The U.S. Food and Drug Administration on Thursday gave full approval to the Alzheimer's drug Leqembi, clearing the way for insurance coverage of the pricey drug.
"The full FDA approval will open the floodgates for people with early Alzheimer's to get this drug. It's a big deal because it's very expensive at $26,500 per year," Robert Vassar, director of Northwestern Medicine's Mesulam Center for Cognitive Neurology and Alzheimer's Disease in Chicago, said in a statement released Thursday. "Now, Medicaid and Medicare will cover it as long as patients enroll in a registry to track their progress," he added.
"It's a big breakthrough because it's the first disease-modifying drug for Alzheimer's. This has been the holy grail since the early 1990s when amyloid was discovered, and people were trying to design drugs to eliminate amyloid from the brain," Vassar explained.
"This is the first successful one. There were many attempts in the past that failed. It really shows that removing amyloid does delay the progression of Alzheimer's disease," he said.
"During the 18-month trial, Leqembi delayed the progression of Alzheimer's by five months, which is pretty significant," Vassar noted.
Thursdays approval did come with one significant caveat, however: The FDA added a so-called black-box warning to Leqembi's labeling, cautioning that in rare cases the medication can trigger "serious and life-threatening events," including brain bleeds, some of which have proven fatal.
Leqembi will only be available to people in the earliest stages of Alzheimer's -- those with mild dementia or what's known as mild cognitive impairment. Labeling will also instruct physicians not to treat patients with Leqembi unless they have already undergone testing to confirm an uptick in levels of amyloid protein in their brain. Amyloid buildup is a key signal of Alzheimer's disease and Leqembi is designed to fight it.
Leqembi (lecanemab), which is made by Eisai Inc. and marketed by Biogen, will be only the second Alzheimer's drug to receive the FDA's blessing in the past two decades; the agency's accelerated approval of the drug Aduhelm in June 2021 generated controversy in the medical community over its lack of effectiveness, the concerns over brain bleeds and the drug's hefty price tag.
But Alzheimer's experts have said the story is somewhat different with Leqembi.
"Unlike Aduhelm, which had an incomplete data set and where clinical trial data failed to demonstrate a definitive slowing in cognitive decline, lecanemab showed statistically significant slowing in cognitive and functional decline, as well as reduction of brain amyloid levels, and downstream beneficial effects on other markers of neurodegeneration," Dr. Sarah Kremen, who leads the Alzheimer's Disease Clinical Trials Program at Cedars-Sinai in Los Angeles, said in a statement when Leqembi was granted accelerated approval back in January.
Still, Leqembi has been linked to two deaths from brain bleeds among people who used it in trials.
And not every patient would stand to benefit from Leqembi, stressed the Cleveland Clinic's Dr. Babak Tousi. He led the portion of the clinical trial that was conducted at the Cleveland Clinic, in Ohio.
"The trial was designed for patients in the earlier stage of Alzheimer's disease, people with mild cognitive impairment or early stage of dementia,"Tousi noted. "It will probably be for people who have early stage of disease, with no to minimal assistance needed for activities of daily living."
The results of the original 18-month trial, which involved about 1,800 patients, gained wide attention when they were published last December in the New England Journal of Medicine, Tousi noted.
In the trial, early-stage Alzheimer's patients who took Leqembi showed a 27% reduction in their mental decline compared to patients in the placebo arm of the trial. The drug's users also showed less evidence of amyloid protein plaques in their brain compared to non-users.
"Lecanemab clearly did what it was designed to do -- it removed amyloid plaque,"said Tousi, who heads the Clinical Trials Program at the Cleveland Clinic Center for Brain Health. "The results demonstrated all the downstream effects we hoped would happen in terms of reduction of biomarkers and less clinical decline on several functional and cognitive measures. So, this difference will likely translate to a longer period of independent living for patients."
Two patient deaths raise questions
Still, the deaths of two patients enrolled in the original trial were troubling. Both died from brain hemorrhages that seemed linked to the use of Leqembi.
In one case, a 65-year-old woman with early-stage Alzheimer's died from a massive brain bleed that some researchers link to Leqembi, according to a report published last November in Science Insider.
ER doctors at Northwestern University Medical Center in Chicago treated the woman with a common but powerful clot-busting drug, tissue-plasminogen activator (tPA). She immediately had substantial bleeding throughout her brain's outer layer.
"As soon as they put it in her, it was like her body was on fire," her husband told Science Insider. "She was screaming, and it took like eight people to hold her down. It was horrific."
The woman died a few days later, the case report said.
Her death followed that of an 80-year-old man who was taking part in Leqembi's phase 3 clinical trial. His death was linked to a possible interaction between the experimental drug and a blood thinner called apixaban (Eliquis).
Rudolph Castellani, a Northwestern neuropathologist who autopsied the woman, determined that she had amyloid deposits surrounding many of her brain's blood vessels.
The woman had been receiving biweekly infusions of Leqembi, which appears to have inflamed and weakened her blood vessels, Castellani said. These vessels then burst when exposed to the clot-buster, something that can happen even in conventional stroke cases.
"It was a one-two punch," Castellani told Science Insider. "There's zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn't been on lecanemab, she would be alive today."
While Eisai declined to comment on the woman's case, the company did issue a statement saying that "All the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause."
Weakened blood vessels
The woman and the man both had widespread cerebral amyloid angiopathy (CAA), a condition in which amyloid deposits gradually replace the smooth muscle of blood vessel walls.
Nearly half of Alzheimer's patients have CAA, and many also suffer from heart ailments that are normally treated with blood thinners, the report noted.
Experts explained to Science Insider that in these types of patients, stripping the amyloid away -- as drugs like Leqembi are meant to do -- could weaken the blood vessels and make them vulnerable to bleeds if exposed to blood thinners or clot busters.
But factors other than the patients' use of Leqembi could have been at play, they pointed out. In the woman's case, an extended period of very high blood pressure could have been a contributing factor. In the man's case, a drug he was taking to counter atrial fibrillation might have played a role in the hemorrhaging.
Besides the two fatal cases, the clinical trial also showed that 2.8% of participants who took the drug had a symptomatic side effect called ARIA-E, which involves swelling in the brain. ARIA-E was not seen among any participants who got the placebo.
Risks versus benefits
However, for the millions of Americans affected by Alzheimer's, any beneficial drug could be welcome.
After Medicare limited its coverage of Aduhelm, citing risks and unclear benefit, the expensive drug was essentially sidelined.
Like Aduhelm, Leqembi -- given via infusion every two weeks -- is a monoclonal antibody that targets amyloid proteins, which tend to clump in the brains of people with Alzheimer's. Years of research have uncovered precious little evidence that clearing these plaques actually helps with memory and thinking problems.
"It's not the be all and end all, but this is the first drug,"Vassar said. "There will be better drugs like it coming out in the future."
More information
Visit the U.S. National Institute on Aging for more on Alzheimer's.
SOURCES: U.S. Food and Drug Administration, news release, Jan. 6, 2023; Babak Tousi, MD, head, clinical trials program, Cleveland Clinic Center for Brain Health, Ohio; New England Journal of Medicine, Jan. 5, 2023 and Dec. 1, 2022; Science Insider, Nov. 27, 2022
