How the new Alzheimer’s drug works—and why the FDA is under fire for approving it

Since Monday, Matthew Schrag’s inbox has been flooded with emails from patients and their loved ones wondering whether to be hopeful about a new Alzheimer’s drug. Called aducanumab, the drug was granted accelerated approval earlier this week by the U.S. Food and Drug Administration. The last time the FDA approved a drug for this devastating disease was in 2003.

But Schrag, a neurologist at Vanderbilt University Medical Center in Nashville, is very unlikely to prescribe the latest therapy. “We don’t know whether it works,” he says, “and the side effects can be really substantial.”

In the U.S., Alzheimer’s disease affects more than six million adults age 65 years or older. It’s the most common cause of dementia and the sixth leading cause of death in this country. After diagnosis, senior patients live four to eight years, on average, and any treatment that can slow the disease’s progression and improve quality of life is desperately sought by their loved ones.

Developed by Massachusetts-based biotech company Biogen and marketed by the brand name Aduhelm, aducanumab eliminates the toxic form of a protein called beta amyloid. This protein accumulates in the brains of Alzheimer’s patients and can disrupt communication between brain cells. Some experts believe that removing amyloid plaque may address the disease’s underlying cause.

In clinical trial data evaluated by the FDA, aducanumab effectively reduced amyloid protein buildup in the brain, and it showed signs of marginal cognitive decline. That means unlike previously approved treatments, the drug could slow the disease’s progression rather than simply targeting symptoms. But the theory that amyloid is the key is vigorously debated, and the FDA’s decision based on the uncertain evidence quickly came under fire.

“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,” Patrizia Cavazzoni, director of the FDA Center for Drug Evaluation and Research, wrote in a press release about the decision. “As a result of FDA’s approval of Aduhelm, patients with Alzheimer’s disease have an important and critical new treatment to help combat this disease.”

But Schrag and many other scientists aren’t quite convinced of the drug’s potential to delay dementia. “The proof of efficacy just isn’t there,” Schrag says. “The clinical benefit was barely detectable.”

Biogen officials declined to comment for this article.

The accelerated approval runaround

In the 1980s, scientists examined the DNA of Alzheimer’s patients and discovered mutations in a gene that produces the beta amyloid protein. The protein is important for the development of nerve cells among other biological activities. Genetic mutations cause beta amyloid to form abnormal clumps called plaques that accumulate in the brain. As these plaques were already thought to be the trigger for Alzheimer’s, beta amyloid proteins quickly became the focus of research and drug development.

Although several pharmaceutical companies developed compounds that reduced the amyloid deposits, they all failed to arrest or reverse dementia. Then, in 2015, early evidence from clinical trials of aducanumab suggested that clearing the amyloid plaques seemed to be accompanied by a somewhat slower decline in cognitive function among some Alzheimer’s patients.

Based on this research, Biogen set up two larger identical clinical trials called Engage and Emerge. The 3,300 participants—patients with mild cognitive impairment or mild dementia due to Alzheimer’s—either received a placebo or a low or high dose of aducanumab’s monthly intravenous infusion.

Both studies were discontinued in March 2019 after an independent interim data analysis indicated aducanumab to be “futile.” Although the compound cleared amyloid deposits, it didn’t stop or slow cognitive decline and was deemed unlikely to benefit patients.

However, the company re-analyzed data in October 2019, including additional data from the time the interim data analysis began through the date when the trial was terminated. That analysis found patients in the Emerge trial who were on high doses of aducanumab showed a 22 percent slower cognitive decline over 18 months, compared to placebo patients. No such declines were recorded among Engage study patients. 

“There is no doubt that it’s a statistically provable effect,” Schrag says, “but the doubt is whether it matters clinically.” This means that the marginally less cognitive decline recorded in the trial may not necessarily improve patients' memory.

Critics of the drug also point to its side effects. About 35 percent of all patients on aducanumab experienced painful brain swelling and, in some cases, bleeding in the brain.

Nonetheless, Biogen, along with Japanese drugmaker Eisai, sought approval from the FDA on the basis of these statistically favorable outcomes. Last November, an independent panel advising the FDA rejected the drug, arguing that there was insufficient evidence to show that the compound benefited Alzheimer’s patients.

On June 7, defying its own advisory committee, the FDA granted the drug accelerated approval. According to the FDA, this type of approval is “intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit.”

Setting a bad precedent

Biogen and Eisai now have until 2029 to complete another clinical trial to confirm the drug’s benefits for Alzheimer’s patients. Many experts argue that a third clinical trial, identical to Engage and Emerge, would have been a better way forward to break the tie.

“In this case, because the previous trials disagreed, it would have been relatively easy had the drug not been approved to complete another trial in two years,” says David Rind, an internal medicine specialist and chief medical officer for the nonprofit Institute for Clinical and Economic Review, which independently reviewed the aducanumab clinical trial data. “Waiting nine years to find out if this works is not really to any benefit of patients.”

In 2016, the FDA authorized Exondys 51 for Duchenne muscular dystrophy, a rare and fatal genetic condition that affects children’s muscles. The decision was made despite weak efficacy data and its own advisory panel’s objections. The results of an ongoing study to confirm benefits from administering Exondys 51, which can cost a patient more than $700,000 each year, are still pending.

Aducanumab treatment is priced at nearly $56,000 each year. How much every Alzheimer’s patient will pay out of pocket will depend on their insurance coverage. Brain scans to monitor side effects and other associated costs will add financial burden on patients.

“That’s an enormous amount of money for a drug we’re not sure works at all for a disease affecting millions of people in the U.S.,” Rind says. Also, to his surprise, the FDA has made the drug available for all Alzheimer’s patients, although the clinical trials only involved those with mild cognitive symptoms.

“Patient advocacy groups likely had a big role in convincing the FDA that it’s still worth it,” reckons Walid Fouad Gellad, an internist in Pittsburg. “They’re willing to accept uncertainty.” The Alzheimer’s Association, for instance, was among those advocating for the FDA approval. 

Many physicians and scientists are now envisioning difficult conversations with families who may feel guilty if they don’t give this drug to their loved ones. But while some people are grateful for the drug’s approval, others find the move unsettling.

“I worry that there is a lot more nuance and detail here that an average person desperate for choices won’t look into,” says Ellie McBroom, the primary caregiver for her Kentucky-based, 62-year-old mother, who was diagnosed with Alzheimer’s disease in 2012. “We want to support scientific advances and processes, but rushing costly treatments that may not have any proven results at the expense of very vulnerable people is risky.”

Experts are also hoping that such approvals don’t stifle research on other drug targets for Alzheimer’s disease. 

Marc Diamond at the University of Texas Southwestern Medical Center studies a protein called tau that’s found in the brain and is linked to cognitive loss. Beta amyloid proteins may trigger the onset of Alzheimer’s, but he and many other neurologists believe that tau’s accumulation may cause the dementia, “which is why I think that studies targeting amyloid beta may have failed to show good benefit for people,” he says.

Diamond is developing therapies targeting tau. In the future, when it’s his drugs’ turn to be scrutinized, Diamond hopes the FDA will comply with their typically high approval standards.