The U.S. Food and Drug Administration (FDA) recently gave its first-ever full approval for a drug designed to slow the progression of Alzheimer’s disease.
The drug, lecanemab, branded as Leqembi, targets beta-amyloid, a protein that can misshape and accumulate in unhealthy levels in the brains of people with the disease. The buildup creates a sticky plaque that interferes with neurons, the brain cells that transmit information. Leqembi counters by binding to the plaque, helping to remove it.
Leqembi is not a cure for Alzheimer’s disease. Nor is it approved for all patients. More on that later. But in a phase 3 clinical trial of some 1,900 patients, the drug demonstrated success in slowing cognitive and functional decline, compared to a placebo. After dozens of failed clinical trials of other drugs, stretching back years, the approval of Leqembi was cause for hope for the nearly 7 million people with Alzheimer’s disease and their loved ones and caregivers, said Dr. Victoria Pelak, professor of Neurology and Ophthalmology at the University of Colorado School of Medicine.
“Any time you see a breakthrough like this, where you actually show and have evidence for slowing of clinical and functional decline, then oftentimes the floodgates open with new discoveries,” Pelak said.
The approval also helps to offset deep-seated pessimism that had reigned among neurologists over decades of dashed hopes for an effective treatment, said Dr. Samantha Holden, medical director of the University of Colorado Memory Disorders Clinic. Holden also practices at the UCHealth Neurology Clinic – Central Park.
“It’s a glimmer of hope I never thought we would have during my career,” said Holden, who is also an associate professor of neurology at the University of Colorado School of Medicine on the Anschutz Medical Campus.
Like Pelak, Holden also believes the Leqembi approval could “build momentum” and attract “intelligent, creative people” to the effort to penetrate the mysteries of Alzheimer’s disease and other forms of dementia.
Leqembi is far from a cure-all, stressed Dr. Peter Pressman, associate professor of Neurology at CU and a colleague of Holden’s in the Memory Disorders Clinic. It is but one path to treating a disease likely driven by many factors. But he added that its approval could at least help to break down a widespread belief among patients, caregivers and even some providers that there is nothing that can be done to arrest the progression of Alzheimer’s disease.
“One of my greatest hopes for Leqembi and medications of its kind go well beyond any purported benefit of the drug itself,” Pressman said. “It goes to refocusing the conversation about dementia away from just ignoring it. If Leqembi elevates opportunities to disseminate information and strengthen access to best treatment practices, that would be awesome.”
Much work to be done to get ready for Leqembi treatments, access to the drug
Despite the FDA approval, Leqembi treatments will not be available at UCHealth for at least several months. Work is underway to ensure resources are in place to administer the drug safely to patients who would benefit most from it and to address other recommendations and requirements stipulated by the FDA and the Centers for Medicare and Medicaid Services (CMS).
“We are completely revolutionizing the care for people living with Alzheimer’s disease, and it’s going to take time,” Holden said. “We appreciate people’s patience as we do this right. The safety of our patients is our first priority.”
To learn more about what the Leqembi approval means for patients and health care providers at UCHealth and the CU School of Medicine, UCHealth Today spoke with Pelak, Holden and Pressman. Each stressed that the approval generates equal measures of hope and sober realization of the demands that the approval has already generated.
Leqembi targets beta-amyloid. What is beta-amyloid and how does it relate to Alzheimer’s disease and its progression?
Beta-amyloid is a protein found in the brains of all people. These proteins can “misfold,” as Pressman put it, meaning they become misshapen. When that happens, they can build up and create the sticky plaque that clogs and slows the network of brain cells that enable thinking and memory. Think of it as a computer network disruption.
Pressman added that misfolding of another key protein, tau, causes tangles inside neurons that also deteriorate brain function. Tau was not the target of the Leqembi trial, but it is another subject of intense research into the sources of Alzheimer’s disease.
“We all have both beta-amyloid and tau,” Pressman said. “As long as they fold in their proper configuration, they are doing the right thing.”
How does Leqembi work?
