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Scientists tie third clinical trial death to experimental Alzheimer’s drug

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As enthusiasm mounts 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 amplify concerns about its safety. Science has obtained medical records showing 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 at Science’s request believe her death was likely caused by the antibody, lecanemab.

“The brain swelling and the microhemorrhages … could be a serious side effect of the study medication,” 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 divulge the fatality at a major Alzheimer’s meeting last month where it detailed data from lecanemab’s phase 3 trial. The death came in an extension of that trial, but some scientists say it should have still been noted at the conference. “The failure of Eisai and [lecanemab codeveloper] 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 revealed death comes on top on other reports of serious brain bleeding and swelling in the core clinical trial and two other deaths in the extension phase—the first reported by STAT and the second by Science—that some scientists have linked to lecanemab.

Eisai, which attributed the prior fatalities 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 fatalities, are reported to Eisai and considered in our evaluation of the study,” a company spokesperson said in a written statement to Science. “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 any trial participants should be considered when evaluating a death. The Florida woman, however, had no obvious health problems, other than her signs of early Alzheimer’s disease, according to her medical records.

Eisai has reported 13 deaths in the core clinical trial, which involved about 1800 people. Deaths are expected given the study population’s age and health, and the company says the numbers were similar in the groups receiving lecanemab and the placebo. But it has not made public the details of each death, so in most cases scientists have been unable to independently assess whether lecanemab contributed to the fatalities.

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 memories and ultimately kills them, although deposits of the protein are also found in 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 examined the woman’s records for Science. “It’s a real clinical syndrome, which 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. 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 lecanemab strip away those plaques, blood vessels can become inflamed and weakened, increasing a person’s susceptibility to ARIA.

In the two previous deaths tied to lecanemab, neurologists say the patients’ use of anticoagulants worsened brain swelling and bleeding. The Florida woman was given a minimal course of the anticoagulant heparin after being hospitalized, but several neurologists discounted it as a contributing factor to her sudden problems and ultimate death.

Whether the woman received infusions of the antibody or a placebo during the core 18-month trial is unclear. But she did get the drug over 6 weeks in the extension phase—in which any participant can opt for treatment. Before the extension trial started, a brain scan revealed signs of a few microhemorrhages, but they were not serious enough to rule her out of the trial.

One of the Florida woman’s daughters provided the medical documents to Science and authorized their review by others. To protect the family’s privacy, Science is withholding the names of the patient, the daughter, a friend who served as the woman’s helper 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 extension trial, in August. “She was so tired. She … didn’t get out of bed for 2 days other than to maybe eat a yogurt or go to the bathroom,” the friend says. A couple of weeks later, after the second infusion, the woman complained of severe headaches, “couldn’t complete sentences,” and increasingly felt confused about everyday matters, her friend recalls.

At a restaurant on 14 September, the woman experienced what seemed like a stroke. She was rushed to the hospital, where her friend informed 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 extension phase of a clinical trial, an MRI scan of her brain (left) had a few microhemorrhages—tiny bleeds (dark spots, examples marked by arrows). Afterward (right), dozens of microhemorrhages were obvious (examples marked by arrows).Provided anonymously to Science

Brain scans showed dozens of areas of bleeding and brain swelling so extensive that the characteristic folds of the cerebral cortex were “merged and squashed” in substantial parts of her 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 potential causes for brain damage indicated in the medical records, he adds, lecanemab almost certainly was the culprit.

The hospital records show the clinical trial site investigator, contacted after the woman was hospitalized, suspected ARIA and urged treatment with steroids—which the physicians tried without significant benefit. She began to suffer from multiorgan failure and pneumonia, and died 5 days after being admitted.

“The patient had extensive swelling of her brain with some small areas of bleeding which caused her to have a seizure and ultimately to die,” says Schrag, who is a CAA specialist. “I am confident this was a side effect from lecanemab.”

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

The family has arranged for an autopsy, which could confirm that the woman had CAA and clarify the antibody’s role 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 for trial participants.

A lack of consensus

The deaths linked to the antibody cast a pall over recent trial results largely seen as hopeful. Eisai has 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 that benefit would be noticeable to many patients or caregivers, and some large subgroups in the trial, including women and people under age 65, did not benefit to a statistically significant threshold.

