Some potentially fatal complications linked to the Alzheimer’s drug Leqembi (lecanemab) have raised concerns among health professionals, who question whether its risks are worth its benefits, particularly for the population of older adults for whom it was approved.
The drug, the approval of which was controversially fast tracked by the US Food and Drug Administration (FDA) early in 2023, was designed to slow cognitive decline in patients in the early stages of Alzheimer’s disease.
However, notes MedicalBrief, the treatment, produced by Eisai and Biogen and which was anticipated to be their winning formula after the failure of their earlier drug, Aduhelm, had a lukewarm reception from neurologists, few of whom consider it a significant medical advance over other historic AD treatments.
Now, there is growing concern about a potentially lethal side effect – innocuously named ARIA – which might sound the death knell for treatments like this.
The complication was named by a group of pharmaceutical executives and academic scientists to describe potentially fatal bleeding and swelling in the brain caused by drugs like Leqembi.
ARIA is short for “amyloid-related imaging abnormalities”, with imaging referring to the MRI scans needed to find the brain bleeding and swelling.
US senior Genevieve Lane (79) volunteered to take Leqembi in a clinical trial because she was forgetting words and misplacing her keys, but infusions of the drug gave her headaches so severe they sent her to bed. A week after the third dose, she was with a friend when her speech slurred and she had a seizure.
The LA Times reports that five days later she was dead.
An autopsy found she died of the side effect ARIA. Her death, and those of two other trial participants, now have US doctors on edge, with them questioning whether a new name should be given to the drug’s potential side effects to better alert healthcare professionals to its risks.
“Clearly, it is more than just an imaging abnormality,” said Dr Matthew Schrag, a Vanderbilt University neurologist who helped with an autopsy that concluded Lane died of brain swelling and bleeding that was probably caused by Leqembi.
“My feeling is that ARIA is too euphemistic of a term. It conveys that this isn’t serious, and it certainly can be.”
Leqembi, known generically as lecanemab, is a monoclonal antibody that works to remove the protein called amyloid from the brain. It received full US Food and Drug Administration approval last July.
Eisai, the Japanese drugmaker which has partnered with Biogen, and which is promoting Leqembi to doctors and people concerned about memory problems, says on its website: “ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur.”
In a recent article, a Stanford University neurologist and his colleagues detailed their concerns about ARIA, which they called a “soothing acronym” for brain bleeding and swelling.
“It certainly has the ring of something that a pharmaceutical company or public relations person would devise,” said Dr Michael Greicius.
Leqembi is approved for mild dementia and mild cognitive impairment, in which patients have more memory problems than others their age but can compensate and continue their daily activities.
People with MCI have been found to be at greater risk for developing dementia, but in many cases their memory problems stay the same or even improve.
The FDA has required that the company warn doctors about ARIA, saying the condition, which affected more than 20% of those taking the drug in a large trial, can be managed by requiring patients to get repeated MRI scans to look for bleeding and swelling.
“The FDA maintains that the benefits of Leqembi outweigh its risks when used according to the approved labelling,” said Dr Teresa Buracchio, director of the FDA’s neuroscience office.
Libby Holman, an Eisai spokesperson, called ARIA a “globally established nomenclature”.
Because of the risk of ARIA, some medical centres are taking extra precautions.
At Keck Medicine of the University of Southern California-Los Angeles, a neurologist is available 24/7 to take calls from families of those taking Leqembi, since a headache or sudden confusion can be a sign of ARIA, said Dr Helena Chui, chair of the neurology department, while at two other medical centres, warnings pop up in a patient’s electronic health record to ensure all staff know the patient is taking Leqembi, because it can interact with certain other medications to make brain bleeding far worse.
In each of the three centres, it takes more than a single doctor to prescribe the drug. Each patient’s case must be reviewed by a panel of doctors and other staff – similar to how complex cancer cases are evaluated.
“We want to keep safety first,” said Dr Keith Vossel, a professor of neurology at UCLA. “This is the most complicated, complex drug we’ve prescribed in the dementia field.”
Other physicians won’t prescribe the drug.
“If there were a medication that worked, I would be the first to use it,” said Dr Clifford Sigel, a neurologist in Santa Monica. “But I won’t be using this in my practice.”
He pointed to a large clinical trial of Leqembi that led to its approval. It found that patients who took the drug saw their memory decline 27% more slowly – or less than half a point on an 18-point cognitive scale – than their counterparts who took a placebo.
Sigel and other doctors doubt patients or their families would notice the difference.
Eisai’s Holman disputed claims that the drug does not work. She noted that a panel of outside experts convened by the FDA had voted unanimously that trial data confirmed its clinical benefit.
The name ARIA dates back to July 2010 when “turmoil ensued” at an international scientific conference that the Alzheimer’s Association holds each year, according to an article by two scientists working in the field.
The FDA had proposed that companies testing new anti-amyloid drugs exclude any volunteer from clinical trials who had more than two brain microbleeds. The tiny haemorrhages are sometimes found in healthy people and those with Alzheimer’s or other illnesses.
