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The U.S. Food and Drug Administration approved aducanumab based on evidence that it reduced buildup of beta amyloid (shown in a positron emission tomography scan) in the brains of people with Alzheimer’s disease.

SEVIGNY ET AL., NATURE, 537, 50 (2016)

Alzheimer’s drug approved despite doubts about effectiveness

The antibody aducanumab today became the first new Alzheimer’s disease drug approved in the United States since 2003. In a controversial decision that shocked some experts, the U.S. Food and Drug Administration (FDA) overruled a group of advisers to conclude that the drug, developed by Biogen, deserved market approval. The decision came despite thin and conflicting evidence from two large clinical trials about the drug’s ability to slow patients’ cognitive decline.

In announcing the decision, FDA acknowledged those studies of patients with early stage disease “left residual uncertainties regarding clinical benefit.” But it opted to approve aducanumab, marketed as Aduhelm, based on strong evidence that it clears a toxic form of the protein beta amyloid, which accumulates in the brains of people with Alzheimers and is thought to drive neuronal damage. Reduction of these plaques is “reasonably likely to predict important benefits to patients,” the agency said.

But several amyloid-targeting drugs failed in recent years to show benefits in large clinical trials. FDA’s decision, welcomed by some researchers and patient advocacy groups, struck others as a dangerous weakening of standards.

“This approval is going to have monstrous ramifications for the FDA and for our health care system in general,” says Joseph Ross, an expert in FDA regulatory policy at the Yale School of Medicine. “Its like they pulled a thread, and the whole thing is going to unwind.” It’s unprecedented, he says, to switch at the last minute from a standard approval process to an “accelerated pathway” that doesn’t require clinical improvements but instead relies on a “surrogate endpoint,” beta amyloid. Health insurance providers and patients will now foot the cost of an unproven therapy, he adds.

FDA will require Biogen to complete a postapproval clinical trial to verify the drugs benefit. The company’s previous two large trials, including more than 3000 people in 20 countries, produced murky results. In 2019, Biogen and the Japanese pharmaceutical company Eisai, which co-developed aducanumab, announced they were halting both trials after an interim analysis of the data suggested the drug provided no benefit to patients. Later that year, they reversed course, providing a new analysis based on newly available patient data. In that analysis, one study revealed a 22% reduction in cognitive decline in the group getting the higher of two aducanumab doses, compared with the group getting a placebo; the second study still found no benefit.

The reversal left many researchers confused and skeptical. Some urged FDA to require another large trial before approval, arguing the company hadn’t shown that potential benefit outweighed the risk of side effects, including brain swelling. At a meeting convened by FDA of an independent advisory committee in November 2020, the experts voted overwhelmingly that data from the positive trial weren’t “primary evidence of effectiveness” of the drug. The possibility of accelerated approval based on amyloid reduction wasn’t discussed.

FDA rarely goes against its advisers’ recommendations. In an analysis of FDA rulings between 2008 and 2015, Ross and colleagues found 89% of drug approval decisions aligned with advisory committee recommendations. Of those that didn’t, 77% involved a more restrictive ruling than advisers had recommended—opting to reject a drug the committee voted to approve. In a letter to the FDA advisory committee justifying the switch to a different approval standard, Billy Dunn, director of the office of neuroscience at FDA’s Center for Drug Evaluation and Research, noted the “tremendous unmet medical need” for Alzheimer’s treatments.

Some researchers and advocacy groups have cheered the decision, while acknowledging that Aduhelm is far from a cure. “History has shown us that approvals of the first drug in a new category invigorates [sic] the field,” Maria Carrillo, chief science officer at the nonprofit Alzheimer's Association, said in a statement.

Fighting cognitive decline by busting amyloid plaques has long been a leading strategy in Alzheimer’s drug development. And the decision “provides, certainly, reason to continue with this line [of research],” says Richard Hodes, director of the U.S. National Institute on Aging. However, he notes strategies for treating Alzheimer’s are rapidly diversifying beyond amyloid.

Other amyloid-targeting drugs are in the pipeline. An antibody developed by Eli Lilly & Co., donanemab, showed signs of benefit in a phase 2 trial described in The New England Journal of Medicine in March. Lilly is now expanding an ongoing trial it hopes will confirm those results in 2023 and support FDA approval. A phase 3 study of lecanemab, an antiamyloid antibody jointly developed by Biogen and Eisai, launched last summer.