Brain shrinkage as a hallmark of lecanemab approval: “The amyloid hypothesis failed to succeed in halting Alzheimer’s disease”

The agency is expected to give a Conditional approval in early 2023 and a full approval later in the year. Lecanemab is not likely to be approved for everyone in the early stages of Alzheimer’s. They make up 2 million of 6 million people with the disease.

Maria Carrillo is the chief science officer of the Alzheimer’s Association and she says this is a landmark for people eligible for this treatment.

“This is a very small effect size with a drug that has some side effects,” including brain shrinkage, says Dr. Madhav Thambisetty, a neurologist at the National Institute on Aging, a part of the National Institutes of Health. The evidence that it slows down the disease is not convincing, he says, and his views are not those of theNIH.

But a long list of antibodies that target beta-amyloid failed to slow down the declines in memory and thinking associated with Alzheimer’s. In fact, so many drugs failed that some researchers began to question what’s known as the amyloid hypothesis – the idea that amyloid is a primary cause of the loss of brain cells that leads to declines in memory and thinking.

The controversy around aducanumab, which the FDA granted accelerated approval on 7 June 2021, has cast a shadow over lecanemab. Many researchers thought that aducanumab, which also goes by the brand name Aduhelm, did not show a strong signal of cognitive decline. The FDA’s own scientific advisory panel recommended against approving the antibody in an 8–1 vote, and three panel members resigned after the FDA authorized it anyway. The FDA did not hold a meeting before approving lecanemab.

Leqembi received accelerated approval to market a drug that could be used to remove amyloid from the brain. The FDA is likely to consider a full approval later this year, after reviewing the evidence that the drug also helps preserve mental function.

In recent months, Science and STAT News reported three people who had been enrolled in the lecanemab phase III study and then died during the extended phase of the trial, when patients receiving placebo can ask to be given the drug. Brain bleeding and seizures were the reasons for their deaths. According to those reports, researchers think that the patients might have died because of a set of conditions known as amyloid-related imaging abnormalities (ARIA). They suspect the antibody weakened blood vessels in the brain as it attacked the amyloid plaques lining them. All the patients were taking anticoagulant drugs at the time, which may have worsened the bleeding.

Patients can experience death or brain damage in rare cases. So far, two deaths have been linked to lecanemab, although both patients had other conditions that could have contributed to the outcome.

“What we’ve learned over time is that a very small proportion of individuals will have symptoms,” Cohen says, “and when symptoms arise, they are usually transient, mild to moderate, and resolve.”

Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or lasting impairment. There is a possibility that people with a gene called ApoE4 have a higher chance of being affected by Alzheimer’s disease. ARIA were less commonplace among noncarriers.

Drug developers and researchers have to prove that these changes are benign and don’t represent a significant adverse event.

The FDA could decide whether to approve Lecanemab, a dementia drug based on its experimental trial, according to Eisai and Biogen

The US Food and Drug Administration could decide this week whether to grant accelerated approval to the experimental dementia drug lecanemab, according to Eisai and Biogen, the companies that make the drug.

Although Leqembi has FDA approval, it is unlikely to be covered by Medicare for many patients. The reason has to do with the earlier Alzheimer’s drug, Aduhelm.

The results show that the trial participants who received lecanemab, as an IV drug, discontinued the trial due to adverse events, compared with the placebo group. Overall, there were serious adverse events in 14% of the lecanemab group and 11.3% of the placebo group.

The FDA could give traditional approval if those trials confirm that the drug gives a clinical benefit. The FDA has procedures in place to take a drug off the market if a confirmatory trial doesn’t show benefit.

More than 300 treatments are being tested for Alzheimer’s. Alzheimer’s disease was first documented in 1906, when Dr. Alois Alzheimer discovered changes in the brain tissue of a woman who had memory loss, language problems and unpredictable behaviors.

Drs. Marwan Sabbagh and Christopher H. van Dyck wrote in that response that they “agree that this case raises important management issues for patients with Alzheimer’s disease.”

The research letter published in the New England Journal of Medicine explained what happened to the participant in the open-label extension phase of the trial.

In an open-label extension, there is no placebo arm; rather, all the participants get the medication in question because an earlier part of the trial has shown so much potential.

This patient is not the only one to die during the open-arm extension. An investigator told the publication about a participant who had died of brain bleeding related to the drug. In that case, drugmaker Eisai pointed to other possible factors.

The research shows that a small percentage of trial participants had a symptom of the swelling in the brain called ARIA-E, when they took the drug. The people who got a placebo did not have that.

In the case of the patient in the new report, Cohen thinks the death was probably related to the blood clot drug but said the combination of that drug and lecanemab “gives us pause.”

The doctors then administered a medicine that can control the bleeding, but the patient became severely agitated and developed communication problems. The patient had many nonconvulsive seizures.

Someone got a tube in their windpipe after spending three days in the hospital. Even with that and other supportive care, the patient died.

An autopsy showed that the patient had extensive brain bleeding and amyloid deposits within many of the blood vessels in their brain that probably contributed to the hemorrhage, the report said.

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CNN requested an interview with the authors of the report, but Northwestern Medicine said they were trying to give relevant data to the medical community.

The doctors wrote that t- PA has caused other patients to die with amyloid deposits in the brain.

Sharon Cohen is a behavioral neurologist who works with patients with Alzheimer’s at the Toronto Memory Program and is an investigator in the lecanemab trial.

She said that the safety of the drug appears to be acceptable. It is within the range of events that we expected and it appears reasonable for this patient population.

She said that if the FDA approves the treatment, there will be some discretion in terms of patient choice and what the doctor feels is best for someone who is taking a anticoagulant or has other risk factors for hemorrhaging.

Dr. Richard Isaacson of the Center for Brain Health at Florida Atlantic University said that the FDA approval was expected.

The first thing I would do was genetic testing for APOE4. I would have a frank discussion with my patients,” he said. “If someone is having side effects, if someone is on a blood-thinning medication, if someone has a problem, they need to discuss this with the treating physician, and they need to seek medical attention immediately.”

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The new drug, which is given intravenously every other week, removes a substance called amyloid from the brain. Sticky amyloid plaques are a hallmark of Alzheimer’s, though many previous drugs that targeted amyloid failed to slow down patients’ loss of mental abilities.

“It’s not a cure. It doesn’t stop the disease completely. The person says that it doesn’t make people better. In very mild disease, it slows down the progression.

“Maybe you could keep driving for an extra six months or a year,” she says. It could be better to keep doing your checkbook for an additional six months.

The government can balance the cost of the drug against savings if people with dementia can delay expensive nursing home care. It would also make it easier for the government to negotiate on the price of Leqembi.

If we can pool all of the dementia patients who are covered under different plans into a single risk pool we might be able to provide coordinated care to those patients.

Since the early 1970s, Medicare has run a special program for people of all ages whose kidneys are failing. That program now costs Medicare about $9 billion a year.

ARIA warning on lecanemab has not been prescribed in the U.S. Food and Drug Administration, and a response to Eisai

Eisai has said that it is inappropriate to draw conclusions on the basis of individual cases, and that it reported the deaths to the FDA as required. Nevertheless, the FDA’s approval requires that lecanemab include a warning about ARIA, and that physicians monitor for the condition, which it says is rarely serious or life-threatening.

Most patients pay over $28,000 for a year of treatment unless they are in a clinical trial because theCMS refused to cover aducanumab under federal insurance plans. CMS — and several clinics that refused to prescribe the drug — cited its questionable efficacy, drawing the ire of advocacy groups who say it should be readily available.