- FDA-approved drug for Alzheimer’s disease progression
- What is Leqembi? Breakthrough drug for Alzheimer’s
- Safety and efficacy of Alzheimer’s drug Leqembi
- Cost of Leqembi for Alzheimer’s treatment
- Potential side effects and controversies of Alzheimer’s drug
FDA requires drug labeling to include a “boxed warning”
U.S. approves first drug that clearly slows Alzheimer’s disease progression
The drug targets deposits of a protein called beta-amyloid and moderates the decline of cognitive functions by 27%.
The U.S. Food and Drug Administration (FDA) on Thursday approved for the first time a drug that modestly slows Alzheimer’s disease, a breakthrough that offers some hope in the treatment of the memory-destroying ailment but also raises difficult questions of safety, efficacy and cost.
The agency had previously granted the drug, called Leqembi, accelerated approval based on its ability to reduce clumps of amyloid in the brain, a hallmark of Alzheimer’s. Thursday’s decision was based on subsequent data showing that the treatment slowed cognitive and functional decline by 27% in 18 months compared with placebo. According to experts, this amounted to a five-month slowing of progression.
“Today’s decision is the first verification that a drug targeting the underlying Alzheimer’s disease process has shown clinical benefit in this devastating disease,” stated Teresa Buracchio, acting director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research. “This confirmatory study has verified that it is a safe and effective treatment for patients with Alzheimer’s disease.”
The drug, which is administered intravenously every two weeks, is for early-stage patients with mild cognitive impairment or incipient dementia caused by Alzheimer’s, and a confirmed accumulation of amyloid in their brains.
The FDA requires that the drug label include a “boxed warning.” This warning, sometimes referred to as a “black box” warning, indicates that Leqembi and other new-generation anti-amyloid drugs can cause brain swelling and bleeding. The side effect, called ARIA – amyloid-related imaging abnormalities – is usually asymptomatic. But on rare occasions, life-threatening incidents can occur, according to the warning.
The deaths of three patients in an expanded part of the main Leqembi trial are believed to be related to the drug. About 21% of trial participants who received the drug suffered swelling or bleeding in the brain, or both, compared with 9% of those who received the placebo.
The boxed warning also notes that patients with two copies of a genetic variant that increases the risk of developing Alzheimer’s-dubbed APOE4-appear to be at increased risk of complications and should undergo genetic testing before receiving the drug.
Elsewhere in the label, the FDA urges physicians to use caution when prescribing Leqembi to people taking blood thinners. Some clinics have stated that they do not plan to give the drug to people taking anticoagulants for fear of possible brain hemorrhages.
Leqembi, from the pharmaceutical companies Eisai, Tokyo, and Biogen, Cambridge, Massachusetts, is a monoclonal antibody, or lab-made protein, that targets beta-amyloid in the brain. It is not a cure, nor does it restore memories damaged by this deadly neurodegenerative disease. But many neurologists say that having a drug that slows Alzheimer’s, however modestly, is a milestone after years of failed trials.
Leqembi is from pharmaceutical companies Eisai, Tokyo, and Biogen, Cambridge, USA (Getty Images).
However, the drug’s side effects and its $26,500-a-year price tag have generated controversy over the drug, also called lecanemab. Some physicians are skeptical about it, doubting that amyloid is the primary cause of Alzheimer’s.
Jerry Avorn, a professor of medicine at Harvard Medical School, worries that patients mistakenly expect the drug to improve their memory and thinking ability. “That’s false,” he says. “It will just make Grandma forget a little bit less.” And he noted that patients receiving the drug will have to undergo multiple brain scans and make frequent trips to infusion centers, which could be burdensome.
Some skeptics have claimed that patients may not notice the drug’s effects. In an editorial last December, following publication of the pivotal trial results, the British medical journal Lancet said the drug’s effect may “not be clinically meaningful” and urged doctors to emphasize reducing dementia risk factors such as hypertension, smoking, diabetes and obesity.
But Ivan Cheung, president and CEO of Eisai (USA), said in an interview Thursday that the data clearly show the drug is “clinically meaningful” for patients and also brings “social value” to caregivers and family members.
Keith Vossel, director of the Alzheimer’s center at the University of California, Los Angeles, was enthusiastic about Leqembi and called it a “scientific breakthrough.”
But he added that dementia experts would have to carefully explain the drug’s benefits and risks. Typically, initial visits with patients last about an hour, but “just a conversation about Leqembi could last 30 minutes because it requires a long discussion about how the drug works and what that means,” he said.
Vossel explained that the clinic would have an “amyloid infusion core” made up of experts who would review patients who meet initial screening requirements to make sure the drug is appropriate. He said the group would function like a “tumor board” in cancer.
