For anyone who has or knows someone who has Alzheimer’s disease — a progressive and irreversible form of dementia that’s ultimately deadly — it can sometimes be difficult to find hope. But a new drug to treat the disease has recently garnered a lot of attention and controversy.
Called aducanumab (Aduhelm), the drug is made by the pharmaceutical company Biogen and was developed in collaboration with two other companies, Eisai and Neurimmune. On June 7, 2021, the U.S. Food and Drug Administration granted accelerated approval for the infusion therapy’s use in patients with mild cognitive impairment. The FDA’s accelerated approval pathway is used for drugs that are intended to treat serious or life-threatening illness if the medication “provides a meaningful therapeutic advantage over existing treatments,” according to the FDA.
How It Works
Dr. Douglas Scharre, director of the division of cognitive neurology at the Ohio State University Wexner Medical Center in Columbus, explains that aducanumab is a monoclonal antibody therapy that’s delivered once a month via IV infusion and aims to slow cognitive decline in patients with mild cognitive impairment. Scharre helped test the drug.
“It’s the first approved disease-modifying treatment aimed at removing amyloid protein from the brain.” Amyloid protein builds up into tangles called plaques in the brains of people with Alzheimer’s disease.
Dr. Mariatu Koroma-Nelson, medical director of Goodwin House Incorporated, a not-for-profit senior living community based in Alexandria, Virginia, notes that this drug “acts like our natural immune system by recognizing amyloid beta” and helping clear it out.
Given that there hasn’t been a drug that could potentially stop the progression of the disease the way that aducanumab might means that there has been a lot of urgency surrounding bringing it to market.
A Controversial Approval
Controversy stems from the results of the drug’s clinical trials. “Of the two Phase III trials performed, one was positive (showed benefit) and the other did not,” Scharre says. This means that the controversy is “mostly about whether the drug works or not.”
Dr. Rawan Tarawneh, assistant professor of neurology also at Wexner Medical Center, explains that these two large Phase III studies involved 3,285 patients at 348 sites in 20 countries and looked at the efficacy of the medication. Study participants were followed closely for 18 months.
“In both studies, the drug was effective in removing amyloid aggregates from the brain,” as measured with imaging equipment. However, only one study showed that the drug “was effective in reducing cognitive decline.” The other study “did not show any clinical benefits,” she explains. “In other words, even though amyloid seemed to be effectively reduced, this only translated into clinical benefit in one study but not the other.”
Biogen notes that some patients with more rapidly progressing disease were included in the study, and that may have made the drug appear less effective. Biogen also argues “that the negative results of one study does not detract from the persuasiveness of the positive study,” Tarawneh says.
But the FDA Peripheral and Central Nervous System Drugs Advisory Committee, a nine-voting-member committee of individuals knowledgeable in neurology, neuropharmacology and related specialties that reviews and evaluates data about safety and effectiveness of drugs used to treat neurological diseases, wasn’t convinced. The committee makes recommendations to the commissioner of food and drugs at the FDA and noted that the overall data presented wasn’t strong enough to support FDA approval of the medication. Their overall vote was negative. As Koroma-Nelson summarizes, “The clinical impact is uncertain at this time.”
Nevertheless, the FDA can choose to approve a medication even if an advisory committee doesn’t vote in favor of approving it, and that’s what happened with aducanumab. “The FDA decided to approve its use based on their reading of all the research findings,” Scharre says. “Some individuals feel that there should be more data showing benefit before it is approved.”
The decision has been so contentious that three members of the advisory panel that voted against approving the medication have resigned from their roles.
Other issues that have been cited by some experts include the possibly prohibitive price tag — this therapy costs $56,000 per year — and potential side effects.
Serious Side Effects
Koroma-Nelson says it’s been associated with the following serious side effects:
— Cerebral edema (swelling of the brain), which has been observed in some 40% of patients who have used the drug.
— Brain bleed.
These side effects have led Koroma-Nelson to caution patients who’ve asked about being treated with this medication.
