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Stopping Alzheimer's Before It Starts Bloomberg businessweek (Online) Stopping Alzheimer's Before It StartsBy: Langreth, Robert, Bloomberg Businessweek, 00077135, 12/26/2022, Issue 4767Rather than treating patients already stricken, new drugs from Eli Lilly and Eisai are being tried years earlier When someone develops high cholesterol, doctors don't wait until the patient's arteries are clogged to start treatment. They prescribe cholesterol-lowering drugs while the person is still healthy to prevent plaque buildup and stop heart attacks. Now some of the world's biggest drug companies are trying to do something similar for millions of aging baby boomers at risk of Alzheimer's disease. In massive final-stage trials under way at Eli Lilly Co. and Eisai Co., researchers plan to test brain-plaque-removing drugs on thousands of healthy adults. The hope is to stave off cognitive decline before it begins, or at least delay it. The quest for a treatment has been littered with one failure after another. Only in the past two years has a new generation of anti-Alzheimer's agents started to show hints of slowing the disease's progress. But even the most promising drugs, including compounds from Eisai and Eli Lilly now under review by the US Food and Drug Administration, slow cognitive decline by only about 30% when given to people who already show symptoms. That's because, by the time people develop obvious signs of Alzheimer's, damage to key brain areas may already be extensive. Recent brain-scan studies suggest toxic proteins, including one called amyloid that's the target of most of the new drugs, accumulate in the brain as long as two decades before they lead to dementia. Neurologists hope that removing amyloid before it has time to cause damage will provide a greater impact for patients. If the concept pans out, healthy adults in their late 50s or early 60s could routinely take blood tests or specialized brain scans that search for buildup of amyloid or tau, another aberrant protein. If positive, they'd then have to decide whether to go on amyloid- lowering drugs to reduce the odds of developing dementia in the distant future. "If you wait until people have symptoms, you may not be able to fully prevent the complications," says Harvard Medical School neurologist Reisa Sperling, who's leading two of the biggest prevention trials. "Removing the amyloid before people are impaired is the key." Sperling, 63, knows firsthand about Alzheimer's. She started noticing subtle symptoms in her late father, then a chemistry professor, around 2008. But when she brought him to a doctor for an evaluation, "they said, 'There is nothing wrong with you, don't worry,' " she recalls. About five years later he was diagnosed with Alzheimer's. Sperling's first big trial, which started in 2014, could produce results next year. Co-sponsored by the National Institute on Aging and Eli Lilly, the almost 1,200-person trial involves testing an amyloid- reducing drug called solanezumab on healthy people age 65 and older with high levels of the brain protein. Because the drug failed in three unrelated trials by Eli Lilly for treatment of patients who've already developed Alzheimer's, researchers are using a much higher dose in the prevention trial. While not as potent as more recent amyloid-lowering drugs, it largely avoids the brain swelling that's a side effect of the newer drugs—a potential advantage should it work, Sperling says. Sperling's more recent trial, started in 2020 and sponsored by Tokyo-based drugmaker Eisai and the National Institute on Aging, is more ambitious. Over four years it's giving infusions of the company's lecanemab or a placebo to healthy people as young as 55 with moderate to high amyloid levels. The goal is to start even earlier in life to prevent damage. Eisai is developing lecanemab with partner Biogen Inc. A third prevention trial involves Eli Lilly's newer amyloid-lowering drug, donanemab, which is under review at the FDA for accelerated approval as a treatment. The company is betting that just nine monthly doses may be needed to remove amyloid in healthy people, keeping cognitive impairment at bay for years. Change in US deaths by underlying cause, 2000-2020 In 1906 the German psychiatrist Alois Alzheimer first noticed what turned out to be deposits of amyloid and tau in the brain of a 51-year-old woman who'd died with severe memory loss. Although the causes of Alzheimer's remain hotly debated, the correlation between high levels of amyloid and cognitive decline has become increasingly clear in recent years as researchers developed brain-scan technologies that make it possible to