decline. That is yet another complexity of the aging brain that could make it harder to know if a potential Alzheimer's drug is working. It also raises the prospect that fragile, elderly patients might one day have to take cocktails of drugs to preserve their cognition.

One solution is to try to isolate people with the purest form of the disease, using imaging scans or other tools to find people with Alzheimer's absent other signs of pathology.

But Bennett is trying to get companies interested in developing drugs that bolster cognitive reserves generally, rather than treat a specific disease. The idea is that there could be proteins that serve a protective effect or negative ones that could be suppressed.

Selkoe pointed out that despite the failures, the urgency of the disease keeps companies pushing forward.

"I'm optimistic," Selkoe said. "Even though they keep on failing, there are lots of other shots on goal."