Clinical trial participant’s autopsy and brain exam stoke Alzheimer’s drug fears | Science

A full autopsy and detailed examination of the brain of a 79-year-old Florida woman who died after receiving lecanemab, an experimental Alzheimer’s therapy, in a pivotal clinical trial has deepened some researchers’ concerns that it poses serious risks for patients who share the woman’s hard-to-diagnose, preexisting condition.

The patient’s history and autopsy “strongly suggests that lecanemab infusions were a catalyst leading to the events resulting in her death,” says Vanderbilt University pathologist Hannah Harmsen, co-author of a recently completed case report, which Science has obtained. The authors say the woman’s fatal brain swelling and hemorrhaging likely resulted when the drug, a monoclonal antibody, attacked the abnormal protein deposits that had built up in her blood vessels.

At the end of March, worries about such side effects led some prominent Alzheimer’s scientists to urge more stringent prescribing criteria for lecanemab than the Food and Drug Administration (FDA) signed off on in 2022 when giving it provisional approval based on biomarker evidence. But some authors of the new case report and others who have studied lecanemab’s side effects argue that the proposed “Appropriate Use Recommendations,” from researchers who all have current or recent ties to the antibody’s makers, still don’t go far enough to protect potential recipients.

The case report and the experts’ recommendations are likely to be hot topics at an FDA advisory panel meeting on the drug, which the agency this week said would be on 9 June. The panel will assess the drug’s pros and cons before FDA makes its final decision on full approval, likely in July.

Lecanemab and another recently approved drug called aducanumab belong to a class of antibodies that bind to beta amy­loid, a protein that is widely thought to drive the progression of Alzheimer’s disease. In January, FDA approved lecanemab for use after clinical trials showed it removed brain amyloid deposits, an effect the agency said was “reasonably likely to predict a clinical benefit.” The agency relied on the same reasoning in its 2021 approval of aducanumab.

For its “accelerated” approval of lecanemab, FDA did not consider what many saw as the key evidence from the antibody’s phase 3 trial. After 18 months of use, lecanemab modestly slowed the devastating cognitive deterioration of Alzheimer’s—the first drug to clearly do so.

But the drug, now marketed as Leqembi by its maker Eisai Co., has also been linked to several deaths and brain injuries, as well as to a reduction in brain volume, during its trials or their extensions. The case report, currently under review at a journal, expands on an earlier preliminary analysis of the Florida woman’s death, which took place in the phase 3 trial’s extension and was first reported by Science.

That initial analysis showed the woman ultimately died from multiorgan failure and pneumonia, 5 days after she began having seizures, brain swelling, and bleeding. The woman had early Alzheimer’s disease and moderate, asymptomatic coronary artery disease, but had otherwise been in good health when she joined the trial.

Like all Alzheimer’s patients, the woman was also at risk of a condition called cerebral amyloid angiopathy (CAA). In Alzheimer’s disease, beta amyloid accumulates between brain cells in hallmark deposits called plaques. But in roughly half of patients, the protein also extensively replaces the smooth muscle of blood vessel walls, rendering them brittle. Antibodies such as lecanemab often strip away this amyloid, making the vessels weak, inflamed, and prone to dangerous bleeding. Other people who died during the lecanemab trial were taking blood thinners, which likely increased their risk. But the Florida woman was not.

It takes sophisticated, expensive brain imaging to detect signs of CAA; only an autopsy can provide a definitive diagnosis. The case report, prepared by neuroscientists and pathologists at Vanderbilt, Boston University, the University of Florida, and a private Florida autopsy company, showed clear evidence of CAA: many brain hemorrhages, and cerebral blood vessels lined with amyloid plaques. The examination of the woman’s brain revealed “remarkable” inflammation and degeneration of blood vessels, says Matthew Schrag, a Vanderbilt neurologist and neuroscientist and the case report’s ­senior author.

