“My first reaction was to be angry,” says JoAnn Wooding. “I’ve gotten over that, and frustration is more the word right now.”
Wooding’s husband, Peter, who was diagnosed with Alzheimer’s in 2016, was among the more than 3,200 people with the disease who volunteered to test a promising drug called aducanumab. Made by Biogen, a U.S. biotech company, and Eisai, a Japanese pharmaceutical manufacturer, the drug seemed, in early studies released the same year, to be the first to both shrink deposits of the protein amyloid accumulating in the brains of patients with Alzheimer’s, and to slow the cognitive decline resulting from their buildup. The study in which Peter was participating was one of two trials designed to confirm that early promise, and, patients and doctors hoped, lead to the first approved treatment that could actually halt the neurodegenerative disease.
But last March, Biogen, after an early review of its data involving half of the patients, decided that the results were not promising enough to continue the trial, and terminated it. Peter and the other volunteers stopped taking the experimental drug and the company began an in-depth analysis of the data it had collected so far.
Its full report, which included all 3,285 patients, revealed a rosier picture. After 18 months of taking aducanumab, participants in one of the studies showed anywhere from 15% to 27% less cognitive decline, as measured by standard tests of memory and cognitive ability, compared to those receiving a placebo. The cognitive protection was most pronounced in those getting the highest dose of the drug. Based on the latest analysis, the company is now asking the Food and Drug Administration to approve aducanumab for the treatment of early Alzheimer’s disease.
“In retrospect, the…analysis [last spring] was incorrect,” says Dr. Alfred Sandrock, chief medical officer at Biogen. “But based on the data we had at the time, we followed the science and made the decision to terminate the studies. With the additional data and the additional analysis, we now know the drug has efficacy.”
The news is bittersweet for the Woodings, who now feel they have lost precious time in holding off the disease ravaging Peter’s brain. After being randomly assigned to receive either aducanumab or a placebo once a month for 18 months, all of the volunteers were then given the opportunity to receive the drug for at least two years. Peter had completed his 18-month test period and had received his fifth infusion of the active drug when Biogen pulled the plug.
“When he was off the drug, there were some changes that came rather quickly, with his short-term memory being the most affected,” says JoAnn. “Over time I could see a difference without the drug.”
How could the two different reviews of the data lead to such startlingly different conclusions? After all, the early phase study of aducanumab was encouraging enough to prompt the company to launch the large, late-stage studies in 350 sites in 20 countries in which Peter participated. The drug seemed to have a unique way of finding and sticking to clumps of amyloid protein, and signaling the body’s immune cells to destroy them.
The conclusion of the data from the first half of patients that emerged in March 2019 was undeniable. There was no statistically significant difference between the cognitive test results from those who had received monthly infusions of aducanumab for 18 months and those who received a placebo. And the drug did have side effects, the most worrisome one being brain inflammation that could be life-threatening. Rather than risk exposing people to the risk of side effects with no perceivable benefit, Biogen CEO Michel Vounatsos decided to terminate the studies.
“The decision was driven by the interests of the patients—to not expose them to a product that the data deemed to be ineffective,” Vounatsos says.
For Sandrock, who had been working with aducanumab since 2007, “The first few weeks after that decision were pretty tough for me. I would meet with the team weekly and say, ‘Are we sure the drug doesn’t work?’ And they said, ‘Look at the data. Face facts.’”
Samantha Budd Haeberlein, head of Biogen’s late-stage clinical development for Alzheimer’s Disease, was equally dumbfounded, even annoyed. “As a scientist, I was completely confused,” she says. “How could it be, when we had such clear data form the [early] clinical trial, such compelling data? How could this have happened? The scientist in me was really irritated—what the hell happened?”
She and a team of statisticians and programmers pooled all the data from the hundreds of study sites and thousands of patients, and combed through it. And when they finally looked at the overall results, they were surprised to find that one of the studies showed a clearly positive trend in reducing cognitive decline, while the other did not show much change in cognitive functions at all. The two studies were identical in terms of the types of patients enrolled and how they were randomly assigned to receive aducanumab or placebo. The only distinction was that one study began earlier than the other.
That made a difference, Haeberlein, believes, since Biogen changed certain aspects of the study design after patients began enrolling. For one, the very first people to volunteer were given much lower doses of the drug if they had the ApoE gene, a mutation that raises a person’s risk for Alzheimer’s—and also seemed to raise the risk of experiencing brain inflammation as a side effect of aducanumab. About two-thirds of the people who participated in the studies carried this high risk gene.
New data that became available after these patients began receiving their infusions, however, revealed that slightly higher doses were still safe and did not result in a marked increase in side effects. So these patients were then given higher doses. But many had either not yet or just begun their new doses when the company analyzed its data on the first half of patients last spring.
When she first looked at the positive results last June, Haeberlein was skeptical. She dug deeper, breaking out how the patients receiving the lower doses fared on their cognitive tests. Those people showed some improvements—more than the placebo group but not as great as those at the higher doses. “That was when we as a team said, ‘Holy cow!’” She walked across the Biogen campus and pulled Sandrock out of a meeting, saying “We’ve got to talk.”
Other data supported the positive effect aducanumab was having on the patients. As part of the study, all of the volunteers periodically had brain scans taken to measure changes in the amount of amyloid buildup. They also had their cerebrospinal fluid tested for signs of the protein—as more amyloid starts to clump together in the brain, levels of the protein circulating in the spinal fluid tend to drop. These tests from the all of the study participants indicated that the people getting the highest doses of aducanumab were indeed also showing declines in amyloid plaques and steady levels of the protein in their spinal fluid. “Patients can’t influence the proteins in their brain,” says Haeberlein. “These wonderful readouts gave us further confidence that what we were looking at was very strong.”
Biogen is now working with the FDA and its study sites to launch a new study, in which all of the people who had participated already would be invited back to receive aducanumab (there will be no placebo group).
The news of the FDA filing is providing much needed hope for the Alzheimer’s field, which has been battered by a series of failed drug trials over the past decade. “This news opened the opportunity to really rush through the door,” says Maria Carrillo, chief science officer of the Alzheimer’s Association. “There are lots of implications for these results, not only for those currently diagnosed with early Alzheimer’s disease, but also for re-energizing prevention trials. This is the very first time in the field that we have had the type of positive news that could be transformational.”
Dr. Steven Salloway, who treats Peter, says “If approved, this drug would make Alzheimer’s disease a treatable condition, from a biological point of view. This would be major league.”
After his study was stopped in the spring, Peter joined another trial testing a different type of experimental treatment for his disease. To join Biogen’s new planned study, he would have to wait for the study to be approved, and then go through a period in which the drug he is currently testing is washed out of his system, which could take months. Even with those hurdles, would he start taking aducanumab again? “I would, I would,” he says. “Hopefully we can make a difference with this disease. We have to stick with it and make a touchdown.”
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