Leqembi is a monoclonal antibody: a molecule designed to attack a specific target, in this case the beta-amyloid proteins that “accumulate inappropriately in the brain,” Pelak said. The antibodies bind to the rogue proteins, helping to clear the plaques from the brain.
Who will benefit most from Leqembi? Should I consider it for a loved one who already has severe cognitive decline due to Alzheimer’s?
The drug is for people with mild cognitive impairment and confirmation of unhealthy levels of beta-amyloids in the brain, as determined through a spinal tap to collect cerebrospinal fluid or by PET (positron emission tomography) scans.
Leqembi is not recommended for people with advanced cognitive decline. Pressman also pointed out that there are cases of people “whose brains were riddled with beta-amyloid at the time of death” but did not show symptoms of dementia. That increases the importance of not only confirming the presence of beta-amyloids, but also associated cognitive impairment.
“We don’t want to give the drug to people who may not need it,” Pressman said.
Does Leqembi cure Alzheimer’s disease?
No. Clinical trials showed Leqembi slowed, but did not stop, the progression of cognitive and functional decline in people with Alzheimer’s disease.
“Even if people receive Leqembi early in the course of their disease, their cognitive function is going to decline down the road,” Holden said. “That’s where a lot of us are cautious of too much focus on these interventions that are still only delaying the inevitable.”
All three clinicians emphasized that Leqembi and other drugs that target beta-amyloids are only one element of a broad and ongoing probe of the roots of Alzheimer’s disease. Pressman noted that the large pipeline of Alzheimer’s drugs in development cover targets like tau, neuro-inflammation, neuro-transmitters, metabolism and many more.
Holden called Leqembi “one piece of a multi-pronged approach to modifying Alzheimer’s disease,” and cautioned that “we can’t ignore the large population of people for whom this treatment is not going to be a possibility.”
How do patients receive treatment with Leqembi?
Patients receive the drug via a 30- to 60-minute infusion every other week, Holden said. That does not include time before and after the procedure, she added.
How much do the treatments cost?
The estimated annual cost of the drug alone is $26,500.
Does insurance cover the cost of Leqembi?
Medicare (CMS) will cover 80% of the cost of the drug, with Medicare patients responsible for the remaining 20% (a little more than $5,000). However, that coverage does not include associated expenses, Holden noted, such as staff to administer the infusion and MRIs three times a year to monitor for brain bleeds and swelling, which are potential side effects of the drug.
Pelak noted that Medicare coverage also requires hospitals administering Leqembi to enter data about their screening and treatment into a registry maintained by CMS.
Does Leqembi have side effects?
Yes. The most serious issues demonstrated in the trial were amyloid-related imaging abnormalities (ARIAs), including swelling in parts of the brain and brain bleeding. Pressman said that most ARIAs are temporary, but a small percentage of patients will have serious problems, including hemorrhaging and seizures.
Are there other factors that increase the risk of using Leqembi?
Yes. People with a gene called APOE4 are at a much greater risk of developing Alzheimer’s disease and other dementias and for brain swelling after receiving Leqembi. The risk is greatest for people who carry two copies of the gene.
Pelak said at this point, the FDA recommends genetic testing for APOE4 “to give a proper risk assessment for patients.” But that adds another thorny layer of ethical and financial complexity for patients considering Leqembi and for the providers managing their care, she noted.
“How can we force genetic testing on patients?” Pelak said. Genetic testing could affect an individual’s insurance coverage, while extensive counseling and testing would increase capacity and cost pressures, she added.
Acknowledging all of these details, Leqembi is approved. Why is it not available at UCHealth yet?
One major reason is the time and effort needed to get the infrastructure in place to accommodate patients qualified to receive the drug. Holden and Pelak noted that while UCHealth and CU did plenty of advance preparation, putting all the pieces in place couldn’t proceed prior to FDA approval.
The pieces include:
- Getting the drug on formulary
- Establishing billing codes for treatment
- Ensuring an adequate number of infusion chairs and the staff to administer the treatments
- Creating workflows in clinics that get patients to treatment efficiently
- Developing a protocol for determining those most likely to benefit from receiving the drug
- Crafting reliable safety monitoring protocols prior to, during, and after infusions.
