The First New Alzheimer’s Drug in 18 Years Is Now Even More Controversial
In June, the Food and Drug Administration (FDA) approved aducanumab, the first new treatment for Alzheimer’s disease in 18 years. But the medication, which is produced by Biogen under the name Aduhelm, has been surrounded by controversy. Now, there’s even more.
Safety data for the medication was just released in JAMA Neurology and it reveals that many people have experienced either brain swelling or bleeding while on the medication. In this particular data, 425 of 1,029 patients (41%) had the negative side effects. Of those, the majority—362—had swelling, but only 94 of them developed symptoms related to the swelling like headache, confusion, dizziness, and nausea.
The data shows that most people who had swelling experienced it early on, especially when patients were given a high dose of the medication.
MRIs found that people who had swelling or bleeding experienced a mild or moderate level of severity, although 12% of those impacted had severe swelling. While no one died during the trials that were featured in the study, a 75-year-old woman died in September while taking the medication.
The woman, who has not been publicly identified, was hospitalized after she took Aduhelm. She was diagnosed with swelling in her brain before she died. It is unclear at this point whether the woman died from the drug or other causes, but it’s under investigation. “We continue to work with the reporting physician as well as global regulators to further understand the case,” Biogen told Reuters.
Aduhelm was both celebrated and criticized after its approval earlier this summer. “This approval is a victory for people living with Alzheimer’s and their families,” said Harry Johns, president and CEO of the Alzheimer’s Association, in a statement.
The FDA’s independent advisory committee overwhelmingly voted in November against recommending that aducanumab be approved, citing a lack of data to prove that the drug actually slowed cognitive decline. Several members of the FDA’s advisory committee also wrote a viewpoint published in the journal JAMA detailing exactly why they voted against the approval of aducanumab.
Scientists at the nonprofit Institute for Clinical and Economic Review also issued a report in May that said there isn’t enough information to show that aducanumab’s benefits outweigh the potential risks.
Other organizations, including The American Geriatrics Society, also view the approval as “premature given the lack of sufficient evidence to support that aducanumab reduces progression of Alzheimer’s disease,” the nonprofit wrote in a public letter to the FDA.
The FDA’s approval of aducanumab is also unusual: The agency granted an accelerated approval pathway, which allows patients who are suffering from a serious disease earlier access to drugs when there is an expectation of a benefit, despite there being some uncertainty about the actual success of the drug. The FDA says that Biogen must verify that there is a clinical benefit in a post-approval trial, otherwise approval of the drug may be withdrawn.
Ahead, we asked experts to explain everything you should know about aducanumab so far.
How does aducanumab work, exactly?
Aducanumab is an amyloid beta-directed antibody, which means that it targets amyloid plaques that are found in the brains of people with Alzheimer’s disease. These plaques are made of toxic proteins and collect between neurons and disrupt cell function, according to the National Institute on Aging (NIA).
Aducanumab is administered as a monthly IV infusion. It’s the first approved dementia treatment that actually attacks the process of Alzheimer’s disease, rather than just its symptoms. “The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer’s—is expected to lead to a reduction in the clinical decline of this devastating form of dementia,” Patrizia Cavazzoni, M.D., director of the FDA Center for Drug Evaluation and Research, said in a press release.
But what does the data say about aducanumab?
Aducanumab went through two phase 3 clinical trials, which included 3,285 participants with early Alzheimer’s disease at 348 sites in 20 countries. One study showed that there was a reduction in mental decline in patients, but the second trial did not. “In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Cavazzoni said. “It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.”
But aducanumab’s path to approval hasn’t been seamless. Biogen announced in March 2019 that it was discontinuing its ENGAGE and EMERGE trials of the drug after an analysis found that the trials were unlikely to meet their goals and that the drug no longer had a chance of benefiting patients.
Three months later, researchers published additional data from 318 study participants who completed the trials, with promising results. Months later, Biogen announced that aducanumab was actually effective, citing results from the EMERGE study that found people who received a high dose of aducanumab (6 or 10 mg/kg) did better than those on a placebo in tests for cognitive function. However, there were no differences between patients who received aducanumab and a placebo in the ENGAGE study.
Now, there’s new safety data from the clinical trial that shows a solid portion of study participants—41%—develop brain bleeding or swelling while on aducanumab.
