Well+Being
Alzheimer's drug that slows cognitive decline gets FDA approval
By Laurie McGinley The Washington Post
Published Jan. 30, 2023
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The FDA said the drug, called lecanemab, is for patients with mild cognitive impairment or mild dementia because of Alzheimer's. The approval was based on a mid-stage trial that showed the treatment's effectively removed a sticky protein, called amyloid beta - considered a hallmark of the illness - from the brain.
A recent trial, which was larger, found the drug slowed the progression of Alzheimer's by 27 percent. The drug will be sold under the brand name Leqembi.
"This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer's, instead of only treating the symptoms of the disease," Billy Dunn, director of the FDA's Office of Neuroscience, said in a statement. He said the agency anticipates receiving the data from the later trial soon.
The decision comes after the FDA endured a barrage of criticism regarding its 2021 accelerated approval of another Alzheimer's drug, called Aduhelm, that had been panned by the agency's outside experts. Lecanemab is getting a warmer reception but disagreements about the drug remain among Alzheimer's experts remain.
Many neurologists and advocates hailed lecanemab, which is given intravenously twice a month, as an important advance - one that follows years of failure involving other Alzheimer's drugs. They said the treatment will allow patients to stay longer in the milder stages of the fatal, neurodegenerative disorder, which afflicts more than 6 million people in the United States.
"This is what the field has been pursuing for decades, a drug that can slow the course of this disease," said Joshua D. Grill, an Alzheimer's researcher at the University of California at Irvine. "It's an important starting point."
But other experts are skeptical, saying the drug's benefits are modest at best, and not enough to outweigh concerns about swelling and bleeding in the brain. Those complications, which can range from minor to extremely serious, are well-known side effects of anti-amyloid treatments. Media reports about the deaths of three patients, potentially linked to the drug, have heightened concerns.
"I would tell a patient, 'In my opinion, the risks exceed the benefits, and it is not clear that it will markedly change your course,' " said Kenneth Covinsky, a geriatrician at the University of California at San Francisco.
Some doctors said the FDA should not have approved the drug on an expedited basis.
"If I were at FDA I would ask for longer studies" to delve deeper into safety concerns and effectiveness, said Matthew Schrag, a neurologist at Vanderbilt University Medical Center.
The FDA decision was affected by unusual timing. The accelerated approval was based on a biomarker - amyloid removal - that is thought to help patients. Typically, the agency requires an additional trial to confirm an accelerated-approval drug provides a clinical benefit to patients. In lecanemab's case, the confirmatory trial was wrapped up in November, after the manufacturers finished applying to the FDA for speedy approval. The study, called Clarity, was the first completed late-stage study to show a slowdown in the progression of Alzheimer's.
The debate over lecanemab underscores the complicated risk-benefit calculation for patients, said Holly Fernandez Lynch, a medical ethics expert at the University of Pennsylvania.
"I think it would be reasonable for one patient to say, 'This is a risk I am willing to take,' and another to say, 'I'm not willing to take this risk because I don't think the benefit will be big enough,' " she said.
Tony Gonzales, 48, a former radio personality who lives in Santa Maria, Calif., is eager to try the drug.
"I am hoping that I will be one of the first to get lecanemab," said Gonzales, who was diagnosed with mild cognitive impairment three years ago after getting lost on his way to work. "Every day, I lose a little bit."
Following the FDA approval, doctors can prescribe the drug, but patients will probably have to wait for widespread access because of insurance issues. Medicare, as part of its review of Aduhelm, the controversial drug approved in 2021, decided that it would cover any anti-amyloid drug approved on an accelerated basis only in clinical trials.
In a statement, Chiquita Brooks-LaSure, administrator of Centers fo rMedicare and Medicaid Services, said CMS "will continue to expeditiously review the data on these products as they become available and are committed to timely access to treatments, including drugs, that improve clinically meaningful outcomes."
Eisai, a Tokyo pharmaceutical firm that developed lecanemab with Biogen, a biotech company in Cambridge, Mass., said it plans to apply to the FDA for full approval shortly, using the Clarity trial data. That process, which could take several months, could pave the way for broader Medicare coverage, though patient outcomes might have to be tracked through registries.
In the Clarity study, which involved 1,800 patients, patients declined whether they got the drug or a placebo. But the lecanemab group deteriorated more slowly. At 18 months, those patients scored a half-point better than the placebo group on an 18-point dementia test involving memory, judgment and other areas, according to the New England Journal of Medicine.
Some doctors say those effects are not large enough to be meaningful to patients and their families, and may not even be noticed. But others argue that the treatment could allow some patients with the fatal disease to enjoy the birth of a grandchild or live at home longer.
"The effect sizes are modest, but they are there and they are consistent," said Jason Karlawish, professor of medicine at the University of Pennsylvania and co-director of the Penn Memory Center. He said doctors prescribing lecanemab would need to be extremely careful in selecting and monitoring patients for possible side effects.
The most worrisome complications - swelling and bleeding in the brain - occurred in about 20 percent of patients in the lecanemab group and 9 percent in the placebo group in the 18-month Clarity trial. The condition, which shows up on brain scans, is called ARIA, for amyloid-related imaging abnormalities. Most patients did not have symptoms and the drug was not linked to any deaths, Eisai said.
