After 190 Tries, Are We Any Closer to a Cure for Alzheimer’s?

Eli Lilly has spent almost three decades working on drugs for Alzheimer’s disease with not much to show for it yet. This year the company began human tests using a totally new approach. Its latest drug targets an aberrant protein called tau that spreads through the brain as Alzheimer’s progresses, accumulating in telltale tangles that strangle brain cells.

Lilly’s tau drug marks a shift in Alzheimer’s research. Drug companies have long focused on a different protein called amyloid that clumps in the brains of Alzheimer’s patients and is thought to trigger the disease. Companies have poured billions into amyloid-blocking drugs with little success. In 2010, Eli Lilly halted trials of semagacestat after patients on the drug deteriorated more quickly than those on a placebo. In 2012, Pfizer and Johnson & Johnson released results of large trials that showed their amyloid treatment didn’t slow progression of the disease. All told, at least 190 Alzheimer’s drugs have failed in human trials, according to Bernard Munos, a senior fellow at FasterCures, a health nonprofit.

Big Pharma might have thrown in the towel if Alzheimer’s weren’t one of the industry’s last big untapped markets. More than 5 million Americans have the disease, and that number may rise to 13.8 million by 2050, according to the Alzheimer’s Association. Existing medicines, which mostly treat symptoms, have combined sales of about $3 billion today. “If any of these drugs actually manage to slow the progress of the disease, their sales potential would be orders of magnitude higher,” says Sam Fazeli, senior pharmaceuticals analyst for Bloomberg Intelligence.

The disease got its name from German psychiatrist Alois Alzheimer, who in 1906 reported that an autopsy of a woman with severe dementia had revealed clumps and tangles in the brain. More than a century later, nobody knows for sure whether amyloid is the main cause of Alzheimer’s or a minor contributor.

The industry has focused on amyloid because the genetic evidence “has been so compelling,” says Roger Perlmutter, head of research at Merck. In 2012, researchers in Iceland discovered a rare gene mutation that appears to protect against Alzheimer’s by lowering amyloid production. Merck expects to complete its first final-stage trial next year of a pill called verubecestat that blocks amyloid production.

As numerous amyloid drugs have fizzled, however, Big Pharma’s interest in alternatives has grown. The industry “is realizing you may need more than getting rid of amyloid to cure the disease,” says Virginia Man-Yee Lee, a professor at the University of Pennsylvania. Since 2014, venture capitalists and other investors have put at least $350 million into startups pursuing novel approaches.

Most drugs targeting tau are years—or even a decade—behind amyloid therapies in terms of clinical trials. Biogen has two drugs targeting tau nearing human trials. For now, its focus is on an amyloid-removing medicine called aducanumab. But in a preliminary trial last year, only some of the doses tested slowed cognition loss, raising questions about the drug’s effectiveness.

Driving some of the interest in tau is research published in 2012 and 2013 showing that the protein can spread between brain cells, which makes it easier for drug companies to develop medicines to combat it. “The amyloid people are still fighting. They are not willing to see the facts in front of them,” says Harvard Medical School professor Jie Shen, whose work suggests that amyloid plays only a modest role in the disease. Samantha Budd Haeberlein, vice president of clinical development at Biogen, has a different perspective. She says that while tau is “possibly the executioner” of brain cells, amyloid is “the gun.”

AbbVie, which has a tau drug in early human trials, says targeting tau could have certain advantages over hitting amyloid. Tau’s buildup is slower than amyloid’s and continues as symptoms develop, meaning it might be possible to treat patients with more advanced stages of the disease and still get “a very valuable therapeutic benefit,” Eric Karran, vice president of AbbVie’s Foundational Neuroscience Center, told analysts in June.

TauRx Pharmaceuticals plans to present results from a final stage trial of its tau drug at a big Alzheimer’s conference in late July. A successful result would have “huge implications” for the entire tau field, says Claude Wischik, the company’s co-founder.

In the meantime, the amyloid drugs will continue moving through the pipeline. Merck, Biogen, and Roche Holding all have treatments in late-stage trials, while Eli Lilly is retesting solanezumab, which didn’t succeed in earlier trials. Steven Paul, a former head of research for Eli Lilly who’s now the chief executive officer of Voyager Therapeutics, is bullish on the current crop of drugs because they’re more potent and are being tested at earlier stages of the disease, when they’re more likely to work. “We have a much greater possibility of success than we did three or four or five years ago,” he says.

Despite the cautious optimism, Michael Hutton, a distinguished medical fellow at Eli Lilly, conjures a “nightmare scenario” in which money for research and development on Alzheimer’s dries up if the latest amyloid drug trials report lackluster results next year. If that happens, “I do suspect we’ll see pullback from some pharmaceutical companies,” he says.

Bloomberg Businessweek Reprints

June 27, 2016

Source: http://www.bloomberg.com/