Besides weakening blood vessel walls, lecanemab and other antiamyloid antibodies may pose another hazard to people with CAA, Harmsen, Schrag, and their colleagues say. As the antibodies remove clumps of amyloid from brain tissue, the agglomerations may clog blood vessels and lead to “an inflammatory cascade” that increases the risk of life-threatening swelling and bleeding.

According to Northwestern University pathologist Rudolph Castellani, the report provides definitive evidence that lecanemab started the chain of events that resulted in the woman’s death. “Leqembi is toxic to the cerebral vasculature in people with CAA and potentially lethal,” says Castellani, who previously reported on a separate lecanemab clinical trial death in an Illinois woman who had CAA and had been given tissue plasminogen activator (tPA), a powerful clot-busting treatment for stroke.

Nicolas Villain, a neurologist and neuroscientist at the Sorbonne University and an investigator on the lecanemab phase 3 trial, also reviewed the case report for Science. The drug triggered the Florida death “beyond any reasonable doubt,” says Villain, whose team has found two other cases of severe brain injuries they believe are linked to the antibody.

Eisai declined to comment about the specifics of the case report, which Science provided to it. In a written statement, a spokesperson said the company would“report any necessary and relevant information to appropriate health authorities” for legal and patient-safety reasons. Eisai also referred to the current FDA-approved prescribing information, which urges doctors to review brain imaging data from a potential recipient for signs of inflammation or bleeding that might indicate CAA and to use caution when considering tPA for a patient on lecanemab.

The authors of the case report say that’s not enough. “This case should prompt a careful evaluation of the safety of lecanemab treatment and a refinement of the approach to pre-screening potential recipients of lecanemab for [CAA],” they conclude.

Even supporters of lecanemab share some of those concerns. On 27 March, 11 Alzheimer’s researchers issued recommendations for the drug’s use in a commentary in The Journal of Prevention of Alzheimer’s Disease. They said Alzheimer’s patients on blood thinners—a significant fraction—should not receive the antibody, and those taking the drug should not be given tPA. The group added that all treatment candidates should undergo genetic analysis to be sure they do not carry two copies of a gene variant called APOE4, which raises the risk of brain swelling and bleeding in people given antiamyloid antibodies.

Those restrictions are stronger than FDA’s own prescribing criteria, and they are notable because the authors all have had consulting or advisory relationships with Eisai, its lecanemab partner Biogen, or both. Most, including Harvard University’s Dennis Selkoe; Jeffrey Cummings of the University of Nevada, Las Vegas; and Stephen Salloway of Brown University, have strongly advocated for the drug’s approval.

The group wrote that Alzheimer’s patients with probable CAA and related brain inflammation, as indicated by brain imaging, should not receive lecanemab. Villain calls that proposal too weak. He and colleagues wrote in an alternate set of recommendations—for the use of antiamyloid antibodies in France—that any Alzheimer’s patients with probable CAA, even those without evidence of brain inflammation, should not receive lecanemab. By that standard, the Florida woman who died would have been excluded from the extension of the drug’s phase 3 trial.

Salloway says the case report “points out that the severity of underlying CAA may be hard to detect” with such imaging. He adds that the Florida woman’s genetic status could be a key factor in her case—the Illinois woman who died after receiving lecanemab carried two copies of APOE4. Eisai has not released whether the Florida woman did as well, despite repeated requests since January, according to her daughter.

Before the severe brain injury that led to her death, the Florida woman had headaches and “brain fog” for several weeks during her treatment in the extension phase of the lecanemab trial—most severely after each infusion of the antibody. Steven Greenberg, a Harvard neurologist and co-author of the lecanemab use recommendations, says her experience can “serve as a caution for us as clinicians to look for any symptoms that might lead to earlier brain imaging and earlier detection” of serious problems. He calls the case report “thorough and careful.”

Although episodes of lecanemab-linked brain swelling or bleeding are most often minor, Greenberg adds, “Clearly there are some that are quite severe and can lead … to a patient’s death. We need to consider lecanemab as a double-edged sword, with benefits and risks.”