measure amyloid levels in the brains of living people. Astrida Schaeffer, a 59-year-old costume historian in southern Maine, joined the lecanemab prevention trial because she "is absolutely terrified" of getting Alzheimer's given her family's extensive history with the disease. Her grandmother, grandmother's sister, mother and an aunt all died from Alzheimer's. Her mother was a high school language teacher who was fluent in five languages before dementia struck, largely taking her ability to speak. A year ago, after hearing about the lecanemab prevention trial, Schaeffer got an amyloid scan as part of the trial screening and learned she had high levels. Every two weeks she drives several hours round trip to Harvard's Brigham and Women's Hospital in Boston for trial-related infusions. Being in the trial "makes me feel less helpless," Schaeffer says, even though she doesn't know whether she's getting the active drug. Despite the hassle of traveling for all the treatments, "if it prevents me from losing my brain, it would be totally worth it," she says. Brain-scan studies suggest amyloid builds up slowly for years before symptoms develop, promoting brain inflammation as well as tau, which ultimately leads to cognitive decline. By the time symptoms are obvious, removing massive amounts of the protein does only so much. In its Phase III trial on 1,800 patients with early Alzheimer's, Eisai's lecanemab removed more than 70% of the brain amyloid but slowed the rate of cognitive decline by 27% over 18 months. Nonetheless, as the best amyloid-lowering treatment trial to date, it's expected to lead to US approvals for the drug next year—and eventually billions of dollars in sales for Eisai. How noticeable the difference will be for most individual patients is unclear. With prevention trials, scientists are hoping for a more dramatic impact, says University of Southern California's Paul Aisen, a neurologist involved in the lecanemab and solanezumab prevention trials. A drug that removes amyloid in healthy people on the verge of cognitive decline might alter their trajectory enough to delay the onset of Alzheimer's by as much as six years, he estimates. The lecanemab and solanezumab trials will examine whether the drugs stave off subtle preclinical cognitive changes in people with high amyloid. But Eli Lilly's donanemab trial aims to prove the drug can prevent disease. The company will wait until more than 400 of a planned 3,300 people progress to mild cognitive impairment or dementia. Then it will count the cases to see if fewer people who took its drug developed cognitive impairment. While the company doesn't expect to be able to prevent symptoms in all cases, "we would hope people in [the] donanemab arm would have less progression to symptomatic stages," says Eli Lilly neurologist Roy Yaari. For Big Pharma, Alzheimer's drug development amounts to a massive—but potentially extremely lucrative—bet. But it also raises thorny questions about what the US is able to afford and whether the benefit would be worth the risk. Some 25% of cognitively healthy older adults have amyloid lurking in their brains. But unlike cheap anti-cholesterol pills, the current amyloid-lowering agents must be injected or infused and are expected to cost $25,000 or more a year. Nobody really knows whether they'll prevent disease. And the more potent drugs risk triggering brain swelling and brain bleeding. Schaeffer In a Phase II treatment trial, patients on Eli Lilly's donanemab saw cognitive decline at a 32% slower rate, but they had a 39% rate of brain swelling or brain bleeding, compared with 8% of those on a placebo. And while lecanemab showed a lower rate of brain swelling, in the "extension" portion of its Phase III treatment trial, two people who took blood thinners while on lecanemab died; Eisai says its drug didn't cause the deaths. Given all the uncertainties, critics say the trials are too short and may detect subtle cognitive differences that aren't clearly meaningful. But the public's widespread fear of Alzheimer's devastating memory and cognition losses makes an abandonment of amyloid reduction research unlikely. "You have potentially millions of people who could be converting into Alzheimer's" in the coming years, says Eliezer Masliah, director of the neuroscience division at the National Institute on Aging. So something that could delay that by several years "could have a tremendous impact." —Robert Langreth THE BOTTOM LINE By the time people are diagnosed with full-blown Alzheimer's, most of them have deposits of brain-wasting amyloid proteins. Drugs to stop that buildup could be worth billions. |
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