The Food and Drug Administration on Thursday gave full approval to the Alzheimer’s drug Leqembi, and Medicare said it would cover much of the high cost, laying the groundwork for widespread use of a drug that can reverse cognitive decline in early childhood. stages of the disease can be slightly delayed. but also entails significant security risks.
The FDA’s decision marks the first time in two decades that an Alzheimer’s disease drug has received full approval, meaning the agency concluded there is solid evidence of a potential benefit. But the agency also added a so-called black-box warning — the most urgent level — to the drug’s label, stating that the drug can cause “serious and life-threatening events” in rare cases and that there have been cases of cerebral hemorrhage. . , “some of which were fatal.”
Leqembi cannot repair cognitive damage, reverse the course of the disease or prevent it from getting worse. But data from a large clinical trial suggests that the drug — given as an intravenous infusion every two weeks — may slow the decline by about five months for about 18 months for people with mild symptoms.
Still, some Alzheimer’s experts have said it’s unclear based on medical evidence whether Leqembi’s ability to slow erosion of memory and cognition would be enough to be noticeable or meaningful to patients and their families. And while most cases of brain swelling and bleeding have been mild or moderate and have resolved, there have been some serious cases.
“The risks are very vivid,” said Dr. Jason Karlawish, a co-director of the University of Pennsylvania Penn Memory Center, who said he will prescribe Leqembi after careful evaluation of patients and explanation of the potential benefits and harms. “Within the first few months, you may experience minor bleeding or swelling in your brain, which may or may not be symptomatic and, if not detected in time, can cause disability.”
“On the other hand,” continued Dr. Karlawish, “the benefits of slowing down are subtle. You will not experience the perception of changes in your cognition or function in the same amount of time.
Although Medicare will cover 80 percent of Leqembi’s $26,500 cost, patients can still pay thousands of dollars in co-payments.
Eisai, a Japanese pharmaceutical company, led the development and testing of Leqembi (pronounced le-KEM-bee). Eisai partners and splits profits with US company Biogen, the maker of the controversial Alzheimer’s drug Aduhelm, for its commercialization and marketing.
The FDA’s approval of Aduhelm was heavily criticized because evidence of potential benefit was inconclusive, with one trial showing modest slowing of the decline, but another showing no slowing. Before that approval, a committee of independent advisers and an FDA board of senior officials said there wasn’t enough evidence that it worked. Many medical centers refused to prescribe Aduhelm, and Medicare has only covered it for clinical trial participants, greatly limiting its availability.
Evidence in support of Leqembi is much clearer, Alzheimer’s experts said.
Leqembi will be available to people with mild dementia or a pre-Alzheimer’s condition called mild cognitive impairment. The FDA label instructs doctors not to treat patients without testing to confirm they have a buildup of the protein amyloid, a hallmark of Alzheimer’s disease that Leqembi attacks.
It is estimated that about 1.5 million people in the United States are in the early stages of Alzheimer’s disease. Many more – about five million – have progressed too far to qualify for Leqembi. Alex Scott, Eisai’s executive vice president of integrity, said the company recommends that patients stop taking Leqembi once they develop moderate Alzheimer’s disease.
Alzheimer’s experts said they would inform some patients that they are at greater risk for brain swelling and bleeding — including those on blood thinners, those with more than four microscopic bleeds in the brain and those with an Alzheimer’s disease-linked gene mutation called APOE4 .
The risk for people with two copies of the APOE4 mutation — about 15 percent of people with Alzheimer’s disease — is so high that the FDA’s black-box warning recommends that all patients be genetically tested to assess their safety risk and spells out that those with two copies of APOE4 mutations are more vulnerable to developing “symptomatic, severe, and severe” brain hemorrhages or swellings.
The black-box warning applies to all drugs that, like Leqembi, are monoclonal antibodies that attack amyloid. Leqembi is the first to receive full approval, but others are in various stages of development.
The warning does not mention patients taking blood thinners, but Leqembi’s label states that “extra caution should be exercised” when considering giving blood thinners to Leqembi patients.
The FDA has given Aduhelm the green light under a program called “accelerated approval,” which can be given to drugs of uncertain benefit under specific criteria, including that the company is still in a clinical trial. Leqembi received accelerated approval in January, but that status meant Medicare would only cover the drug in limited circumstances.
