Three advisers quit the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee within days of the agency approving Biogen’s Alzheimer’s drug Aduhelm (aducanumab) on June 7, 2021. One of them, Aaron Kesselheim, called it “the worst drug approval in U.S. history.”
The approval was the first for an Alzheimer’s drug in nearly two decades, and the first for a medication with a “disease-modifying” mechanism that goes after the plaques of beta-amyloid in the brain. It came under the FDA’s accelerated approval pathway, on the strength of a surrogate marker: the drug cleared amyloid plaques. Whether it actually slowed mental decline was the open question.
Trials that stopped and restarted
Biogen halted two Phase 3 trials, ENGAGE and EMERGE, in March 2019 after an independent futility analysis said the drug was unlikely to help patients. In October of that year the company reversed course. A larger dataset, it said, showed that higher doses reduced clinical decline. In EMERGE, the high dose slowed decline by 22 percent against placebo. ENGAGE, an identical trial, showed a reduction of only 2 percent, which was not statistically significant.
In November 2020 the FDA’s outside panel weighed the evidence. Ten of its eleven experts voted against approval, saying the pivotal study had not shown strong evidence the drug worked. Brain swelling or bleeding turned up in 41 percent of patients in the studies. The agency approved the drug anyway.
Price, access and investigations
Biogen priced Aduhelm at $56,000 a year. The Institute for Clinical and Economic Review said that was not in “reasonable alignment with its clinical benefits,” and that the drug would have to cost between $3,000 and $8,500 a year to meet common cost-effectiveness thresholds.
In April 2022 the Centers for Medicare and Medicaid Services limited coverage to people enrolled in randomized controlled trials. Europe went another way. The European Medicines Agency rejected the drug in December 2021, and Biogen withdrew its application there in April 2022.
Acting FDA commissioner Janet Woodcock asked the Department of Health and Human Services’ inspector general in July 2021 to review contacts between FDA officials and Biogen before the approval. In December 2022, two House committees reported that the FDA had broken its own protocols, held unreported meetings with the company and given the drug a broad label covering all Alzheimer’s patients, though it had been tested only in early disease. The same report said Biogen had projected peak revenue of $18 billion a year and knew its $56,000 price was “unjustifiably high.”
Supporters pointed to a disease with few treatment choices. Groups including the Alzheimer’s Association backed the approval, and the Association has denied that at least $1.4 million it received from Biogen and Eisai since 2018 influenced its position.
The end of Aduhelm
Biogen had to run a confirmatory trial to show that clearing plaques helps cognition. In January 2024 it ended that study, called ENVISION, and abandoned commercial development of Aduhelm for financial reasons. Existing patients were expected to keep access until November 2024.
Patients and families weighing any Alzheimer’s treatment should talk to their doctor about the benefits and the risks.