This story was supported by the Science Fund for Investigative Reporting.

A full autopsy and detailed examination of the brain of a 79-year-old Florida woman who died after receiving lecanemab, an experimental Alzheimer’s therapy, in a pivotal clinical trial has deepened some researchers’ concerns that it poses serious risks for patients who share the woman’s hard-to-diagnose, preexisting condition.

The patient’s history and autopsy “strongly suggests that lecanemab infusions were a catalyst leading to the events resulting in her death,” says Vanderbilt University pathologist Hannah Harmsen, co-author of a recently completed case report, which Science has obtained. The authors say the woman’s fatal brain swelling and hemorrhaging likely resulted when the drug, a monoclonal antibody, attacked the abnormal protein deposits that had built up in her blood vessels.

At the end of March, worries about such side effects led some prominent Alzheimer’s scientists to urge more stringent prescribing criteria for lecanemab than the Food and Drug Administration (FDA) signed off on in 2022 when giving it provisional approval based on biomarker evidence. But some authors of the new case report and others who have studied lecanemab’s side effects argue that the proposed “Appropriate Use Recommendations,” from researchers who all have current or recent ties to the antibody’s makers, still don’t go far enough to protect potential recipients.

The case report and the experts’ recommendations are likely to be hot topics at an FDA advisory panel meeting on the drug, which the agency this week said would be on 9 June. The panel will assess the drug’s pros and cons before FDA makes its final decision on full approval, likely in July.

Lecanemab and another recently approved drug called aducanumab belong to a class of antibodies that bind to beta amy­loid, a protein that is widely thought to drive the progression of Alzheimer’s disease. In January, FDA approved lecanemab for use after clinical trials showed it removed brain amyloid deposits, an effect the agency said was “reasonably likely to predict a clinical benefit.” The agency relied on the same reasoning in its 2021 approval of aducanumab.

For its “accelerated” approval of lecanemab, FDA did not consider what many saw as the key evidence from the antibody’s phase 3 trial. After 18 months of use, lecanemab modestly slowed the devastating cognitive deterioration of Alzheimer’s—the first drug to clearly do so.

But the drug, now marketed as Leqembi by its maker Eisai Co., has also been linked to several deaths and brain injuries, as well as to a reduction in brain volume, during its trials or their extensions. The case report, currently under review at a journal, expands on an earlier preliminary analysis of the Florida woman’s death, which took place in the phase 3 trial’s extension and was first reported by Science.

That initial analysis showed the woman ultimately died from multiorgan failure and pneumonia, 5 days after she began having seizures, brain swelling, and bleeding. The woman had early Alzheimer’s disease and moderate, asymptomatic coronary artery disease, but had otherwise been in good health when she joined the trial.

Like all Alzheimer’s patients, the woman was also at risk of a condition called cerebral amyloid angiopathy (CAA). In Alzheimer’s disease, beta amyloid accumulates between brain cells in hallmark deposits called plaques. But in roughly half of patients, the protein also extensively replaces the smooth muscle of blood vessel walls, rendering them brittle. Antibodies such as lecanemab often strip away this amyloid, making the vessels weak, inflamed, and prone to dangerous bleeding. Other people who died during the lecanemab trial were taking blood thinners, which likely increased their risk. But the Florida woman was not.

It takes sophisticated, expensive brain imaging to detect signs of CAA; only an autopsy can provide a definitive diagnosis. The case report, prepared by neuroscientists and pathologists at Vanderbilt, Boston University, the University of Florida, and a private Florida autopsy company, showed clear evidence of CAA: many brain hemorrhages, and cerebral blood vessels lined with amyloid plaques. The examination of the woman’s brain revealed “remarkable” inflammation and degeneration of blood vessels, says Matthew Schrag, a Vanderbilt neurologist and neuroscientist and the case report’s ­senior author.

