Medical Review Group Questions Usefulness of Some Alzheimer’s Drugs

“Not all drugs in the class are the same,” says Laura Nisenbaum, executive director of drug development for the Alzheimer’s Drug Discovery Foundation. “If you’ve seen one anti-amyloid therapy, you’ve seen one anti-amyloid therapy.”

Dr. Andrew Budson, associate director of Boston University’s Alzheimer’s disease research center and a professor of neurology, pointed out that only one study for each of the two U.S.-approved drugs was included, “plus 15 additional studies for drugs that were shown not to work,” he says.

“It should be no surprise that if you average 15 studies for drugs that don’t work with two studies for drugs that do work, that the average result shows that, as a class, these drugs don’t work,” Budson says. “I just don’t think that this review is relevant for people living with Alzheimer’s disease in the United States.” 

However, Nonino noted in a press conference that the group also separately analyzed the studies of Leqembi and Kisunla and that “they are perfectly in line with the pooled estimates.”

Dr. David A. Wolk, director of the Penn Alzheimer’s Disease Research Center and division chief of cognitive neurology at the University of Pennsylvania, said that examining them together “is conflating drugs into a single class when clearly, they have different degrees of target engagement. One simply cannot treat all these studies as equal.”

“Bundling these drugs together to make an overall conclusion is odd,” agrees Dr. Jason Karlawish, professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine and codirector of the Penn Memory Center.

“The field is still sorting out what kinds of anti-amyloid molecules and dosages are effective. Lecanemab and donanemab show this.” Karlawish is also a member of AARP’s Global Council on Brain Health.

The dissenting doctors also stressed that 18 months was not enough time for an accurate assessment. “The benefits continue to be seen the longer patients stay on the drugs,” Nisenbaum says. The Cochrane authors agreed that 18 months is short for assessing drugs given to people in early stages of a slowly progressing disease, but that was the length of the randomized controlled trials.

Of the other early drugs included in the Cochrane paper (aducanumab, bapineuzumab, crenezumab, gantenerumab and solanezumab) only one, aducanumab (brand name Aduhelm), gained FDA approval in 2021, but it was discontinued by its manufacturer three years later, after Medicare refused to cover it.

The Cochrane researchers also noted the drugs’ increased risks of brain swelling and bleeding, which are recognized as potential dangers, and urged the research community to consider shifting its focus to other brain mechanisms for drug targets.     

“I see Alzheimer’s patients in my clinic every week, and I wish I had an effective treatment to offer them,” said Richard.

“Existing approved drugs offer some benefit for some patients, but there remains a high unmet need for more effective treatments,” he said. “Sadly, anti-amyloid drugs do not offer this and bring additional risks. Given the absence of correlation between amyloid removal and clinical benefit, we need to explore other pathways to help address this devastating disease.”

Nisenbaum agreed. “Amyloid is one part of the solution but not the entire solution,” she said. “We know we are going to need combinations. These [two drugs] are the first showing the slowing of decline. Now we need to take that effect and target other drivers of the disease.”

Meanwhile, patients taking either of the two drugs should not feel anxious because of the Cochrane report, she says. “This is a single study, and it should not change decisions overnight,” she said. “These are individual, personal decisions that should be made by each patient in consultation with their physician.” “I still think that these are worthwhile drugs that are disease-modifying but have known risks of bleeding and swelling that we discuss during informed consent,” says Dr. Mia Yang, an internist and associate professor of gerontology and geriatrics at Wake Forest School of Medicine who also practices at Atrium Health Neurology in Charlotte, North Carolina.​​

A representative of Eisai, the biotech company that makes Leqembi, sent the following statement: “The Cochrane analysis is scientifically deeply flawed by inappropriately combining ineffective antibodies and failed studies with effective, regulatory approved anti-amyloid treatments. The U.S. Food and Drug Administration (FDA) has stated that lecanemab is part of a ‘newer generation of anti-amyloid therapies targeting aggregated amyloid and has learned from previous failures.’ Extensive long-term clinical data out to four years and real-world experience with tens of thousands of patients globally show that patients who receive lecanemab continue to benefit from treatment. Lecanemab has been approved by more than 50 regulatory authorities around the world, including the FDA.”