Still, the trial represented the most favorable results for any antiamyloid therapy so far and has prompted calls from some Alzheimer’s scientists and patient groups for FDA to quickly green-light the drug.

Earlier this month, a lecanemab “consensus statement”—whose initial signers have worked as consultants to Eisai or Biogen or have conducted research for the recent lecanemab trial—began to circulate online. Nearly half of the more than 200 scientists or medical practitioners who had signed the statement as of 20 December are recent consultants or grantees of one or both companies, Science has determined. (Some but not all disclosed a conflict of interest.)

The document describes lecanemab as a “foundational gamechanger” for the illness and calls for its approval and “no barrier” to widespread availability of the antibody. It notes possible safety concerns associated with ARIA but does not mention the deaths and serious brain injuries some have linked to the drug. FDA is expected to decide on lecanemab’s approval, and whether to require any warnings or cautions for prescribers, by 6 January 2023.

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

An Alzheimer’s patient receiving lecanemab would require as many as five MRIs annually to properly monitor for ARIA, he says, and a vast education program would be needed to ensure that doctors outside of major medical centers can recognize problems found in the brain scans. Smith also calls for 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 would work with 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 Science Fund for Investigative Reporting.

Update, 22 December, 11:55 a.m.: In a revised statement provided to Science after the publication of this story, Eisai says it did not disclose the death at the November Alzheimer’s conference “because the information provided to Eisai to date does not indicate that ARIA occurred or that it was suspected to be linked to the death,” and because it has not finished analyzing data from the extension trial.

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Health Canada approves updated Moderna COVID-19 vaccine

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TORONTO – Health Canada has authorized Moderna’s updated COVID-19 vaccine that protects against currently circulating variants of the virus.

The mRNA vaccine, called Spikevax, has been reformulated to target the KP.2 subvariant of Omicron.

It will replace the previous version of the vaccine that was released a year ago, which targeted the XBB.1.5 subvariant of Omicron.

Health Canada recently asked provinces and territories to get rid of their older COVID-19 vaccines to ensure the most current vaccine will be used during this fall’s respiratory virus season.

Health Canada is also reviewing two other updated COVID-19 vaccines but has not yet authorized them.

They are Pfizer’s Comirnaty, which is also an mRNA vaccine, as well as Novavax’s protein-based vaccine.

This report by The Canadian Press was first published Sept. 17, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

The Canadian Press. All rights reserved.

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These people say they got listeria after drinking recalled plant-based milks

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TORONTO – Sanniah Jabeen holds a sonogram of the unborn baby she lost after contracting listeria last December. Beneath, it says “love at first sight.”

Jabeen says she believes she and her baby were poisoned by a listeria outbreak linked to some plant-based milks and wants answers. An investigation continues into the recall declared July 8 of several Silk and Great Value plant-based beverages.

“I don’t even have the words. I’m still processing that,” Jabeen says of her loss. She was 18 weeks pregnant when she went into preterm labour.

The first infection linked to the recall was traced back to August 2023. One year later on Aug. 12, 2024, the Public Health Agency of Canada said three people had died and 20 were infected.

The number of cases is likely much higher, says Lawrence Goodridge, Canada Research Chair in foodborne pathogen dynamics at the University of Guelph: “For every person known, generally speaking, there’s typically 20 to 25 or maybe 30 people that are unknown.”

The case count has remained unchanged over the last month, but the Public Health Agency of Canada says it won’t declare the outbreak over until early October because of listeria’s 70-day incubation period and the reporting delays that accompany it.

Danone Canada’s head of communications said in an email Wednesday that the company is still investigating the “root cause” of the outbreak, which has been linked to a production line at a Pickering, Ont., packaging facility.

Pregnant people, adults over 60, and those with weakened immune systems are most at risk of becoming sick with severe listeriosis. If the infection spreads to an unborn baby, Health Canada says it can cause miscarriage, stillbirth, premature birth or life-threatening illness in a newborn.

