Three recently developed drugs—lecanemab (Leqembi), aducanumab (Aduhelm), and donanemab—each target a different form of amyloid plaque in the brain.
Lecanemab has been approved by the U.S. Food and Drug Administration (FDA) after a phase 3 trial found that the drug reduced markers of amyloid in early Alzheimer's disease at 18 months and slowed disease progression. The agency previously approved aducanumab under its Accelerated Approval pathway, which gives tentative clearance to drugs that have a therapeutic benefit for people with serious illnesses but whose clinical benefits may be uncertain. Results of the phase 3 trial of donanemab found that the drug significantly slowed progression at 76 weeks in people with early symptomatic Alzheimer's disease and amyloid and tau pathology.
Approval of these drugs has met with mixed response. Whether lecanemab “has a meaningful net benefit is not obvious given the data we have,” says James F. Burke, MD, professor of neurology at the Ohio State University Wexner Medical Center and author of an editorial in Neurology about lecanemab.
The debate is about the degree to which lecanemab slows decline and whether that decline is clinically meaningful, says David A. Wolk, MD, FAAN, director of the Alzheimer's Disease Research Center at the University of Pennsylvania. “Some argue that, despite a 25 to 35 percent slowing [of disease progression], the absolute amount is within a range that would be difficult to recognize.”
How They Work
The brain naturally makes amyloid protein, but in some people, the proteins start to clump together, forming plaques and putting them at risk of developing memory loss and Alzheimer's, says Erik S. Musiek, MD, PhD, endowed professor of neurology at the Knight Alzheimer Disease Research Center at the Washington University School of Medicine in St. Louis. “Lecanemab doesn't cure the disease, and it doesn't bring back memory. It slows the course,” Dr. Musiek says. “Assuming it takes an average of three to four years to progress from mild to moderate dementia, this drug could provide a year of extra time in the mild stage.”
How They Are Administered
The drugs are delivered intravenously. Lecanemab is given every two weeks, aducanumab and donanemab every four weeks. Infusions last about 45 to 60 minutes. Patients may find infusion centers in their communities; some must go to centers affiliated with large hospitals or universities, Dr. Musiek says. Additionally, they must undergo one MRI before treatment and then one before the fifth, seventh, and 14th infusions—and at one year. Over the next year, they must have more MRIs and checkups with a neurologist every six months, Dr. Musiek says. That “substantial inconvenience” is another reason Dr. Burke questions the idea of requiring people with cognitive problems to travel frequently for treatment, scans, and related appointments.
Who Is Eligible
Patients must have very mild symptoms consistent with Alzheimer's disease and meet certain criteria on cognitive tests, Dr. Musiek says. People who have other cognitive disorders, cancer, kidney issues, or other serious diseases may be ineligible. Patients who pass basic eligibility requirements must undergo biomarker testing through amyloid PET imaging or a spinal fluid test to determine if they have amyloid buildup in their brains. Medicare announced coverage for PET amyloid scans in October, but they are still expensive and infrequently used outside of academic medical centers. A new blood test is not yet widely available, Dr. Musiek adds.
How Much They Cost
The annual price of the drug is $28,200 for aducanumab and $26,500 for lecanemab, according to makers Biogen and Eisai, respectively. This does not include the cost of infusion, initial eligibility testing, or safety monitoring. While the Centers for Medicare and Medicaid Services (CMS) will not cover aducanumab except when taken during a clinical trial, it will cover FDA-approved drugs as long as patients have mild cognitive impairment from Alzheimer's or mild Alzheimer's dementia plus amyloid consistent with the disease. CMS will require patients using lecanemab to enroll in a registry so it can gather information about how the drug works. Medicare covers 80 percent of all costs related to these drugs, and supplemental plans may cover some of the rest. Medicare Advantage plans and many other insurance companies may offer coverage of lecanemab, but the details are still evolving, says Dr. Musiek. For Dr. Burke, the cost is an astronomical problem. “If the drug's entire target population were treated, the aggregate medication expenditures would be $120 billion per year,” he and his colleagues wrote.
Possible Side Effects
Brain swelling, small brain bleeds, headache, and falls are some of the reported side effects of aducanumab. In the donanemab clinical trial, side effects included infusion-related reactions, hypersensitivity, anaphylactic reactions, microhemorrhages, and amyloid-related imaging abnormalities (ARIA), which can result in temporary brain swelling and small bleeds in or on the brain. Three patients who took donanemab had serious ARIA and died. Lecanemab side effects include headache, infusion-related reactions, ARIA, and potentially fatal intracerebral hemorrhages. These risks are concerning, Dr. Wolk says, but “the vast majority of these cases are asymptomatic and reversible when symptomatic.” People with the APOE4 gene—a strong risk factor for Alzheimer's—are more likely to have ARIA accompanied by swelling, small or large brain hemorrhages, or long-term, chronic slow bleeding in the brain. People on blood thinners are eligible for these drugs, Dr. Musiek says, but they should know the risk.
How to Get Started
People can talk to their primary care physicians, who would do initial screenings and then refer them to neurologists, who would send eligible patients to a memory center where they would receive the drug, says Dr. Musiek.
