In Alzheimer’s study, drug fails to prevent advance of disease
The Alzheimer’s drug crenezumab did not slow or prevent cognitive decline in a long-running study of Colombian families who carried a genetic mutation that put them at near-certain risk to develop the mind-robbing disease.
The study of 252 people tested whether pharmaceutical giant Roche’s antibody crenezumab could slow or halt the disease if participants took the medication before memory or thinking problems surfaced. The drug did not demonstrate a significant benefit in tests measuring cognitive abilities or memory function among study participants, Roche said Thursday in a news release.
The study began enrolling patients in 2013 to test the idea that Alzheimer’s disease could be prevented or delayed if otherwise healthy people took medication years before developing problems. Roche teamed with researchers from Phoenix-based Banner Alzheimer’s Institute and the University of Antioquia in Colombia, who identified extended families with a rare genetic mutation that brought on Alzheimer’s disease early, usually when they were in their mid-40s.
Study participants who inherited the genetic trigger, known as the Paisa mutation, were randomly assigned to either get the drug or a placebo. Another placebo group included people without the mutation. None of the participants knew their genetic status when receiving the drug or placebo.
Crenezumab is part of a class of antibody drugs designed to counter amyloid beta protein accumulation in the brains of Alzheimer’s patients. Amyloid is one of the markers of Alzheimer’s, and researchers theorize that if the drug could clear amyloid from people before they develop symptoms, it could delay or halt the disease.
Roche and Banner Alzheimer’s Institute said small differences favoring the drug over the placebo were observed but did not rise to the level of being statistically significant. Roche will release initial data from the trial Aug. 2 at the Alzheimer’s Association International Conference in San Diego.
“We’re disappointed that crenezumab did not show a significant clinical benefit,” Eric Reiman, the executive director at Banner Alzheimer’s Institute and a study leader, said. “Our hearts go out to the families in Colombia and to everyone else who would benefit from an effective Alzheimer’s prevention therapy as soon as possible.”
Reiman said 94% of study participants completed the trial and received the drug or placebo over five to eight years. No risks with taking the drug were identified over the course of the study, Roche said.
In 2019, Roche halted two studies of crenezumab in groups of patients showing early signs of Alzheimer’s. Roche is studying another anti-amyloid drug, called gantenerumab, and expects to report results this year.
Pierre Tariot of Banner Alzheimer’s Institute said important analysis must be completed. Participants received higher dosages as the study progressed, so researchers want to know whether escalating dosages made a difference. Researchers must analyze biological changes in brain scans and fluid that surrounds the spine and brain.
“This is by no means the end of the story,” Tariot said.
Stephen Salloway, a professor of neurology and psychiatry at Brown University, said the results are disappointing.
“I don’t want to throw the baby out with the bathwater because one drug with one particular target is ineffective,” said Salloway, who directs a memory and aging program at Butler Hospital in Providence, Rhode Island.
Salloway said the Alzheimer’s researchers are waiting for results from larger studies evaluating other amyloid-targeting drugs. Biogen and Eisai expect to report results this year from a large study of the drug lecanemab. Eli Lilly makes an Alzheimer’s drug called donanemab and expects late-stage results next year. The Food and Drug Administration approved Biogen’s Aduhelm last year after two clinical trials yielded mixed results.
“I think to pursue prevention trials with amyloid-lowering drugs makes sense,” Salloway said.
Randall Bateman, a Washington University professor of neurology, said Alzheimer’s researchers are interested in the Colombian study’s findings because the drug was administered before memory and thinking problems surfaced.
When the data is released, researchers will want to know whether there’s any signal the drug benefited study participants and whether it affected amyloid markers such as plaques that build up in the brain or tau, another protein found in Alzheimer’s patients.
“The question really is would it be more effective if we go earlier?” Bateman said. “I think there’s biological reasons to believe it will, but to date, we don’t have any evidence of that.”
Bateman expects larger prevention studies underway will deliver pivotal information about potential treatments.
“What’s really gratifying is seeing so many groups launching and implementing prevention trials,” Bateman said. “In the long run, this will have a huge public health benefit.”