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

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 has obtained medical records showing that a 79-year-old Florida woman participating in an ongoing antibody trial died in mid-September after experiencing extensive brain swelling and bleeding, as well as seizures. More neuroscientists who reviewed the records at ScienceHer death is believed to have probably been caused by the antibody, lekanemab.

“Brain swelling and microbleeds … could be serious side effects 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 at a major Alzheimer’s meeting last month, where it detailed data from a phase 3 trial of lekanemab. The death occurred in an extension of that trial, but some scientists say it should have been recorded at the conference anyway. “The failure of Eisai i [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 neuroscientist Matthew Schrag, who also reviewed the woman’s records.

The newly discovered death comes on top of other reports of serious bleeding and swelling of the brain in the pivotal clinical trial and two other deaths in the extension phase — First he reported STAT and other per Science—which some scientists have linked to lekanemab.

Eisai, which has attributed previous deaths and brain injuries to factors unrelated to lekenamab, 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 evaluation of the study,” a company spokesperson said in a written statement to Science. “This information has been submitted to the FDA [Food and Drug Administration] and other regulatory bodies”, as well as independent study review committees.

The spokesman added that the age and health status 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 pivotal clinical trial, which involved about 1,800 people. The deaths were expected given the age and health of the study population, and the company says the numbers were similar in the lekanemab and placebo groups. But it did not publicly release details of each death, so in most cases scientists could not independently assess whether lekanemab contributed to the deaths.

Lekanemab is one of several experimental Alzheimer’s drugs that target beta amyloid, a 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, even though 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 illustrates,” says Boston University neurologist and neuroscientist Andreas Charidimou, who reviewed the woman’s records for Science. “It’s a real clinical syndrome, which can be fatal.”

Although lekanemab targets the soluble version of beta amyloid, it also binds to extracellular beta amyloid “plaques,” which are 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 such as lekanemab remove these plaques, blood vessels can become inflamed and weakened, making a person more susceptible to ARIA.

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

It is not clear whether the woman received the antibody infusion or a placebo during the original 18-month trial. Ali received the drug for 6 weeks in the extension phase—in which each participant can opt for treatment. Before the trial extension began, a brain scan revealed signs of several microbleeds, but they were not serious enough to exclude her from the trial.

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

A textbook case

The woman’s friend described a harrowing sequence of events that began with the patient’s first infusion of antibodies in an extension 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 a friend. A few weeks later, after the second infusion, the woman complained of severe headaches, “couldn’t finish her sentences” and felt increasingly confused about everyday things, her friend recalled.

In a restaurant on September 14, a 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 an experimental drug. Seizures began, causing her to thrash her arms and legs, requiring restraints for her safety.

A brain scan showed dozens of areas of bleeding and brain swelling so extensive that the characteristic cortical folds were “fused and crushed” in significant parts of her brain, Charidimou says. He calls it “a textbook case of severe ARIA, both clinical and imaging.” Given the absence of other potential causes of brain damage listed in the medical records, he adds, lekenemab was almost certainly the culprit.

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

“The patient had extensive brain swelling with some small areas of bleeding that caused the seizure and death,” says Schrag, a CAA specialist. “I’m convinced this was a side effect of lekenemab.”

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

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

Lack of consensus

Antibody-related deaths cast a pall over recent trial results that were generally considered promising. Eisai reported that lekanemab slowed the rate of cognitive decline in patients with early Alzheimer’s disease by an average of 27% over 18 months, a statistically significant effect. Neurologists differ on whether this benefit would be seen in many patients or caregivers, and some large subgroups in the trial, including women and people younger than 65, did not benefit to a statistically significant threshold.

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

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

The document describes lekanemab as a “fundamental game changer” for the disease and calls for its approval and “no barriers” to widespread availability of the antibody. It cites potential safety issues associated with ARIA, but fails to mention the deaths and serious brain injuries some have linked to the drug. The FDA is expected to decide by Jan. 6, 2023, whether to approve lekanemab and whether to require any warnings or precautions for doctors who prescribe it.

Smith, who did not sign the prolecanemab letter, acknowledges that people with early Alzheimer’s disease may consider the possibility of even very modest cognitive benefits worth the risk of debilitating cases of ARIA or even death. But he believes any FDA approval should come with caveats.

An Alzheimer’s patient receiving lekanemab would need as many as five MRIs a year to properly monitor ARIA, he says, and an extensive education program would be needed to ensure that doctors outside of major medical centers can recognize problems detected in brain scans. . Smith also urges the FDA to require a registry that records ARIA-related problems if it approves lekanemab.

Eisai’s spokesperson said that if lekanemab 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 risks”. “

They supported this story Science Fund for Investigative Journalism.