Alzheimer's drug approved despite murky results

doi:10.1126/science.372.6547.1141

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DOI	10.1126/science.372.6547.1141
	Alzheimer's drug approved despite murky results
	Kelly Servick
	2021-06-11
发表期刊	Science
出版年	2021
英文摘要	The antibody aducanumab this week became the first new Alzheimer's disease drug approved in the United States since 2003, and the first ever that aims to interfere with the underlying disease process. In a controversial decision, the U.S. Food and Drug Administration (FDA) overruled its 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 a 7 June news release, Patrizia Cavazzoni, director of FDA's Center for Drug Evaluation and Research (CDER), acknowledged that those studies “left residual uncertainties regarding clinical benefit.” FDA will give Biogen 9 years for a required postapproval clinical trial to verify efficacy. It opted to approve aducanumab, an intravenously delivered antibody marketed as Aduhelm, based on evidence that it clears a toxic form of the protein beta amyloid, which accumulates in the brains of people with Alzheimer's and is widely thought to drive neuronal damage. Plaque reduction is “reasonably likely to predict important benefits to patients,” Cavazzoni wrote. Busting amyloid plaques has long been a leading strategy in Alzheimer's drug development. But several amyloid-targeting drugs failed in recent years to show cognitive benefits in large clinical trials. FDA's decision was welcomed by some researchers, physicians, and patient advocacy groups, but 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 Yale School of Medicine. “It's 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 relies on a “surrogate endpoint,” beta amyloid, instead of clinical improvement. Health insurance providers and patients will now foot the cost of an unproven therapy, he adds. Aduhelm has a list price of $56,000 per year, Biogen announced this week. The two large trials of the drug, which included more than 3000 people with early-stage Alzheimer's disease 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. Later that year, they reversed course, providing a new analysis in which patients getting the higher of two aducanumab doses in one study had a 22% reduction in cognitive decline, compared with people getting a placebo. The second study still found no benefit. The reversal left many researchers confused and skeptical ( Science , 13 December 2019, p. [1298][1]). Some argued the company hadn't shown that potential benefit outweighed the risk of side effects, including brain swelling. In November 2020, FDA convened a meeting of an independent advisory committee, which voted overwhelmingly that data from the positive trial weren't “primary evidence of effectiveness” of the drug. In a letter to the committee explaining the approval, Billy Dunn, director of CDER's office of neuroscience, noted “tremendous unmet medical need” for Alzheimer's treatments. But in the past, the agency has rarely gone against its advisers' recommendations. In an analysis of FDA rulings between 2008 and 2015, Ross and colleagues found that 89% of drug-approval decisions aligned with advisory committee recommendations. Of those that didn't, 77% rejected a drug the committee voted to approve. Aducanumab now faces “a very complicated rollout,” says neurologist Liana Apostolova of the Indiana University School of Medicine, who welcomes the approval but was surprised to find no detail in the drug's label about which Alzheimer's patients should get it. Insurance companies will have to set those parameters, she says. People with far more advanced disease than participated in Biogen's trials will want access, she adds, yet possible benefits and risks for these patients are unknown. (Apostolova has consulted for Biogen and Eli Lilly & Co., which is also developing an antiamyloid drug.) The approval also raises questions about people with amyloid plaques but no cognitive problems, says Emory University neurologist Allen Levey. Because “this label is very generic, it could mean they're even opening this up for [preventive] treatment for healthy people.” Some researchers and advocacy groups have cheered the decision, while acknowledging that Aduhelm is far from a cure. “History has shown us that … the first drug in a new category invigorates the field,” Maria Carrillo, chief science officer at the Alzheimer's Association, said in a statement. The decision will encourage more research on amyloid, says Richard Hodes, director of the U.S. National Institute on Aging. Other amyloid-targeting drugs are in the pipeline. Eli Lilly's antibody donanemab showed signs of benefit in a phase 2 trial described in The New England Journal of Medicine in March. Eli Lilly is expanding an ongoing trial the company 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. But Hodes notes strategies for treating Alzheimer's are rapidly diversifying beyond amyloid. Other approaches target inflammation, buildup of another protein called tau, and metabolic abnormalities. Supporters and detractors of the FDA decision alike hope more and better options are on the way. [1]: http://www.sciencemag.org/content/366/6471/1298
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推荐引用方式 GB/T 7714	Kelly Servick. Alzheimer's drug approved despite murky results[J]. Science,2021.
APA	Kelly Servick.(2021).Alzheimer's drug approved despite murky results.Science.
MLA	Kelly Servick."Alzheimer's drug approved despite murky results".Science (2021).