Eli Lilly and Company is reporting positive results in a small trial of donanemab, an experimental antibody treatment for Alzheimer’s disease. The firm’s announcement comes as the US Food and Drug Administration weighs the fate of a controversial competitor antibody for the disease made by Biogen.
The field of Alzheimer’s disease treatment has been plagued by failed and inconclusive trials. Still, some experts consider Lilly’s announcement hopeful for the millions of people with the illness who have waited decades for a treatment.
“It potentially is very exciting,” says David Holtzman, an Alzheimer’s disease expert at the Washington University School of Medicine, describing one of Lilly’s reported findings—a 32% drop in cognitive decline as measured by one of many tests given to people who got the antibody. Holtzman says other experimental Alzheimer’s treatments haven’t delivered that kind of result. “Of anything that’s been reported,” he says, “I’m not aware there has potentially been that big of an effect.”
The Phase 2 trial followed 272 people for about a year and a half. The study was placebo-controlled—one group of participants did not get the treatment—and it was double-blind, so neither the participants nor the providers knew who was getting the treatment and who wasn’t. John Sims, the senior medical director for neurodegeneration at Lilly, says people were taken off the treatment as imaging studies showed the clumps of protein that characterize Alzheimer’s disappeared from their brains.
“We had a lot of patients become amyloid-negative,” Sims says. Company officials will present the data at a meeting in March, he says. Lilly has also submitted the results for publication.
Alzheimer’s is a neurodegenerative disease marked by a loss of cognitive ability and memory. While some companies are investigating small-molecule treatments, others, like Lilly and Biogen, are investigating antibodies that might trigger the immune system to clear out clumps of a protein called amyloid-β that are suspected of killing neurons associated with cognition and memory.
Biogen asked the FDA to approve its antibody, aducanumab, despite confusing data and a trial that was halted early because it didn’t appear the drug was working. The firm’s recent approval meeting was contradictory: FDA officials sounded praise for the treatment while external reviewers panned it.
In contrast to aducanumab, which binds to a common string of amino acids in amyloid-β plaques, donanemab binds to a less-common section of the amyloid-β protein containing an altered amino acid called pyroglutamate. Based on postmortem studies, nearly everyone who has Alzheimer’s disease has some pyroglutamate, Sims says, but it makes up a very small percentage of amyloid-β.
It’s not clear whether the presence of pyroglutamate adds to the toxicity of amyloid-β plaques, but Sims says it is characteristic of older plaques. Company scientists developed the antibody by looking for small, immune-stimulating amino acid sequences called epitopes they could only find in amyloid-β plaques.
Holtzman, whose lab created another Alzheimer’s disease antibody that Lilly licensed, says treatments like donanemab work like this: The antibody, a Y-shaped molecule, sticks to its target in the amyloid-β plaque. The tail of the antibody attracts brain immune cells called microglia, which more or less eat the protein clumps.
But microglia also trigger inflammation and swelling, which seem to have plagued other antibodies that target more abundant parts of the amyloid-β clumps. In some people, the swelling can lead to headaches or seizures. In the Lilly trial, about 6% of people whose brain scans showed inflammation had swelling with symptoms, which Sims says is lower than in other antibody trials.
Holtzman says donanemab is a test of the idea that targeting just a tiny part of the amyloid clumps will spur the immune system to clear out the plaques without triggering the larger inflammatory response. “It might result in more rapid clearance without having some of the potential side effects,” he says.
Despite the sword hanging over Biogen’s aducanumab, Sims says that Lilly is confident in its results and is talking to FDA officials about next steps. Success in bringing this antibody to market could bolster the idea that amyloid-β is the root cause of the illness. That being said, Sims is careful to point out that there is no correlation between disease progression and the amount of amyloid plaques in a person’s brain.
Lilly’s study also measured the effect of the antibody on another protein, called tau, also found in the brains of people with Alzheimer’s disease. Tau was critical to trial design, Sims says. Once researchers selected trial participants based on the presence of amyloid, they then refined their trial pool further by the presence of what he describes as a “Goldilocks level” of tau—not too little, not too much.
“Tau is more directly linked to progression of the disease,” Sims says.
While Lilly waits to release data from the trial, the firm has moved onto other donanemab studies, including one that allows the placebo group from the Phase 2 trial to receive the treatment.
Holtzman credits Lilly for its perseverance in the field and says he is looking forward to viewing the data. “They are one of the companies that’s worked the longest. . . . on these kinds of approaches. It’s hard for me to believe that this isn’t really solid data,” he says.
This story was updated on Jan. 15, 2021, to clarify that 6% of people in Lilly's trial had swelling with symptoms, not swelling alone.