Clinical trial results released Sunday show two experimental drugs that target a protein tied to Alzheimer's disease failed to slow down the disease's progression, marking the latest failure in researchers' quest to find a treatment and leaving some to question whether scientists should consider new approaches to target the disease.
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About Alzheimer's disease
Alzheimer's disease is a type of dementia traditionally defined as a clinical syndrome involving the progressive decline of cognitive abilities—particularly memory loss—that ultimately results in the loss of independence. About 5.8 million Americans have Alzheimer's disease, and CDC projects that number will reach 13.9 million by 2060 as baby boomers age. There is no proven treatment for the disease, though there are medications that temporarily alleviate the disease's symptoms.
Pharmaceutical companies over more than a decade have spent billions of dollars on research to find a treatment for Alzheimer's. Research has largely focused on the beta amyloid protein, which accumulates in the brains of patients with Alzheimer's years before they experience memory loss. Researchers have hypothesized that the buildup in the brain from the beta-amyloid was responsible for the cognitive decline seen in Alzheimer's patients.
However, an estimated 150 to 300 experimental Alzheimer's treatments have failed to show clinical benefits—and many of those treatments targeted the beta amyloid protein.
Another failure for treatments targeting amyloid protein
In the latest clinical trial, called DIAN-TU, researchers set out to test whether two experimental treatments—Eli Lilly's solanezumab and Roche's gantenerumab—could prevent or delay patients from developing Alzheimer's disease. Both treatments are designed to attack the beta amyloid protein.
The clinical trial—which was sponsored by Eli Lilly and Roche's Genentech, the Alzheimer's Association, NIH, Washington University in St. Louis, and some philanthropies—involved 194 participants who carried a gene mutation that causes a buildup of amyloid, which leads to the accumulation of hard plaques in the brain and nearly always results in Alzheimer's disease. All of the trial's participants were younger than a typical patient with Alzheimer's and none of them had brain abnormalities, such as mini strokes. Most of the trial's participants did not have symptoms of dementia, the New York Times reports.
Researchers gave Eli Lilly's solanezumab to 52 participants and Roche's gantenerumab to another 52 participants. About 40 of the participants' family members received no treatment and served as a comparison group, the Times reports.
During the clinical trial, participants received either monthly infusions or injections of one of the two experimental drugs for an average of five years. The participants also received annual blood tests, brain scans, cognitive tests, and spinal taps as part of the trial.
On Sunday, the researchers announced that the experimental treatments did not slow or stop cognitive decline among the trial's participants. The researchers said they are still analyzing the trial's results, which they plan to present at scientific conferences in Vienna in April and in Amsterdam in July.
Richard Hodes, director of the National Institute on Aging, said further analysis is needed to determine whether the experimental treatments eliminated amyloid from participants' brains.
However, Eli Lilly said it will not seek regulatory approval for solanezumab based on the trial's initial results, while Roche said the company could not draw firm conclusions about gantenerumab's effect on patients with inherited Alzheimer's from the initial results.
According to the Wall Street Journal, both companies are continuing to test their experimental treatments in other clinical trials, with some of those trials testing much higher doses of the drugs.
Is it time for a new path forward?
Still, some companies and researchers have questioned whether the long list of failed trails for drugs targeting the beta amyloid protein suggest scientists should focus on other potential ways to treat Alzheimer's disease—and some are pursuing such research.
Richard Hodes, director of the National Institute on Aging, said there are many early-stage clinical trials focusing on new ways of combating Alzheimer's. "Out of 46 pharmacological trials, 30 have targets other than amyloid," he said. "We are well on our way to moving toward these other potential targets."
But others aren't ready to switch gears just yet, the Times reports. According to the Times, some researchers have said experimental treatments targeting the beta amyloid protein might not have worked in the past because the doses were too low or the patient populations used for the trials should have been younger.
For example, Biogen last year announced that it would seek FDA approval for its own amyloid-targeting therapy aducanumab. Biogen initially said early-stage trials appeared to show the drug had no clinical benefits, but later the company said a closer look at its study data determined that aducanumab showed some effect in patients who received higher doses of the drug.
Others have noted that Alzheimer's always progresses the same way—with amyloid accumulating in a patient's brain, then a protein called tau appearing and a patient's neurons dying—which suggests attacking amyloids is key to preventing the disease.
Petersen said, "Amyloid and tau define the disease. Bingo. To not attack amyloid doesn't make sense."
At least for now, research on anti-amyloid drugs will continue. The National Institute on Aging has awarded a grant for another study examining treatments for patients with rare genetic mutations that cause the overproduction of amyloid. But, unlike other trials, this one will involve participants being treated with anti-amyloid drugs likely decades before they are expected to develop the disease's symptoms (Kolata, New York Times, 2/10; Loftus, Wall Street Journal, 2/10; Garde, STAT+, 2/10 [subscription required]).