The announced Alzheimer’s drug works, but there are safety concerns

Researchers have gotten their first look at phase III clinical trial data for a much-hyped investigational Alzheimer’s drug — and while the data shows it has modest cognitive benefits for humans, scientists are concerned about its safety.

The results, presented Nov. 29 at the Clinical Trials on Alzheimer’s Disease conference in San Francisco and simultaneously published in the New England Journal of Medicine, confirmed that the treatment, a monoclonal antibody called lecanemab, reduced cognitive decline compared to placebo 27% slowed an 18-month study of nearly 1,800 participants. The antibody’s developers — Tokyo-based pharmaceutical company Eisai and Cambridge, Massachusetts-based biotechnology company Biogen — announced these top-line results in a press release in September.

But the revelation comes amid media reports that lecanemab may have contributed to the deaths of two people who took part in the study – adding to an ongoing debate over whether the experimental drug’s modest benefits are worth the safety risks involved. Eisai has denied that lecanemab played a role in one death and has yet to determine if it played a role in the other.

“It’s quite a complicated balancing act between risks and benefits,” says Rob Howard, a dementia psychiatrist at University College London. And he worries about how patients and families desperate for Alzheimer’s treatments will weigh the two sides if lecanemab is approved by regulators.

“All available safety information indicates that lecanemab therapy overall is not associated with an increased risk of death,” Eisai said in a Nov. 29 statement.

If a link is found between lecanemab and the deaths, it could “pose a real mystery” to the U.S. Food and Drug Administration (FDA) as it decides how to decide on lecanemab, says Caleb Alexander, a specialist in internal medicine Medicine and Epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland and a member of the FDA Advisory Committee. In early January, the FDA is due to decide whether to grant special approval to the experimental drug.

benefits and risks

The researchers are pleased with the rapid publication of study data on lecanemab. Some have previously criticized the introduction of another monoclonal antibody treatment for Alzheimer’s: aducanumab. Like lecanemab, aducanumab was designed to sweep clumps of a protein called amyloid-β out of the brain; Many researchers believe this protein is a major cause of Alzheimer’s. The FDA controversially approved aducanumab, also being developed by Biogen, last year on the basis that it removes amyloid from people’s brains, but with no clear evidence of any cognitive benefit.

In contrast, lecanemab is the first of its kind to slow mental decline in a robust clinical trial. During the study, called Clarity AD, clinicians administered the treatment to a cadre of people with early-stage Alzheimer’s in more than a dozen countries. Half received biweekly intravenous infusions of lecanemab, while the others received a placebo. Scientists rated people’s cognition primarily using a metric called Clinical Dementia Rating-Sum of Boxs (CDR-SB), which assesses a person’s abilities in six domains, including memory and problem-solving, using an 18-point scale.

At 18 months, participants treated with lecanemab scored an average of 0.45 points better than those treated with placebo on CDR-SB. Other cognition tests used in the study echoed these findings, and the treatment group showed reductions in amyloid and other disease biomarkers.

However, some researchers have questioned whether this shift is large enough to be noticeable in an individual. A one-point difference in CDR-SB is the minimum to be clinically important, Howard says.

“It’s a modest benefit,” says Brent Forester, director of the Geriatric Psychiatry Research Program at McLean Hospital in Belmont, Massachusetts, who helped conduct the clinical trial for lecanemab. His concerns are about safety. About 20% of people who received lecanemab had brain scan abnormalities that suggested swelling or bleeding — although fewer than 3% of those who received the antibody had symptoms related to those abnormalities.

This safety profile is superior to that of aducanumab. Forty percent of people who received this antibody in phase III clinical trials showed brain swelling on scans. But Forester is still concerned because if approved, lecanemab would be given to relatively well-functioning people who happen to be in the early stages of Alzheimer’s. Complications can therefore worsen their quality of life.

During Clarity AD, 13 people taking lecanemab developed symptomatic cerebral hemorrhage — or stroke — while only 2 people in the placebo group did, according to the conference presentation. That’s just 1.4% of the treatment group, Howard says, but “that’s not a trivial risk profile.”

Further exploration required

Both of the media-reported deaths occurred during Clarity AD’s “open-label extension,” a period when a study was officially ended, but participants receiving a placebo can opt into the experimental treatment. Both were stroke-related complications.

In one case reported by STAT News, a participant who was taking a prescribed anticoagulant, or “blood thinner,” for a heart condition died after suffering a heart attack and four mini-stroke-like events. The other person, reported by Science, died of a brain hemorrhage after receiving stroke rescue medication. As reported by both outlets, scientists think it’s plausible that lecanemab may have weakened the brain’s blood vessels by sweeping away amyloid protein that lines the vessels in these people’s brains. The drugs may then have helped induce bleeding.

It’s somewhat difficult to disentangle whether lecanemab played a role in the deaths because of its association with anticoagulants and other factors, said Marwan Sabbagh, a neurologist at the Barrow Neurological Institute in Phoenix, Arizona, while presenting data at the conference. “These things will continue to be explored,” he said. Although the cerebral hemorrhage rate is low with lecanemab, it increases with anticoagulants, he added.

“Honestly, I would be in the camp of not prescribing monoclonal antibodies to people who are on anticoagulation [medicines]says Liana Apostolova, a neurologist at Indiana University School of Medicine in Indianapolis, who advised Eisai and Biogen.

Whether the deaths will affect the FDA’s scheduled Jan. 6 decision on lecanemab is “anyone’s guess,” Alexander says. The agency will consider whether to grant the drug candidate “accelerated approval” based on data from phase II clinical trials showing that lecanemab removes amyloid-β from the brain. Approval would be conditional on Eisai and Biogen conducting follow-up studies to confirm a clinical benefit that Clarity AD is designed to deliver.

If lecanemab is approved, Forester says, “I would suspect there will be recommendations for careful monitoring.”

This article is reproduced with permission and was first published on November 30, 2022.