How well does lecanemab affect memory and thinking? The amyloid hypothesis versus the FDA’s approval of Aduhelm in patients with Alzheimer’s
Lecanemab, like many of those other drugs, contains lab-made monoclonal antibodies designed to remove a substance called beta-amyloid from the brain. Beta-amyloid is a protein that tends to form clumps in the brains of people with Alzheimer’s, and ultimately results in the sticky plaques that have become a hallmark of the disease.
“There was a feeling of elation, like this was a milestone in the fight against Alzheimer’s disease,” says Dr. Eric Reiman, executive director of Banner Alzheimer’s Institute in Phoenix.
“Brain shrinkage represents disease progression,” he says. There’s a concern that these drugs may be making the process worse.
The decline in memory and thinking associated with Alzheimer’s could not be stopped by a long list of anti-Beta-amyloid antibodies. 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.
Since then, the federal Medicare program has decided it will cover Aduhelm treatment only for patients enrolled in a clinical trial. Few patients have received the drug as a result of that decision.
“It had effects on a range of cognitive and functional measurements that are important to families and family caregivers,” Reiman says. I will be shocked if the FDA doesn’t approve it.
The most prevalent adverse events in the lecanemab group were reactions to the IVs, which can cause brain swelling and bleeding, and ARIA, which can lead to death.
In rare cases, though, patients can experience brain damage or even death. 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.”
Cohen says that people who are taking blood thinners or have high levels of amyloid in the brain are at a higher risk of ARIA. She says that there will be patients for whom this is not a good therapy.
He says it’s incumbent upon drug developers and researchers to try and prove that the changes are benign.
“If and when this drug is approved by the FDA, it will take clinicians some time to be able to parse out how this drug may or may not be effective in their own individual patients,” especially since carriers of the APOE4 gene could be at higher risk of side effects, Dr. Richard Isaacson, adjunct associate professor of neurology at Weill Cornell Medicine, who is not involved in studying lecanemab or its development, said in November.
She added that the Alzheimer’s Association hopes that the Centers for Medicare and Medicaid Services “will move quickly” to cover the drug and “revise its coverage decision that currently blocks access to this treatment.” CMS determines whether to cover FDA-approved therapies based on whether it deems them to be safe and effective.
There were adverse events which caused the trial participants to stop the trial, compared with those who didn’t. Overall, there were serious adverse events in 14% of the lecanemab group and 11.3% of the placebo group.
If the FDA gives accelerated approval, it will still be studied in more robust trials. The FDA can grant traditional approval if those trials confirm the clinical benefit of the drug. If the confirmatory trial doesn’t show benefit, the FDA could take the drug off the market.
The death of a woman who had cerebral hemorrhages in the open-label phase of the Alzheimer’s Association trial of lecanemab
The Alzheimer’s Association has more than 300 Alzheimer’s treatments in clinical trials. Dr. Alois Alzheimer discovered changes in a woman’s brain tissue in 1906, the first known case of Alzheimer’s disease.
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 Wednesday in the New England Journal of Medicine, shares details about what happened to the participant in the open-label extension phase of the trial of lecanemab.
There is no placebo arm in an open-label extension because the earlier part of the trial has shown a lot of potential.
The patient wasn’t the only one to die. The health publication Stat reported that an investigator told them about the death of another participant who had bleeding in the brain that was related to the drug. In that case, the drugmaker pointed to other possible factors.
According to the research, about 2.5% of trial participants had a side effect which was called ARIA-e and it involved swelling in the brain. None of the participants who got a placebo had that.
“The extensive number and variation in sizes of the cerebral hemorrhages in this patient would be unusual as a complication of t-PA solely related to cerebrovascular amyloid,” the report says. The combination of clot-busting drug with lecanemab may have led to cerebral hemorrhages.
The patient became very agitated after the doctors gave them a medicine to control the bleeding. The patient also had frequent nonconvulsive seizures.
After three days in the hospital, the person got a tube in their windpipe to help them breathe. The patient died even after supportive care.
A report said that an autopsy showed that the patient had a lot of brain bleeding and amyloid deposits in their brain, which was probably the cause of the hemorrhage.
Source: https://www.cnn.com/2023/01/04/health/lecanemab-trial-report/index.html
The FDA’s decision on lecanemab for patients with t-PA have been reported by a behavioral neurologist
It was an effort to provide data to the medical and scientific community, which is why the authors of the report were not interview by CNN.
The doctors also write in the response that other patients who have gotten t-PA have died with these amyloid deposits within blood vessels in the brain.
Sharon Cohen is a behavioral neurologist who is involved with Alzheimer’s patients at the Toronto Memory Program and is an investigator in the lecanemab trial.
The drug’s safety appears to be acceptable, she said. It seems reasonable and it is within the range of adverse events that we expected.
She said that the FDA could make a decision on whether or not to approve the treatment for someone who is taking anticoagulants and has other risk factors for hemorrhaging.