Besides weakening blood vessel walls, lecanemab and other antiamyloid antibodies may pose another hazard to people with CAA, Harmsen, Schrag, and their colleagues say. As the antibodies remove clumps of amyloid from brain tissue, the agglomerations may clog blood vessels and lead to “an inflammatory cascade” that increases the risk of life-threatening swelling and bleeding.

According to Northwestern University pathologist Rudolph Castellani, the report provides definitive evidence that lecanemab started the chain of events that resulted in the woman’s death. “Leqembi is toxic to the cerebral vasculature in people with CAA and potentially lethal,” says Castellani, who previously reported on a separate lecanemab clinical trial death in an Illinois woman who had CAA and had been given tissue plasminogen activator (tPA), a powerful clot-busting treatment for stroke.

Nicolas Villain, a neurologist and neuroscientist at the Sorbonne University and an investigator on the lecanemab phase 3 trial, also reviewed the case report for Science. The drug triggered the Florida death “beyond any reasonable doubt,” says Villain, whose team has found two other cases of severe brain injuries they believe are linked to the antibody.

Eisai declined to comment about the specifics of the case report, which Science provided to it. In a written statement, a spokesperson said the company would“report any necessary and relevant information to appropriate health authorities” for legal and patient-safety reasons. Eisai also referred to the current FDA-approved prescribing information, which urges doctors to review brain imaging data from a potential recipient for signs of inflammation or bleeding that might indicate CAA and to use caution when considering tPA for a patient on lecanemab.

The authors of the case report say that’s not enough. “This case should prompt a careful evaluation of the safety of lecanemab treatment and a refinement of the approach to pre-screening potential recipients of lecanemab for [CAA],” they conclude.

Even supporters of lecanemab share some of those concerns. On 27 March, 11 Alzheimer’s researchers issued recommendations for the drug’s use in a commentary in The Journal of Prevention of Alzheimer’s Disease. They said Alzheimer’s patients on blood thinners—a significant fraction—should not receive the antibody, and those taking the drug should not be given tPA. The group added that all treatment candidates should undergo genetic analysis to be sure they do not carry two copies of a gene variant called APOE4, which raises the risk of brain swelling and bleeding in people given antiamyloid antibodies.

Those restrictions are stronger than FDA’s own prescribing criteria, and they are notable because the authors all have had consulting or advisory relationships with Eisai, its lecanemab partner Biogen, or both. Most, including Harvard University’s Dennis Selkoe; Jeffrey Cummings of the University of Nevada, Las Vegas; and Stephen Salloway of Brown University, have strongly advocated for the drug’s approval.

The group wrote that Alzheimer’s patients with probable CAA and related brain inflammation, as indicated by brain imaging, should not receive lecanemab. Villain calls that proposal too weak. He and colleagues wrote in an alternate set of recommendations—for the use of antiamyloid antibodies in France—that any Alzheimer’s patients with probable CAA, even those without evidence of brain inflammation, should not receive lecanemab. By that standard, the Florida woman who died would have been excluded from the extension of the drug’s phase 3 trial.

Salloway says the case report “points out that the severity of underlying CAA may be hard to detect” with such imaging. He adds that the Florida woman’s genetic status could be a key factor in her case—the Illinois woman who died after receiving lecanemab carried two copies of APOE4. Eisai has not released whether the Florida woman did as well, despite repeated requests since January, according to her daughter.

Before the severe brain injury that led to her death, the Florida woman had headaches and “brain fog” for several weeks during her treatment in the extension phase of the lecanemab trial—most severely after each infusion of the antibody. Steven Greenberg, a Harvard neurologist and co-author of the lecanemab use recommendations, says her experience can “serve as a caution for us as clinicians to look for any symptoms that might lead to earlier brain imaging and earlier detection” of serious problems. He calls the case report “thorough and careful.”

Although episodes of lecanemab-linked brain swelling or bleeding are most often minor, Greenberg adds, “Clearly there are some that are quite severe and can lead … to a patient’s death. We need to consider lecanemab as a double-edged sword, with benefits and risks.”

This story was supported by the Science Fund for Investigative Reporting.