Why is aducanumab so controversial?
“With every first drug of any kind, it gets scrutinized more by doctors and scientists than similar drugs that follow,” says William T. Hu, M.D., Ph.D., an associate professor and chief of cognitive neurology at the Rutgers Robert Wood Johnson Medical School. But there are a few reasons why some scientists and doctors are wary of the medication:
Aducanumab has potential risks and side effects.
Biogen says online that aducanumab can cause “serious side effects,” including temporary swelling and bleeding in the brain. Most people don’t have symptoms, Biogen says, but some may have a headache, confusion, dizziness, vision changes, and nausea. That’s why the company recommends that patients undergo MRI scans before and during treatment.
Amit Sachdev, M.D., medical director for the Department of Neurology and Ophthalmology at Michigan State University who has managed brain swelling in dementia trials, says that the risks of brain swelling are “real” and have the potential to be deadly, so “close monitoring is very important.”
Biogen also notes that some people have had allergic reactions to the medication, like swelling of the face, lips, mouth, or tongue, along with hives. “It will be important to study if the benefits outside of a clinical trial setting outweigh these [possible] side effects,” Dr. Hu says.
Clifford Segil, D.O., a neurologist at Providence Saint John’s Health Center in Santa Monica, Calif., says that the latest safety data “confirms what many neurologists believe: That there’s more harm than benefit in taking this drug.” Having brain bleeding and swelling “is not minor,” he adds.
"These numbers certainly draw one's attention and it will be interesting to see as time continues what the numbers for the general public will be," says Mary McPhail-Ciufo, D.O., a Spectrum Health neurologist who specializes in Alzheimer’s and dementia care.
It’s unclear if aducanumab is actually effective.
Again, Biogen actually stopped two phase 3 clinical trials of the medication after an analysis showed that it was unlikely to be helpful for patients. Even after more data became available, only one trial showed that aducanumab performed better than a placebo. Ultimately, “there is conflicting data from the clinical trials as to whether or not it works,” Dr. Sachdev says.
Dr. Segil agrees. “I don’t think it works,” he says. “It’s heartbreaking that the FDA has approved a medication that has no efficacy. Many academic centers are choosing not to use this because of that and the side effects.”
It’s expensive.
Biogen announced in a press release to investors that the cost of the medication will be $56,000 a year. However, the company said, “the out-of-pocket cost for patients with insurance will vary depending on their coverage.” The regular MRIs during treatment would also be an additional cost.
The price is “simply way too high,” says Dr. Sachdev. “I would have liked to see the pricing for emerging dementia medications follow the pricing trend for the new migraine medications, which use very similar technology and cost much less,” he says. By comparison, injectable migraine medication D.H.E 45 is $11,767 for a carton of 10 ampules.
Some doctors still plan to talk to their patients about aducanumab as an option.
Whether the risks outweigh the potential benefits still isn’t clear, but some doctors say they’ll at least talk to their patients about aducanumab. “There’s no question that aducanumab clears amyloid,” says Scott Kaiser, M.D., board certified geriatrician and Director of Geriatric Cognitive Health for the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, Calif. “The only question is if it reliably reduces the progression of cognitive decline and, if it does so, to a significant degree.”
Because it’s “clearly effective” in reducing amyloid in the brain, Dr. Hu also “would recommend it to people with mild memory symptoms due to Alzheimer’s disease.”
Dr. Sachdev agrees. “I believe the drug removes amyloid [and] I will prescribe this drug to my own patients,” he says. However, he emphasizes that doctors need more guidance on which patients are best suited for the drug and which may be at a higher risk of side effects.
But Dr. McPhail-Ciufo urges careful consultations between patients and their care providers. "Patients and their loved ones should be concerned enough to make sure that they receive the medication from a provider who is trained in dispensing this drug and providing close follow-up care,” she says. "They should be screened thoroughly and if they are screened out of use for this drug then hopefully they are educated as to why they are not a candidate."
Dr. Segil says he’s not prescribing aducanumab to his patients. “I answer questions about this every single day,” he says. “I tell my patients that it’s heartbreaking this medication is out there. A professional advisory committee advised against this and it was still approved by the FDA. I don’t think it helps.”
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