Scientists Link Third Death in Clinical Trial to Experimental Alzheimer’s Drug | Sciences

As excitement grows over a new experimental antibody that appears to slow cognitive decline in some Alzheimer’s patients, a third drug-related death during its clinical trial may raise concerns about its safety. Sciences has obtained medical records showing that a 79-year-old Florida woman participating in an ongoing trial of the antibody died in mid-September after experiencing extensive brain swelling and bleeding, as well as seizures. Multiple neuroscientists who reviewed the records in SciencesThe application believes his death was likely caused by the antibody, lecanemab.

“Swelling of the brain and microbleeds … could be a serious side effect of the study drug,” and should be evaluated by trial investigators, says Ellis van Etten, a neuroscientist and neurologist at Leiden University.

The clinical trial’s sponsor, Japanese biotech Eisai Co., did not disclose the death at a major Alzheimer’s meeting last month, where it detailed data from the phase 3 trial of lecanemab. The death came in an extension of that essay, but some scientists say it still should have been noted at the conference. “Eisai’s failure and [lecanemab codeveloper] For Biogen to disclose this case … is concerning and undermines my confidence that the reported safety data is complete,” says Vanderbilt University neurologist and neuroscientist Matthew Schrag, who also reviewed the woman’s records.

The newly disclosed death joins other reports of severe brain haemorrhage and inflammation in the core clinical trial and two other deaths in the extension phase: the First reported by CONDITION and the second for Sciences— that some scientists have linked to lecanemab.

Eisai, who has attributed the earlier deaths and brain injuries to factors unrelated to lecanemab, declined to comment on the death of the Florida woman, citing concerns about patient privacy. “All serious events, including deaths, are reported to Eisai and considered in our evaluation of the study,” a company spokesperson said in a written statement to Eisai. Sciences. This information is provided to the FDA [Food and Drug Administration] and other regulatory authorities,” as well as independent review boards for the study.

The spokesperson added that the age and medical condition of trial participants must be taken into account when assessing a death. The Florida woman, however, had no obvious health problems other than signs of early Alzheimer’s disease, according to her medical records.

Eisai has reported 13 deaths in the main clinical trial, which involved about 1,800 people. Deaths are expected given the age and health of the study population, and the company says the numbers were similar in the lecanemab and placebo groups. But it hasn’t made details of each death public, so in most cases scientists haven’t been able to independently assess whether lecanemab contributed to the deaths.

Lecanemab is one of several experimental Alzheimer’s drugs that target amyloid beta, the protein that accumulates in the brains of people with the disease. Many in the field believe it is responsible for the death of brain cells that steals people’s memories and ultimately 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-related imaging abnormalities (ARIA) because it is diagnosed through brain imaging. “We need a name change…because these are not just imaging abnormalities, as this case illustrates,” says Boston University neurologist and neuroscientist Andreas Charidimou, who sifted through the woman’s records for evidence. Sciences. “It’s a real clinical syndrome, which can be fatal.”

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

In the two previous lecanemab-related deaths, neurologists say the patients’ use of blood thinners worsened inflammation and bleeding in the brain. The Florida woman was given a minimal course of the blood thinner heparin after being hospitalized, but several neurologists ruled it out as a contributing factor to her sudden problems and ultimately her death.

It is not clear whether the woman received infusions of the antibody or a placebo during the 18-month core trial. She received the drug for 6 weeks in the extension phase, in which any participant can opt for the treatment. Before the extension trial began, a brain scan revealed signs of some microbleeds, but these were not severe enough to rule her out of the trial.

One of the daughters of the Florida woman turned over the medical documents to Sciences and authorized its review by others. To protect the privacy of the family, Sciences is withholding the names of the patient, the daughter, a friend who helped the woman during the study, and the clinical trial site where the patient received lecanemab.

A textbook case

The woman’s friend described a series of harrowing events that began with the patient’s first infusion of the antibody as part of the extension trial, in August. “She was so tired. She… didn’t get out of bed for 2 days other than to eat yogurt or go to the bathroom,” says the friend. A couple of weeks later, after the second infusion, the woman complained of severe headaches, “she couldn’t complete sentences” and she became increasingly confused with everyday affairs, her friend recalls.

At a restaurant on September 14, the woman experienced what appeared to be 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 flail her arms and legs, requiring restraints for her safety.

brain scans with arrows pointing to microbleeds
Before a Florida woman received lecanemab in an extension phase of a clinical trial, an MRI of her brain (left) showed some microbleeds: small bleeds (dark spots, examples marked with arrows). Afterwards (right), dozens of microbleeds became evident (examples marked with arrows).Provided anonymously to Sciences

Brain scans showed dozens of areas of brain bleeding and inflammation so extensive that the characteristic folds of the cerebral cortex were “fused and squashed” into substantial parts of his brain, Charidimou says. He calls it “a textbook case of severe ARIA, both the clinical presentation and the imaging manifestations.” Given the absence of other possible causes of brain damage indicated in the medical records, he adds, lecanemab was almost certainly to blame.

Hospital records show that the clinical trial site investigator, contacted after the woman was hospitalized, suspected ARIA and urged steroid treatment, which doctors tried without significant benefit. She began to suffer from multiple organ failure and pneumonia, dying 5 days after being admitted.

“The patient had a lot of swelling in her brain with some small areas of bleeding that led to a seizure and ultimately death,” says Schrag, an AAC specialist. “I’m sure this was a side effect of lecanemab.”

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

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

lack of consensus

The antibody-related deaths cast a shadow over recent trial results that are largely considered hopeful. Eisai has reported that lecanemab reduced 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 that benefit would be noticeable to many patients or caregivers, and some large subgroups in the trial, including women and people younger than 65, did not benefit up to a statistically significant threshold.

Still, the trial represented the most favorable results for any anti-amyloid therapy to date and has prompted calls from some scientists and Alzheimer’s patient groups for the FDA to quickly give the drug a green light.

Earlier this month, a lecanemab “consensus statement”, whose initial signatories worked as consultants to Eisai or Biogen or conducted research for the recent lecanemab trial, began circulating online. Nearly half of the more than 200 scientists or physicians who had signed the declaration as of December 20 are recent consultants or beneficiaries of one or both companies, Sciences has determined. (Some, but not all, disclosed a conflict of interest.)

The document describes lecanemab as a “critical game changer” for the disease and calls for its approval and “no barriers” to the widespread availability of the antibody. It points out potential safety concerns associated with ARIA, but fails to mention the deaths and serious brain injuries that some have linked to the drug. The FDA is expected to decide on the approval of lecanemab and whether it requires warnings or precautions for prescribers by January 6, 2023.

Smith, who has not signed the pro-lecanemab letter, acknowledges that people with early Alzheimer’s might find the possibility of even very modest cognitive benefits worth the risk of debilitating cases of ARIA or even fatal outcomes. But he thinks that any FDA approval should come with caveats.

An Alzheimer’s patient receiving lecanemab would require up to five MRIs a year to adequately monitor ARIA, he says, and an extensive education program would be needed to ensure that doctors outside major medical centers can recognize problems found in brain scans. . Smith is also asking the FDA to require a registry recording ARIA-related problems if it approves lecanemab.

The Eisai spokesperson said that if lecanemab is approved, the company would 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 supported by the Sciences Fund for Investigative Reports.

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