Scientists link third clinical trial death to experimental Alzheimer’s drug | Science

Scientists link third clinical trial death to experimental Alzheimer’s drug | Science

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As enthusiasm grows for a new experimental antibody that appears to slow cognitive decline in some Alzheimer’s patients, a third death linked to the drug during its clinical testing may heighten concerns about its safety. Science obtained medical records showing that a 79-year-old Florida woman participating in an ongoing trial of the antibody died in mid-September after suffering extensive brain swelling and bleeding, as well as seizures. Multiple neurologists who reviewed the records in the ScienceThe request believes her death was likely caused by the antibody, lecanemab.

“Brain swelling and microhemorrhages … can be a serious side effect of the study drug” and should be evaluated by researchers, says Ellis van Etten, a neuroscientist and neurologist at Leiden University.

The clinical trial’s sponsor, Japanese biotech company Eisai Co., did not disclose the death rate at a major Alzheimer’s meeting last month, where it detailed data from the phase 3 trial of lecanemab. The death came during this ordeal, but some scholars say it should have been celebrated at the conference anyway. “The failure of Eisai and [lecanemab codeveloper] For Biogen to disclose this case … is troubling and undermines my confidence that the reported safety data are complete,” said Vanderbilt University neurologist and neurologist Matthew Schrag, who also reviewed the woman’s records.

The newly discovered death comes on top of other reports of serious brain bleeding and swelling in the pivotal clinical trial and two other deaths in the extension phase — first reported by STATISTICS and on secondly from Science— which some scientists associate with lecanemab.

Eisai, which attributed the previous deaths and brain injuries to factors unrelated to lecanemab, declined to comment on the Florida woman’s death, citing patient privacy concerns. “All serious events, including deaths, are reported to Eisai and taken into account in our assessment of the study,” a company spokesperson said in a written statement to Science. “This information has been provided to the FDA [Food and Drug Administration] and other regulatory authorities’, as well as independent study review boards.

The spokesman added that the age and medical condition of all trial participants should be taken into account when assessing death. However, the Florida woman had no apparent health problems other than signs of early Alzheimer’s disease, according to her medical records.

Eisai reported 13 deaths in the main clinical trial, which enrolled about 1,800 people. The deaths were expected given the age and health of the study population, and the company said the numbers were similar in the lecanemab and placebo groups. But it did not release details of each death, so in most cases scientists were unable to determine whether lecanemab contributed to the deaths.

Lecanemab is one of several experimental Alzheimer’s drugs that target beta amyloid, the protein that builds up in the brains of people with the disease. Many in the field believe it is responsible for the brain cell death that robs people of their memories and eventually kills them, although deposits of the protein are also found in the brains of healthy people.

Amyloid-seeking antibodies often cause brain swelling and bleeding, a condition known as amyloid-associated imaging abnormalities (ARIA) because it is diagnosed by brain imaging. “We need a name change … because these are not just imaging abnormalities, as this case shows,” said Boston University neuroscientist Andreas Charidimu, who reviewed the woman’s records for Science. “This is a real clinical syndrome that can be fatal.”

Although lecanemab targets a soluble version of beta amyloid, it also binds to the extracellular beta amyloid “plaques” considered a hallmark of Alzheimer’s disease. About half of Alzheimer’s patients have a condition called cerebral amyloid angiopathy (CAA), in which beta amyloid plaques replace the smooth muscle of blood vessel walls. When antibodies like lecanemab remove these plaques, blood vessels can become inflamed and weakened, making a person more susceptible to ARIA.

In the previous two lecanemab-related deaths, neurologists said the patients’ use of anticoagulants worsened brain swelling and bleeding. The Florida woman was given a minimal course of the anticoagulant heparin after she was hospitalized, but several neurologists dismissed it as a contributing factor to her sudden problems and eventual death.

It is unclear whether the woman received infusions of the antibody or a placebo during the main 18-month trial. But she received the drug for 6 weeks in the extension phase – in which each participant can choose a treatment. Before the extension trial began, a brain scan revealed signs of several microbleeds, but they weren’t serious enough to rule her out of the trial.

One of the Florida woman’s daughters provided the medical records of Science and authorize their review by others. To protect family privacy, Science withheld the names of the patient, the daughter, a friend who was the woman’s assistant during the study, and the clinical trial site where the patient received lecanemab.