It may also be difficult or expensive for some patients to comply with the treatment given that it’s administered by infusion and requires repeated MRI imaging, Koroma-Nelson notes. “More clinical research is needed to explore the clinical benefits for patients in all stages of AD,” she adds.
In response to the flap, on July 9, the FDA’s acting commissioner Dr. Janet Woodcock called for an independent federal investigation into the process that led to the approval of aducanumab.
For the time being, aducanumab is still approved for use in patients with early-stage Alzheimer’s disease. Biogen says that more than 900 infusion sites across the U.S. are ready to administer the drug.
A Growing Problem
The long-awaited promise of aducanumab and other potential new drugs to treat Alzheimer’s offers families dealing with the effects of the disease some much-wanted hope. But controversy surrounding the new drug has dampened expectations for millions of Americans who either have or are at risk of developing Alzheimer’s disease because there hasn’t been a treatment that could reverse the progressive nature of the disease.
“Alzheimer’s disease is the most common cause of dementia,” Tarawneh says. A progressive, neurodegenerative brain disease, Alzheimer’s “affects memory and cognitive functions including problem-solving, orientation, language and visual spatial skills,” which eventually lead to functional problems that interfere with the person’s ability to perform daily activities such as driving and managing finances, she explains.
In severe cases, “basic activities such as dressing, walking and eating also become difficult.”
In addition to cognitive problems, Alzheimer’s disease can also bring on a range of behavioral and emotional changes, including:
— Changes in sleep or appetite patterns.
“AD is the sixth leading cause of death among U.S. elderly, accounting for more deaths than breast and prostate cancer combined,” says Tarawneh. Here in the U.S., a new AD diagnosis is made every 65 seconds, and an estimated 6.2 million Americans are currently living with Alzheimer’s.
The problem is only growing, Tarawneh adds. “The number of affected individuals is expected to triple in the next 30 years. It’s estimated that by 2050 there will be over 30 million people in the U.S. and over 100 million people in the world with AD,” making Alzheimer’s a “global epidemic.”
This coming surge of cases is especially concerning because there’s no cure for Alzheimer’s, “and we have not been able to identify methods or treatments that can effectively prevent, slow down or reverse” the changes that occur in the brain that cause the symptoms of AD, Tarawneh says.
Current Treatments for Alzheimer’s
Currently, the treatments that are available focus on addressing symptoms. These medications fall into two major categories, Tarawneh explains:
— Cholinesterase inhibitors, which are used in all stages of AD. These include Aricept (donepezil), Exelon (rivastigmine) and Razadyne (galantamine). These medications are prescribed to treat symptoms related to memory, thinking, language, judgment and other cognitive processes. “These medications are recommended for mild to moderate stages of Alzheimer’s disease for symptomatic treatment of cognition and global functioning. Donepezil also showed cognitive benefits in moderate to severe AD,” Koroma-Nelson says.
— NMDA antagonists. One medication in this class of drugs — memantine (Namenda XR) — is currently used to treat Alzheimer’s. It’s used in moderate to severe stages of AD to improve memory, attention, reason, language and the ability to perform simple tasks. It can be used alone or with other treatments. Memantine “showed modest benefits in patients with moderate to severe AD,” Koroma-Nelson says. It works by “blocking the N-methyl-D-aspartate (NMDA) receptor to protect the brain from further damage and restore brain proteins.”
These treatments can “help stabilize the clinical symptoms by slowing down the clinical progression and allowing individuals to maintain their current level of functioning for several years,” Tarawneh says. This is great, but the problem is, even with that slowing of the progression, the disease will continue to get worse and patients will decline.
In addition to those treatments, “there are non-pharmacological and pharmacological treatment options” that can help “manage symptoms, improve quality of life and maximize functional status,” Koroma-Nelson says.
Among the medications that may be used in Alzheimer’s patients are:
— Anxiolytics, also known as antianxiety medications.
— Sleep aids.
— Appetite stimulants.
— Vitamin E supplements.
Koroma-Nelson adds that non-pharmacological interventions that have been shown helpful include:
— Leisure activities.
— Training in coping strategies.
— Structured exercise programs.
