The Food and Drug Administration on Thursday has given full approval to the Alzheimer’s drug Leqembiand Medicare said it would cover much of its high cost, laying the groundwork for widespread use of a drug that can modestly slow cognitive decline in the early stages of the disease but also carries significant safety risks.
The FDA’s decision marks the first time in two decades that an Alzheimer’s drug has received full approval, meaning the agency has concluded there is solid evidence of potential benefit. But the agency also added a so-called black-box warning – the most urgent level – the label of the drugstating that in rare cases the drug can cause “serious and life-threatening events” and that there have been cases of brain bleeding, “some of which have been 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 the drug — administered every two weeks as an intravenous infusion — can slow decline by about five months over about 18 months for people with mild symptoms.
However, some Alzheimer’s experts said it is unclear from the medical evidence whether Leqembi’s ability to delay erosion of memory and cognition would be sufficient to be noticeable or significant to patients and their families. And while most cases of brain swelling and bleeding were mild or moderate and resolved, there were some serious cases.
“The risks are very vivid,” said Dr. Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, who said he would prescribe Leqembi after carefully evaluating patients and explaining the potential advantages and disadvantages. “In the first few months, you may have small bleeds or swellings in your brain, which may or may not be symptomatic and if not detected in time can cause disability.”
“In contrast,” Dr. Karlawish continued, “the benefits of slowing down are subtle. You will not experience the perception of changes in your cognition or function at the same time.”
Although Medicare will cover 80 percent of Leqembi’s $26,500 cost, patients could still shoulder thousands of dollars in co-pays.
Eisai, a Japanese pharmaceutical company, led the development and testing of Leqembi (pronounced le-KEM-bee). Eisai partners and shares profits with the American 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 the evidence of potential benefit was inconclusive, with one trial showing a modest slowing of decline but another showing no slowing. Before that approval, a panel of independent advisers and an FDA council of senior officials said there wasn’t enough evidence that it worked. Many medical centers refused to prescribe Aduhelm, and Medicare covered it only for clinical trial participants, sharply limiting its availability.
Evidence supporting Leqembi is much clearer, Alzheimer’s experts said.
Leqembi will be available for people with mild dementia or pre-Alzheimer’s disease 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 that Leqembi is targeting.
About 1.5 million people in the United States are estimated to be in the early stages of Alzheimer’s. Many more – around five million – have progressed too far to be eligible for Leqembi. Alex Scott, Eisai’s executive vice president of integrity, said the company recommends patients stop using Leqembi once they develop moderate Alzheimer’s disease.
Alzheimer’s experts said they will tell some patients they are at increased risk for brain swelling and bleeding — including those taking blood thinners, those with more than four microscopic bleeds in the brain and those with an Alzheimer’s-linked gene mutation called APOE4 .
The risk to people with two copies of the APOE4 mutation—about 15 percent of people with Alzheimer’s—is so high that the FDA’s black-box warning recommends that all patients be genetically tested to assess their safety risk and specifies that those with two APOE4. copies are more vulnerable to developing “symptomatic, serious and severe” brain bleeding or swelling.
The black-box warning will apply 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 says that “additional caution should be exercised” when considering whether to give blood thinners to Leqembi patients.
The FDA greenlit Aduhelm under a program called “accelerated approval,” which can be given to drugs with uncertain benefit under specific criteria, including that the company conducts another clinical trial. Leqembi received expedited approval in January, but that status meant Medicare would only cover the drug in limited circumstances.
The FDA decision granting full approval to Leqembi means that Medicare will cover it for eligible patients.
However, some patients won’t be able to afford the 20 percent Medicare doesn’t cover, potentially around $6,600 a year. Including costs of medical visits and required regular brain scans, some of which will be reimbursed by Medicare, the treatment could take approx. $90,000 a yearsome 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 climb to $5.1 billion dollars if the number of patients reaches about 216,000. That could lead to increased premiums for all Medicare beneficiaries, not just those receiving Leqembi, the study said.
In interviews, Ivan Cheung, the president and chief executive of Eisai’s US operations, estimated that in the first three years, about 100,000 patients would receive the drug.
The Medicare agency adds a requirement that doctors prescribing Leqembi send medical information about each patient before and while they are being treated with the drug. The information will be stored in patient records and evaluated to learn more about the benefits or harms of Leqembi, the agency said.
“With the FDA’s decision, CMS will cover this drug broadly while continuing to collect data that will help us understand how the drug works,” Centers for Medicare and Medicaid Services administrator Chiquita Brooks-LaSure said in a statement.
Some advocacy groups, such as the Alzheimer’s Association, have criticized the registration requirement, calling it an unnecessary barrier to access. But medical experts say registry programs are common and easy to enforce. Their concern is that the registry won’t compare Leqembi patients with others, so it won’t be able to tell whether Leqembi slows cognitive decline.
The FDA’s approval on Thursday was based on a large trial indicating that patients receiving Leqembi shrank 27 percent more slowly over 18 months than patients receiving a placebo. The difference between those who received the drug 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 that for a slowing of decline to be clinically significant, or visible to patients and families, the difference between the groups must be at least one point.
Leqembi patients also declined more slowly on three secondary measures of cognition and daily function, and data on biological markers were generally stronger for Leqembi than for the placebo. All these measures moving in the same direction reinforce the idea that the drug can benefit patients, experts say.
However, a report on the data, published in The New England Journal of Medicine and co-written by scientists from Eisai, concluded that “longer trials are warranted to determine the effectiveness and safety.”
Security concerns have been fueled by reports of deaths of three clinical trial participants who experienced brain swelling and brain bleeding, two of whom were treated with blood thinners. Eisai said it was unclear whether Leqembi contributed to their deaths because the patients had complex medical problems.
“You have small benefits and a certain risk for serious adverse events, and that has to be balanced,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California, who said he would prescribe Leqembi. . to carefully evaluated patients.
“If its effectiveness was greater, we wouldn’t be talking about adverse events 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 the effort, it’s not worth it the pity. 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 might only consider the drug’s risks worthwhile if they were much more impaired.
Dr. Karlawish said one recent patient refused to be evaluated for possible treatment, indicating that “‘I want more benefits, I don’t see the value.'” But, he said, “I still have other patients who would say. , You mean you can give me medicine that could slow down the disease?”
In the trial, nearly 13 percent of patients receiving Leqembi experienced brain swelling, which was mostly mild or moderate, while less than 2 percent of patients receiving the placebo experienced such swelling. Most brain swelling did not cause symptoms, generally appeared soon after use began and resolved within a few months. About 17 percent of Leqembi patients experienced a brain bleed, compared with 9 percent of patients receiving a placebo. The most common symptom of brain bleeds was dizziness.
Overall, the results suggest that the risk of brain bleeding and swelling was significantly lower than for patients in Aduhelm trials.
Dr. Jerry Avorn, a professor of medicine at Harvard Medical School who studies drug regulation and use, said doctors will feel pressure to prescribe Leqembi from patients, families and advocacy organizations. Medical institutions will also have a “huge financial incentive” because of the Medicare reimbursement, which “they could then spend on social workers and all the other things that Medicare won’t reimburse,” he said, adding “every economically self-respecting memory center is going to see that as economic benefit.”