The FDA Just Approved a “Milestone” Alzheimer’s Drug
On Thursday, the FDA approved the use of Leqembi (lecanemab) as a treatment for early Alzheimer’s disease. It is the first drug to show clear evidence for slowing down memory loss for people in the early stages of the condition.
“Leqembi is the first fully FDA approved drug that is disease modifying for Alzheimer’s disease; a milestone in this field,” says Thomas Wisniewski, the director of Alzheimer’s Disease Research Center at NYU Langone Health. “However, the drug is appropriate for a select set of patients with early disease and the clinical benefits are relatively modest.”
While Leqembi does not reverse or cure Alzheimer’s, the FDA’s recent approval makes it possible for people who are eligible for the drug to access it. Leqembi was first given accelerated approval in early January but since it did not undergo the complete approval process, Medicare refused to cover it. At a steep price tag of $26,500 a year, people had to pay out of pocket for this medication. The FDA’s latest decision paves the way to expand Medicare coverage for this drug in people 65 years and older — the age group most affected by Alzheimer’s.
Leqembi is a type of antibody that targets clumps of protein fragments in the brain called amyloid-beta plaques. For reasons scientists still do not fully understand, piles of protein begin sticking together between neurons and eventually these clumps become hard to avoid as their presence interferes with neurons sending important chemical messages to each other.
The plaques also disrupt the cellular functions needed to keep neurons alive. Deprived of nutrients to sustain itself and unable to call for help, the neuron dies. There is also research suggesting the toxicity of amyloid-beta plaques stimulates the release of an immune cell called microglia. Microglia acts as the janitor of the brain, sweeping up any cellular debris and dysfunctional cells. The messy situation of amyloid-beta plaques could create an uncontrolled immune response where microglia crowd around the plaques as a way to limit neurotoxicity while also releasing inflammatory responses that injure nearby cells.
Leqembi stops this neurodegenerative process from happening by reducing the number of amyloid-beta plaques in the brain. As an antibody, Leqembi hunts down the beta-amyloid protein. Once found, it tags the protein which tells the immune system that it needs to be removed from the body immediately. The decrease in amyloid plaques is expected to slow down disease progression and delay cognitive impairments, which could add up to extra time patients can spend with their loved ones.
The drug is a liquid administered as an intravenous infusion. The recommended dosage is 10 mg/kg delivered for one hour once every two weeks. The dosage can change depending on the amyloid-beta plaques in the brain.
Strong results from a phase 3 clinical trial testing the effectiveness of Leqembi convinced the FDA that the antibody is capable of preserving cognition in people with Alzheimer’s.
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The Study 301 (CLARITY AD) trial enrolled 1,795 people between 50 to 90 years of age with early Alzheimer’s (defined as mild cognitive impairment or mild dementia) with brain scans showing signs of amyloid-beta plaques in the brain. Each person was randomly selected to receive either 10 mg/kg of Leqembi once every two weeks or a placebo.
People taking Leqembi showed less signs of amyloid-beta plaques which corresponded with a significant decrease in cognitive impairment compared to the group who did not take the antibody. After 18 months, the researchers observed the Leqembi group slowed down their progression to Alzheimer’s by 27 percent.
“Today’s action is the first verification that a drug targeting the underlying disease process of Alzheimer’s disease has shown clinical benefit in this devastating disease,” Teresa Buracchio, the acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a FDA press release. “This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer’s disease.”
The drug news comes two years after the FDA gave approval to another Alzheimer’s drug called Aduhelm. The drug is supposed to slow cognitive decline by stimulating the immune system to clear out amyloid-beta plaques. However, the evidence surrounding its effectiveness has been called into question which prompted Medicare to refuse coverage of the controversial drug, leaving people with little means to afford the $28,000 price tag.
One reason for the hotly contested approval is that the data focused on the amount of amyloid plaques reduced rather than a clinical measure such as delaying cognitive decline, explains Kellyann Niotis, MD, a preventative neurologist and Flow Advisory Council member. The clinical trials on Leqembi showed both a reduction in brain amyloid levels and was associated with less cognitive and functional decline at 18 months.
The results do not mean that Leqembi is a miracle drug, though there is reason to be hopeful. “My personal take is that Alzheimer’s disease is so complex — it’s unlikely that any single agent will be the solution,” Niotis cautions. “To make a real impact, we are going to have to hit this disease at all angles with behavior changes, prevention efforts and by coupling multiple therapies with different targets such as amyloid tau, and neuroinflammation. This is a step in the right direction.”
In the trial, people taking the drug reported headaches and infusion-related reactions. The researchers also observed signs of brain swelling along with a tiny amount of brain bleeding — though this was more frequent among people carrying the ApoE4 gene or who are on blood thinners.
A risk of brain swelling and hemorrhages means people need to get regular checkups and brain scans, adding to the time patient and doctor need to invest on this treatment plan. It will also take time to train doctors on how to conduct screenings and safely administer the treatment.
Another issue is the slow rollout of this drug, which may not be available for months. Before the full approval, Medicare only covered the drug for people in clinical trials but will now have to test the eligibility of millions of people. Given the high cost and potentially life-threatening side effects, it is possible the drug will only be offered to a select few next year. Even so, Wisniewski warns that Medicare has only agreed to cover 80 percent of costs which may leave patients footing an expensive medical bill.
“While a new drug to combat Alzheimer’s is certainly a welcomed breakthrough, how it will translate into clinical practice remains a question. These drugs may be more or less effective, and more or less dangerous, depending on the individual patient,” Niotis says. “It will take years of real-world clinical experience to answer these questions.”
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