The FDA decision giving Leqembi full approval means Medicare will cover it for eligible patients.
Still, some patients won’t be able to afford the 20 percent that Medicare doesn’t cover, potentially about $6,600 a year. Including the cost of medical visits and required regular brain scans, some of which are reimbursed by Medicare, treatment could run to about $90,000 a year, some experts estimate.
A recent study estimated that covering the drug and necessary services for about 85,000 patients would cost Medicare $2 billion a year and rise to $5.1 billion if the number of patients reached about 216,000. That could lead to an increase in premiums for all Medicare beneficiaries, not just those receiving Leqembi, the study said.
In interviews, Ivan Cheung, the chairman and CEO of Eisai’s US operations, estimated that about 100,000 patients would receive the drug in the first three years.
The Medicare agency is adding a requirement that doctors who prescribe Leqembi submit medical information about each patient before and while they are treated with the drug. The information will be kept in patient registries and evaluated to learn more about the benefits or harms of Leqembi, the agency said.
“With the FDA decision, CMS will cover this drug broadly while continuing to collect data that will help us understand how the drug works,” said Centers for Medicare and Medicaid Services administrator Chiquita Brooks-LaSure, in a statement.
Some advocacy groups, such as the Alzheimer’s Association, have criticized the registration requirement, calling it an unnecessary barrier to entry. But medical experts say registration programs are common and easy to comply with. Their concern is that the registry won’t compare Leqembi patients to others, so it won’t be able to say whether Leqembi slows cognitive decline.
The FDA’s approval on Thursday was based on a large study that indicated that patients who received Leqembi declined 27 percent more slowly over 18 months than patients who received a placebo. The difference between those given drugs and placebo was small — less than half a point, on an 18-point cognitive scale that assesses functions such as memory and problem solving. Some Alzheimer’s experts say slowing the decline is clinically meaningful or noticeable to patients and families if the difference between the groups is at least one point.
Leqembi patients also deteriorated more slowly on three secondary measures of cognition and daily functioning, and the data on biological markers was generally stronger for Leqembi than placebo. All of these measures moving in the same direction reinforce the idea that the drug could benefit patients, experts say.
Still, a report on the data, published in The New England Journal of Medicine and co-authored by Eisai scientists, concluded that “longer trials are warranted to determine efficacy and safety.”
Safety concerns have been fueled by reports of deaths from three clinical trial participants who experienced brain swelling and cerebral hemorrhage, two of whom were treated with blood thinners. Eisai has said it is unclear whether Leqembi contributed to their deaths because the patients had complex medical problems.
“You have small benefits and some risk of serious side effects, and that has to be weighed,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California, who said he will prescribe Leqembi to carefully evaluated patients.
“If the efficacy was greater, we wouldn’t talk about side effects as much because we would see a clear benefit,” he said, adding, “I think a lot of people will see this and say it’s not worth it, it isn’t it worth twice a month infusions.”
Dr. Karlawish said the decisions facing patients and families will be complicated. Because eligible patients have only mild symptoms of cognitive decline, some might choose to take any drug that could prolong that relatively functional stage, while others would only find the drug’s risks worth it if they become much more disabled. goods.
Dr. Karlawish said a recent patient refused to be evaluated for possible treatment, indicating that “‘I want more benefits, I don’t see the value’.” But he said, “However, I have other patients who would say, You mean you can give me a drug that can slow down the disease?
In the study, nearly 13 percent of patients who received Leqembi experienced brain swelling, which was usually mild or moderate, while less than 2 percent of patients who received the placebo experienced such swelling. Most brain swellings caused no symptoms, generally developed shortly after the start of use and resolved within a few months. About 17 percent of Leqembi patients experienced cerebral hemorrhages, compared with 9 percent of patients who received a placebo. The most common symptom of cerebral hemorrhage was dizziness.
Overall, the results suggest that the risk of cerebral hemorrhage and swelling was significantly lower than in patients in studies of Aduhelm.
Dr. Jerry Avorn, a professor of medicine at Harvard Medical School who studies medication regulation and use, said doctors will feel pressure to prescribe Leqembi from patients, families and advocacy groups. Medical institutions will also have a “huge financial incentive” because of the Medicare reimbursement that “they could then spend on social workers and all the other stuff that Medicare doesn’t reimburse,” he said, adding “any economically self-respecting memory center is going to see this as an economic windfall.”