“Because of the risk and complexity of the diagnosis and the discussions of the drug’s risks and benefits, we need strong protocols in place, not only for those who are eligible, but also to determine if someone is ineligible,” Pelak added.
“It’s a slow-moving process,” Holden conceded. “But we have to do it right while we make sure we keep our doors as open as possible to everybody.”
Two years ago, another drug, aducanumab (brand name Aduhelm), received FDA approval to treat Alzheimer’s disease. Aducanumab also targets beta-amyloid. Can I get that drug?
That is a qualified yes. Aducanumab, approved in 2021, raised serious concerns because of the high incidence of ARIAs associated with it, as well as questions about its effectiveness. In 2022, CMS announced that it would cover aducanumab treatment only for patients enrolled in clinical trials. Pelak is principal site investigator for the ENVISION trial, a nationwide study of aducanumab’s effectiveness in slowing the progression of Alzheimer’s disease compared to a placebo. She said she hopes to begin enrolling patients in the next few months.
Are there other amyloid-targeting therapies on the horizon?
Yes. Donanemab, another drug designed to clear beta-amyloid proteins, showed promise in slowing cognitive and function decline in people with early-stage Alzheimer’s disease in a nationwide phase 3 clinical trial. Holden noted that donanemab outperformed aducanumab in a head-to-head study published late in 2022, but it awaits FDA approval.
Why is early intervention so important for people who notice signs of cognitive decline?
As noted above, Leqembi and the other drugs that target beta-amyloids are intended for people in the early stages of the disease, not for those with more severe symptoms. That is one reason, Holden said, that it is important to “help get people into clinical care and away from avoidance” of warning signs like memory loss and confusion.
In addition, while Alzheimer’s disease is the most common culprit in dementia, there are other important causes, including Lewy body dementia and vascular disease, among others.
“Proper diagnosis is critical to discovery and treatment of dementia,” Pelak said. “We need to figure out why a person has dementia or determine if cognitive impairment is due to causes other than dementia, such as depression or small strokes.”
The sooner a person seeks help for signs of cognitive decline, the better their outlook will be, Holden stressed.
“People living with dementia under the care of a neurologist generally do better and for longer,” she said.
If I’m not eligible to receive Leqembi or one of these other treatments, do I have other options?
Yes. “There are ongoing studies that definitely show that diet and exercise can improve brain aging and decrease cognitive decline in its mild phase,” Pelak said.
“We can empower people and give them autonomy over their brains’ futures,” Holden said. “The strongest intervention is still lifestyle,” including physical exercise and a Mediterranean diet, she added.
What are the major challenges presented to the health care system with the advances in treatments for Alzheimer’s disease?
All three providers pointed to a workforce ill-equipped to fully address the needs of millions of people with Alzheimer’s disease and other forms of dementia. Pressman noted in an April NeurologyLive article that the main responsibility for diagnosing and managing dementia falls on primary care, which he called “the already strained backbone of the American medical system.” He advocates for developing automated systems and other measures to help providers with cognitive screenings, assessments, treatment options and further guidance.
“Everybody recognizes the primary care issue,” Pelak agreed. “Screening to help people recognize when a cognitive issue is due to Alzheimer’s disease is very important. We are working on ways to find and create resources to help PCPs and geriatricians not be overburdened with the act of figuring out whether or not someone with cognitive complaints has Alzheimer’s disease.”
The need to bolster help for primary care providers is especially acute because of a severe nationwide shortage of behavioral neurologists, who specialize in the diagnosis and treatment of dementia, Holden said. “There are not enough of us to go around,” especially if those who don’t qualify to receive Leqembi are to get the best care possible, she added.
“Million-dollar blockbuster drugs are usually for very rare conditions,” Holden concluded. “Now we are talking about 7 million people with Alzheimer’s disease. This is a turning point in many different ways, including for the health care system as a whole and how we deliver care equitably for a population that has basically been ignored.”