Two years ago, the FDA granted accelerated approval to another antibody drug called Aduhelm. Some of the trial data indicated that the drug slowed Alzheimer’s, but the information was so confusing and contradictory that the drug failed on the market and never received traditional approval.
More than 6.5 million Americans have Alzheimer’s, and this figure does not include people with mild cognitive impairment, who often go undiagnosed.
Pamela Spicer, director of therapeutics at Citeline, a company that tracks drug development globally, predicted that initial demand for Leqembi would be moderate. “Deployment is not going to be immediate,” she said. Even at academic medical centers, where the drug is likely to be offered, it may not be widely available for several months while doctors establish safety protocols and learn how to ensure Medicare coverage for patients.
Medicare, the federal health program for older Americans, did not cover Leqembi after receiving accelerated approval. Instead, it said it would cover the treatment once it received full FDA approval, as long as prescribers participated in registries that gathered evidence on how drugs in the class that includes Leqembi work in the real world.
The requirement has been sharply criticized by some advocacy groups, such as the Alzheimer’s Association, who claim that some physicians might not want to participate in a registry, which would slow patient access. In the past, such registries have been used mostly for complex medical devices, not drugs.
But some physicians say collecting data on how Leqembi affects patients could be helpful in answering questions and does not pose a significant burden.
In a statement Thursday, Chiquita Brooks-LaSure, administrator of the Centers for Medicare and Medicaid Services, which manages Medicare, said CMS was committed to helping Alzheimer’s patients “have timely access to innovative treatments that can lead to better care and improved outcomes.” He added, “With the FDA’s decision, CMS will broadly cover this medication while continuing to collect data that will help us understand how the drug works.”
Even with coverage, patients could face substantial drug bills; typically patients are responsible for 20% of the cost of infused medications.
The Department of Veterans Affairs already covers the drug, although not for people who have two copies of the APOE4 gene. Private insurers often follow Medicare’s lead.
John Driscoll, 80, of Manhattan Beach, California, has been receiving Leqembi for three years as part of the trial, called Clarity AD. Initially receiving infusions, he now injects himself in the thigh as part of a study to test self-administration, a formulation not yet approved by the FDA.
Driscoll, who is being treated at UCLA, believes the drug, along with the support of a large and loving family, is slowing her decline, although she doesn’t know to what extent. “My memory loss is not as overwhelming,” he says.
But he acknowledges that the drug won’t stop it from getting worse. “I choose not to pout or cry about it,” he says. “I just keep going.”
Laurie Scherrer of Albertville, Alabama, who was diagnosed with early-onset Alzheimer’s a decade ago at age 55, said she had a bad experience with Aricept, which treats symptoms such as confusion, and isn’t interested in Leqembi.
“I’ve found that having a purpose and a positive attitude and mindset, and exercising and breathing fresh air, has worked better than any drug,” says Scherrer, who is on the board of directors of an organization called the Dementia Action Alliance, which organizes support groups and activities for people with dementia. “A drug doesn’t get you out of the recliner.”
Another anti-amyloid drug, from Eli Lilly, is on the horizon. The company is scheduled to release results from the lead trial of the drug, called donanemab, this month, and it may win FDA approval by the end of the year or early next year.
The arrival of two anti-amyloid drugs could mean billions of dollars in additional spending for Medicare, analysts say, but the cost depends on how many patients receive them, which is unknown.
Eisai has projected that 100,000 people could receive Leqembi or a similar drug after three years. Some analysts believe that estimate is too low.
Amyloid is believed to be one of the factors-though not the only one-contributing to Alzheimer’s disease. Clinical trials are also testing drugs against inflammation and tau tangles, another characteristic feature of Alzheimer’s disease.
To qualify for Leqembi, patients must prove they have amyloid accumulated in the brain, which is determined by spinal taps or expensive positron emission tomography (PET) scans that Medicare generally does not cover.
Joanne Pike, president and CEO of the Alzheimer’s Association, which has been pushing Medicare to offer unrestricted coverage of Leqembi, said people should not underestimate the value of even a few months of slower deterioration.
“This gives people more months of recognition of their spouse, children and grandchildren,” Pike said in a statement. “This also means more time for a person to drive safely, deal accurately and promptly with family finances, and participate fully in hobbies and interests.”
Harvard’s Avorn sees it differently and plans a “demarketing” campaign to highlight the drawbacks of Leqembi. He hopes to dissuade primary care physicians from referring patients to places where they could get Leqembi.
“If it would make an improvement, I’d say, ‘Hooray, let’s do it,'” Avorn adds. “But once people see that it’s a modest slowing of deterioration, people will weigh it more carefully.”
Neurologist Jeffrey M. Burns, of the University of Kansas, acknowledged that physicians need more information about how the drug works. “It may be an incremental change or a big step forward,” he said. “But it’s a whole new era. Finding patients who can respond is a whole new way to go after the disease.”