The Future of Alzheimer’s Treatment
Aducanumab has nabbed lots of headlines lately, but it’s not the only drug that could change the treatment of AD in the future. In addition to symptom-modifying drugs that slow the progression of the disease, several companies are also working hard to create even better treatments that go to the root of the problem and reverse the disease process itself.
One medication called ALZ-801 is being developed by biotech firm Alzheon. That medication targets a specific gene that can inhibit amyloid plaque formation.
Another called donanemab, or N3pG, made by pharmaceutical company Eli Lilly, targets both amyloid beta and another protein, called tau, that’s also involved in the development of Alzheimer’s. That medication recently earned a “breakthrough therapy designation” from the FDA for the treatment of Alzheimer’s. That designation means the FDA will expedite the antibody therapy’s development and review.
These and other developmental disease-modifying medications “target disease pathology,” Tarawneh says, and are an exciting frontier in the treatment of Alzheimer’s. “As of early 2020, there were over 120 investigational AD treatments in different stages of clinical trials,” she notes.
In the past, many of the disease-modifying medications targeted amyloid proteins that accumulate in the brain and cause a disruption of cognitive function and death of brain cells. This type of medication has been somewhat disappointing, though, so some researchers have turned their attention to tau.
Tau appears to be “more closely related to cognitive function and brain atrophy,” Tarawneh says, so targeting that protein offers a potentially very promising alternative treatment pathway to amyloid-targeting treatments.
In addition to targeting tau, researchers are looking to medications that address other changes that occur in the Alzheimer’s brain in an attempt to alter the course of the disease. Treatments that slow or reverse inflammation, immune dysfunction and damage to the blood vessels in the brain are also being investigated. These have all been implicated in some way in the inexorable advance of Alzheimer’s disease.
Tarawneh notes that in trying to find the answer to what will work best, there’s been an effort to get patients enrolled in clinical trials before they start showing symptoms of AD “to increase the chances of success in improving clinical outcomes. This is because by the time patients with AD have even mild memory loss, they have already sustained significant neuronal loss, and it may already be too late to intervene, as these changes are irreversible once they happen.”
The idea is to get a head start on the disease before patients become symptomatic.
If you do start to notice symptoms, Scharre urges you to speak with your doctor as soon as you can. “If you notice a change in your memory or thinking, get in to see your provider as these treatments work the best if started very early in the course of the disease.”
And you should keep up with lifestyle interventions that are known to benefit the brain and body. Namely:
— Exercising regularly.
— Engaging in brain stimulating activities including social activities.
— Reducing stress.
“Lifestyle modifications, especially among individuals with cardiovascular disease or risks, has been shown to slow cognitive decline,” Koroma-Nelson says.
Personalized Treatment as a “Cure”
As science continues to unravel the mysteries of how AD develops and progresses, researchers are working to create better treatments for it, Tarawneh says. She believes “the future of AD therapeutics lies in personalized medicine approaches, in which the choice of drugs to use will be individualized based on biomarker and imaging data, disease stage and other individual factors.”
In other words, at some point in the future, a blood test or another kind of biological analysis may reveal specific details about an individual’s disease pattern which could allow doctors to prescribe super-targeted treatments that look different for that person than for someone else with Alzheimer’s.
Much like how cancer treatment is becoming increasingly personalized and tailored to the biology of the individual’s specific disease state, so too will AD treatment become highly specific to each individual patient.
While there’s reason to hope, there’s a lot more work to be done before Alzheimer’s disease can be cured — though Scharre says he believes that a cure is possible. “I believe we’re on our way to at least stave off or postpone the dementia symptoms of this disorder. It’ll likely take the combination of several medications that target different aspects of the disease, such as amyloid protein, tau protein, chronic inflammation and blood-brain barrier issues among others,” but there’s plenty of reason to hope.
In the meantime, the Alzheimer’s Association notes that “ultimately, the path to effective therapies is through clinical studies.” You can access information about current trials and enroll yourself or a loved one via their TrialMatch site.
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Update 07/20/21: This story was previously published at an earlier date and has been updated with new information.