But in an extended portion of the trial - in which all participants were permitted to take the drug - three patients on lecanemab died in incidents potentially linked to the medication, according to reports in Science and Stat, a medical news website. One patient was also being treated with a blood thinner for atrial fibrillation, according to the reports. Another was a 65-year-old woman who arrived at a Chicago-area emergency room showing signs of a stroke. She was given tPA, an anti-clotting medication, and subsequently had massive brain bleeding and died.
Doctors at the Northwestern University Feinberg School of Medicine in Chicago described that woman's case in a letter to the editor published Wednesday in the New England Journal of Medicine. They said an autopsy showed the woman had a condition called cerebral amyloid angiopathy - extensive amyloid in the brain's blood vessels - and suggested lecanemab may have contributed to her death.
Some experts believe lecanemab's stripping away of amyloid, combined with tPA, might have weakened the patient's blood vessels.
In a response in the same publication, investigators who led the Clarity trial argued there have been cases in which other people with the condition have had brain hemorrhages when given tPA, even though they hadn't received anti-amyloid drugs. They said they understand why the case generated concern but that tPA "appears to be the proximate cause of the death."
Some doctors say they have already decided they would not give lecanemab to patients on blood thinners.
Ivan Cheung, chairman and CEO of Eisai in the United States, said in an interview before the FDA approval that the company remains "confident of the safety profile" of the drug - and that the benefits outweigh the risks.
Lecanemab is a monoclonal antibody, a man-made protein that binds to amyloid beta, marking it for destruction by the immune system. Eisai and Biogen previously developed Aduhelm, the drug that received accelerated approval in 2021 despite conflicting data from trials that were halted before completion. Doctors largely rejected the medication, which failed to get broad Medicare coverage and fizzled in the marketplace.
The action on lecanemab comes shortly after two House committees issued a scathing report criticizing the FDA and Biogen for a review process they described as "rife with irregularities." The FDA and Biogen denied inappropriate behavior, and the agency said it has made changes consistent with the report's recommendations.
Even amid lingering questions, lecanemab has been welcomed more warmly than Aduhelm, largely because it achieved statistical success in a well-run trial. In addition, unlike with Aduhelm, Eisai - not Biogen - has taken the lead on lecanemab and appears determined to avoid some of the mistakes that dogged Aduhelm. The label, for example, said the drug is just for early-stage patients, rather than anyone with Alzheimer's, which was the initial Aduhelm indication.
A looming issue is price. In 2021, Biogen and Eisai set the initial price of Aduhelm at $56,000 annually, which fueled the backlash against the drug. Within months, the companies had slashed the price in half.
On lecanemab, the Institute for Clinical and Economic Review, a nonprofit that analyzes the value of drugs, said in a recent report that the drug should be priced between $8,500 and $20,600 a year to be cost effective. The research group said the data on the drug appears to be "promising but inconclusive."
The real cost to consumers ultimately depends on whether Medicare and private insurance companies decide to cover lecanemab.
In December, the Alzheimer's Association submitted a formal request to CMS to reverse its policy restricting coverage for anti-amyloid treatments. It said the Clarity data showed that those therapies can be effective and should be made immediately available to patients with what is essentially a terminal disease.
"We would hope that is quick and timely because time matters for a treatment that targets the early stage," Joanne Pike, president of the organization, said.
In a statement, CMS said it will review the association's request, adding that it "is very concerned about the growing and devastating impacts of Alzheimer's disease and is committed to making effective treatments available to people with Medicare."
David S. Knopman, a neurologist at Mayo Clinic in Rochester, Minn., said the ultimate value of lecanemab will be determined by a question the 18-month clinical trial could not answer: What happens to patients after 18 months? Does the therapeutic benefit grow, disappear or stay the same?
If it increases, "that would be a real win," Knopman said. If it fades, so will enthusiasm for the drug, he said. Subsequent trials and clinical use should provide the answer.
If demand for lecanemab takes off, the logistics could be challenging - and especially difficult for individuals who do not have access to sophisticated health care facilities. Experts warn that the United States has an inadequate system for diagnosing and treating Alzheimer's.
To be eligible for the drug, patients must have a buildup of amyloid in their brains, something typically found by spinal taps or specialized PET scans. But not all doctors perform spinal taps and the scans are not routinely covered by Medicare, though CMS is reviewing its policy. Simple blood tests to detect amyloid are available but not yet in widespread use.
In addition, there is a nationwide shortage of neurologists and geriatricians, as well as specialized equipment and facilities - a squeeze that is likely to get worse. By 2050, almost 13 million people in the United States are expected to have Alzheimer's, unless medical treatments make a big impact, according to the Alzheimer's Association.
At the same time, the long-running debate over the role of amyloid beta and whether slashing it can slow or stop Alzheimer's is unlikely to end. Late-stage data for Eli Lilly's anti-amyloid drug, called donanemab, could provide additional information in coming months. The company has already applied to the FDA for accelerated approval.
"Lecanemab is not the hoped for 'game changer,' " said a recent editorial in the BMJ, once known as the British Medical Journal. "Rather, it is further evidence that anti-amyloid therapies do not produce clinically meaningful benefits for people with Alzheimer's disease."
Others disagree, saying lecanemab shows that reducing amyloid beta can slow the progression of the illness. But they acknowledge that additional medications, and combinations that focus on multiple targets in the brain, must be developed to tame the disease.
"The bottom line is that this is an inflection point in treating Alzheimer's," said Gil Rabinovici, a neurologist at the University of California at San Francisco. "The big picture is we are making progress."
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