A textbook case

The woman’s friend described a harrowing series of events that began with the patient’s first infusion of the antibody as part of the extended trial in August. “She was so tired. She … didn’t get out of bed for 2 days, except maybe to eat yogurt or go to the bathroom,” says the friend. A few weeks later, after the second infusion, the woman complained of a severe headache, “couldn’t finish sentences” and felt increasingly confused about everyday things, a friend recalled.

In a restaurant on September 14, the woman suffered something like a stroke. She was rushed to the hospital, where her friend informed the doctors that the woman was taking the experimental drug. Seizures began, causing her to thrash her arms and legs, requiring restraints for her safety.

Before a Florida woman received lecanemab in an extended-phase clinical trial, an MRI scan of her brain (left) showed several microhemorrhages—small hemorrhages (dark spots, examples marked with arrows). Subsequently (right), dozens of microhemorrhages were evident (examples marked with arrows).Submitted anonymously to Science

Brain scans showed dozens of areas of bleeding and cerebral edema so extensive that the characteristic folds of the cerebral cortex were “fused and crushed” in significant parts of her brain, Charidimu said. He calls it “a textbook case of severe ARIA, both the clinical presentation and the imaging findings.” Given the lack of other potential causes of brain damage listed in the medical records, he adds, lecanemab is almost certainly the culprit.

Hospital records show that the investigator at the clinical trial site, who was contacted after the woman was hospitalized, suspected ARIA and insisted on treatment with steroids — which doctors tried without significant benefit. She began to suffer from multiple organ failure and pneumonia and died 5 days after admission.

“The patient had extensive swelling of her brain with some small areas of bleeding, which caused her to have a seizure and eventually die,” says Schrag, who specializes in CAA. “I’m pretty sure it’s a side effect of the lecanemab.”

Eric Smith, a neuroscientist at the University of Calgary who also reviewed the case materials, agrees that the drug probably caused the death. He previously consulted for Eisai partner Biogen and was an investigator for the two companies’ other anti-amyloid drug aducanumab (sold as Aduhelm), which won FDA marketing approval last year.

The family has arranged for an autopsy that could confirm the woman had CAA and clarify the antibody’s role in her death, but it has not been completed, the daughter said. Eisai’s spokesman said the company “is thorough and proactive” in its efforts to obtain any safety information, including autopsy results of trial participants.

Lack of consensus

The deaths linked to the antibody cast a pall over recent trial results that were largely seen as encouraging. Eisai reported that lecanemab slowed the rate of cognitive decline among early Alzheimer’s patients by an average of 27% over 18 months, a statistically significant effect. Neurologists differ on whether this benefit will be noticeable in many patients or their caregivers, and some large subgroups in the study, including women and people under the age of 65, did not benefit at a statistically significant threshold.

Still, the trial represents the most favorable results of any anti-amyloid therapy to date and prompted some Alzheimer’s scientists and patient groups to the FDA to quickly greenlight the drug.

Earlier this month, lecanemab “consensus statement”—whose original signatories worked as consultants for Eisai or Biogen or conducted research on the recent lecanemab trial—began circulating online. Almost half of the more than 200 scientists or medical practitioners who had signed statement as of December 20 are recent consultants or beneficiaries of one or both companies, Science has determined. (Some, but not all, disclosed conflicts of interest.)

The paper describes lekanemab as a “fundamental game changer” for the disease and calls for its approval and “no barrier” to widespread availability of the antibody. It noted possible safety concerns associated with ARIA, but did not mention the deaths and serious brain injuries that some have linked to the drug. The FDA is expected to make a decision on the approval of lecanemab and whether to require warnings or cautions for prescribers by January 6, 2023.

Smith, who did not sign the prolekanemab letter, acknowledges that people with early Alzheimer’s disease may judge the possibility of even very modest cognitive benefits to be worth the risk of debilitating cases of ARIA or even a fatal outcome. But he thinks any FDA approval should come with caveats.

An Alzheimer’s patient receiving lecanemab will require up to five MRIs a year to properly track ARIA, he says, and an extensive education program will be needed to ensure that doctors outside major medical centers can recognize problems found on the scans. the brain. Smith also urged the FDA to require a registry that records ARIA-related problems if it approves lecanemab.

Eisai’s spokesperson said that if lecanemab is approved, the company will work with the FDA to ensure that doctors and patients “understand how to monitor the patient for side effects, such as ARIA,” adding that “for many patients, the benefits will outweigh the risks . “

This story was sponsored by Science Investigative Reporting Fund.

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