The agency also said it would require any volunteer who experienced a brain microbleed during the clinical trial to stop taking the drug.
Those working on the trials viewed the new FDA requirements as “excessively restrictive”, said the report by the association, an NPO that has become a powerful force in dementia science.
The industry and academic scientists feared the FDA proposal would stall research on the experimental drugs, the report said, and limit their use.
The drug companies asked the association to debate the FDA’s guidance at its Research Roundtable. Pharmaceutical and medical testing companies can become members of the roundtable by paying the association a $50 000 annual fee.
The association said “one key question” was whether ARIA was a temporary symptom of the new drug – like nausea and hair loss are side effects of chemotherapy – or evidence that anti-amyloid medicines may have more serious adverse effects. That question was never settled.
“Current knowledge doesn’t provide definitive answers to this critical question,” the association said in the 2011 report.
Despite the unknowns, the roundtable proposed that volunteers be allowed into the trials even if they had as many as four brain microbleeds. They said volunteers could keep getting the drug infusions if they developed brain bleeding, providing they did not have significant worsening of symptoms, like headaches and confusion.
The roundtable also proposed calling the brain bleeding and swelling ARIA.
The FDA “subsequently revised and updated the original advice … in a manner consistent” with the suggestions, wrote three of its members.
The association declined to answer questions on whether the name ARIA should be changed.
An FDA official told The LA Times that the industry group’s advice was just one of the factors the agency considered before it revised its 2010 guidelines.
More than a decade later, little more is known about why ARIA occurs or how to recognise it.
Stroke and ARIA
One problem is that a patient with ARIA can look as if they’re having a stroke. And when stroke patients are taken to an emergency room, the first treatment doctors often consider is a clot-dissolving medicine called tPA, which can worsen brain bleeding.
Now, Southern California doctors have been teaching emergency room staff to find out whether patients thought to be having a stroke may be taking Leqembi.
An FDA database that collects reports of adverse drug reactions from doctors and others shows 23 deaths of patients taking Leqembi, but Holman at Eisai said it would be incorrect to assume the deaths were caused by the drug. She said Alzheimer’s patients have a higher risk of death because of the natural course of the disease.
In the large trial, less than 1% of patients died – the same rate whether they were taking the drug or the placebo.
Buracchio at the FDA said the agency takes “all adverse event reports seriously”. But she said the agency’s evaluation of the reports “must take the treated population into account”, which in this case is typically older or elderly adults.
To teach doctors about ARIA, Eisai created a website called understanding-aria.com. It tells doctors that ARIA “usually resolves without intervention or treatment modification”.
In a brochure for healthcare providers, Eisai assures physicians that infusions may continue if an MRI shows evidence of microbleeds, as long as there are four or fewer and that the discomfort doesn’t disrupt the patient’s activities.
Microbleeds
For Genevieve Lane, an MRI discovered four brain microbleeds before she started taking Leqembi in the trial.
After her death, an autopsy found more than 30 microbleeds in her brain, including some that could not be seen on the MRI, according to a report in Nature Communications.
The report’s authors, who included Schrag at Vanderbilt, questioned whether the pre-treatment limit of four brain microbleeds was stringent enough and called for higher standards.
The FDA told The LA Times that it had reviewed the available data and had not identified a specific number of pre-existing micro-haemorrhages that would make it unsafe for patients to take drugs like Leqembi.
“However, we will continue to monitor the accruing safety data,” the agency said.
Other doctors have questioned what happens to the memories of those who suffer ARIA, even if the bleeding and swelling appear to resolve.
Dr Madhav Thambisetty, a senior researcher at the National Institute on Ageing, said he was concerned by a report in a French journal about two women with mild dementia who experienced serious ARIA during a trial. One suffered severe seizures; 11 months later, her memory score dropped by nine points on a 30-point scale. The other patient developed a brain bleed described as “massive”; she lost a significant part of her vision, and her memory score declined by 12 points on the same scale.
Thambisetty said he and Dr Rob Howard of University College London wrote to Eisai last year to request information about what happened to the cognition of those who suffered ARIA in trials.
Eisai has not responded.
“I’m concerned about the lack of full and transparent reporting,” Thambisetty said. “It’s really important to know what happens to these patients.”
Holman said the company’s analysis of trial data showed that ARIA did not affect cognition.
Greicius, the Stanford professor, also asked Eisai for trial data that would break down results for each volunteer to better understand ARIA and whether patients benefited as more amyloid was removed from their brains.
The response from Eisai, he said, was, “Thanks for your interest, but we can’t release the data.”
Nature article – Microbleeds in dementia—singing a different ARIA (Open access)
See more from MedicalBrief archives:
US doctors slow to offer newly-approved Alzheimer’s drug
Alzheimer’s drug beset by various challenges
Concern over FDA's fast-track approval of Alzheimer’s drugs