The U.S. Food and Drug Administration (FDA) has approved Aduhelm (aducanumab) for the treatment of Alzheimer’s disease, despite controversy surrounding the scientific evidence for its effectiveness. According to a July 2021 update to its labeling, Aduhelm is intended for people with mild cognitive impairment or mild dementia stages of disease.
In a press release, the FDA called the approval of Aduhelm “significant in many ways.” It’s the first novel therapy for the disease since 2003, and the first treatment to target amyloid beta plaques in the brain, which are thought to play a role in causing Alzheimer’s — the sixth leading cause of death among Americans.
Reactions to the FDA's decision have been mixed. “This is a win-win for patients and science. It makes the drug available now to address the serious unmet need of providing a treatment for patients with Alzheimer’s,” says Howard Fillit, MD, the founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation in New York City. “That is so important, because this is a progressive disease, so every day without treatment is a lost opportunity,” Dr. Fillit says.
Others have expressed skepticism and even outrage toward the approval, including several members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee who resigned in protest of the FDA’s decision.
Aduhelm got its green light through the FDA’s accelerated approval pathway, which is reserved for drug treatments for illnesses that are serious or life-threatening. When a drug is approved in this type of circumstance, available evidence shows the drug can provide more meaningful benefits than existing treatments in some ways, but some uncertainty remains about the drug’s overall benefit, the FDA explained.
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To Approve or Not to Approve? A Timeline of Aduhelm
In the press release, the FDA acknowledged the controversy surrounding Aduhelm’s approval.
“We are well aware of the attention surrounding this approval. We understand that Aduhelm has garnered the attention of the press, the Alzheimer’s patient community, our elected officials, and other interested stakeholders,” wrote Patrizia Cavazzoni, MD, the director of the FDA Center for Drug Evaluation and Research.
“At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward,” Dr. Cavazzoni said, noting that the FDA had concluded the benefits of Aduhelm outweigh the risks among patients with Alzheimer’s disease.
Identical Studies, Different Results
The approval of Aduhelm was based on data from two identical phase 3 clinical trials called EMERGE and ENGAGE. According to the FDA, one study (EMERGE) showed that Aduhelm treatment appeared to be associated with a decrease in Alzheimer’s-related decline, while the other (ENGAGE) did not.
As a result, Aduhelm’s manufacturer, Biogen, and its partner, Eisai, announced in March 2019 that they were discontinuing the EMERGE and ENGAGE trials after an analysis conducted by an independent committee showed that Aduhelm would likely not meet its primary endpoint, or the main result measured at the end of a study to see if the treatment was effective for its intended purpose.
In October 2019, Biogen reversed course and announced it would still seek approval of Aduhelm based on new data that was previously unavailable, which the agency considered to be game-changing. In a press release, Biogen said it believed “data from a subset of ENGAGE support the findings from EMERGE,” even though ENGAGE did not meet its primary endpoint.
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Advisory Committee Says No; FDA Says Yes
Biogen’s new position on Aduhelm did little to convince the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee that Aduhelm should be approved. In a November 2020 vote, which was held to inform the FDA’s final decision on Aduhelm, the committee voted overwhelmingly against the drug.
Despite this, the FDA announced in June 2021 that it had decided to move forward with the approval because, even though it didn’t meet its primary endpoint in one of the studies, Aduhelm “consistently and very convincingly” decreased amyloid plaques in the brain, which are thought to play a role in causing Alzheimer’s, according to Cavazzoni.
“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” Cavazzoni wrote.
Ongoing and Future Studies Could Lead to the Drug’s Removal From the Market
In an ongoing clinical trial called EMBARK, researchers are studying the safety of Aduhelm in patients who previously participated in the EMERGE and ENGAGE trials before they were halted.
Additionally, manufacturers of drug treatments like Aduhelm that gain accelerated approval by the FDA are required to perform a post-approval study called a phase 4 confirmatory trial in order to fully prove the drug’s anticipated benefit.
If this study falls flat, Aduhelm’s approval could be revoked, Cavazzoni noted. “If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market,” Cavazzoni wrote.
Cautious Optimism for Aduhelm
Many, including the Alzheimer’s Association, are celebrating the FDA’s decision.
“This FDA drug approval ushers in a new era in Alzheimer’s treatment and research,” said Maria C. Carrillo, PhD, the chief science officer at the Alzheimer’s Association, in a press release. “History has shown us that approvals of the first drug in a new category invigorates the field, increases investments in new treatments, and encourages greater innovation. We are hopeful that this is the beginning — both for this drug and for better treatments for Alzheimer’s.”
The Alzheimer’s Foundation of America expressed cautious optimism for the approval of Aduhelm. “Today’s accelerated approval of aducanumab by the FDA, the first new Alzheimer’s drug on the market in nearly two decades, provides hope as another important step in the fight against Alzheimer’s disease. We are hopeful that it will improve the quality of life for individuals living with Alzheimer’s disease and their caregivers,” the foundation said in a statement, noting that the clinical benefit of Aduhelm still needs to be confirmed in a post-approval study.
Although the approval of Aduhelm is a step in the right direction, says Douglas Scharre, MD, a neurologist and the director of the division of cognitive neurology at the Ohio State University Wexner Medical Center in Columbus, it’s just a baby step when it comes to treating people with Alzheimer’s.
“The critical part with using this drug is going to be finding the appropriate patient. It’s not for everyone who has Alzheimer’s. It’s not an Alzheimer’s cure,” explains Dr. Scharre, who is one of the researchers who studied the effects of Aduhelm in clinical trials. Studies for other potential treatments that could be used in combination with Aduhelm are ongoing, he adds.
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With Aduhelm, Earlier Is Better
People best suited for treatment with Aduhelm are those who are in the very beginning stages of Alzheimer’s disease and are experiencing mild cognitive issues, says Scharre.
Why is Aduhelm most helpful early on in the course of the disease? According to Scharre, the drug removes amyloid from the brain, which he explains is one of the “initial boulders” that sets off the avalanche of Alzheimer’s.
But once that avalanche has caused decline in other areas of the brain, Aduhelm won’t be helpful, Scharre warns. “When you can remove the initial boulder of amyloid early on, you’ll have a fabulous result. But if you wait too long in the course, and the amyloid boulder has hit about 20 other boulders, all these other boulders are still destroying the brain. So, it’s not going to work as well in the later stages,” he says.
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