The Canadian Press spoke to 10 people, from the parents of a toddler to an 89-year-old senior, who say they became sick with listeria after drinking from cartons of plant-based milk stamped with the recalled product code. Here’s a look at some of their experiences.

Sanniah Jabeen, 32, Toronto

Jabeen says she regularly drank Silk oat and almond milk in smoothies while pregnant, and began vomiting seven times a day and shivering at night in December 2023. She had “the worst headache of (her) life” when she went to the emergency room on Dec. 15.

“I just wasn’t functioning like a normal human being,” Jabeen says.

Told she was dehydrated, Jabeen was given fluids and a blood test and sent home. Four days later, she returned to hospital.

“They told me that since you’re 18 weeks, there’s nothing you can do to save your baby,” says Jabeen, who moved to Toronto from Pakistan five years ago.

Jabeen later learned she had listeriosis and an autopsy revealed her baby was infected, too.

“It broke my heart to read that report because I was just imagining my baby drinking poisoned amniotic fluid inside of me. The womb is a place where your baby is supposed to be the safest,” Jabeen said.

Jabeen’s case is likely not included in PHAC’s count. Jabeen says she was called by Health Canada and asked what dairy and fresh produce she ate – foods more commonly associated with listeria – but not asked about plant-based beverages.

She’s pregnant again, and is due in several months. At first, she was scared to eat, not knowing what caused the infection during her last pregnancy.

“Ever since I learned about the almond, oat milk situation, I’ve been feeling a bit better knowing that it wasn’t something that I did. It was something else that caused it. It wasn’t my fault,” Jabeen said.

She’s since joined a proposed class action lawsuit launched by LPC Avocates against the manufacturers and sellers of Silk and Great Value plant-based beverages. The lawsuit has not yet been certified by a judge.

Natalie Grant and her seven year-old daughter, Bowmanville, Ont.

Natalie Grant says she was in a hospital waiting room when she saw a television news report about the recall. She wondered if the dark chocolate almond milk her daughter drank daily was contaminated.

She had brought the girl to hospital because she was vomiting every half hour, constantly on the toilet with diarrhea, and had severe pain in her abdomen.

“I’m definitely thinking that this is a pretty solid chance that she’s got listeria at this point because I knew she had all the symptoms,” Grant says of seeing the news report.

Once her daughter could hold fluids, they went home and Grant cross-checked the recalled product code – 7825 – with the one on her carton. They matched.

“I called the emerg and I said I’m pretty confident she’s been exposed,” Grant said. She was told to return to the hospital if her daughter’s symptoms worsened. An hour and a half later, her fever spiked, the vomiting returned, her face flushed and her energy plummeted.

Grant says they were sent to a hospital in Ajax, Ont. and stayed two weeks while her daughter received antibiotics four times a day until she was discharged July 23.

“Knowing that my little one was just so affected and how it affected us as a family alone, there’s a bitterness left behind,” Grant said. She’s also joined the proposed class action.

Thelma Feldman, 89, Toronto

Thelma Feldman says she regularly taught yoga to friends in her condo building before getting sickened by listeria on July 2. Now, she has a walker and her body aches. She has headaches and digestive problems.

“I’m kind of depressed,” she says.

“It’s caused me a lot of physical and emotional pain.”

Much of the early days of her illness are a blur. She knows she boarded an ambulance with profuse diarrhea on July 2 and spent five days at North York General Hospital. Afterwards, she remembers Health Canada officials entering her apartment and removing Silk almond milk from her fridge, and volunteers from a community organization giving her sponge baths.

“At my age, 89, I’m not a kid anymore and healing takes longer,” Feldman says.

“I don’t even feel like being with people. I just sit at home.”

Jasmine Jiles and three-year-old Max, Kahnawake Mohawk Territory, Que.

Jasmine Jiles says her three-year-old son Max came down with flu-like symptoms and cradled his ears in what she interpreted as a sign of pain, like the one pounding in her own head, around early July.

When Jiles heard about the recall soon after, she called Danone Canada, the plant-based milk manufacturer, to find out if their Silk coconut milk was in the contaminated batch. It was, she says.

“My son is very small, he’s very young, so I asked what we do in terms of overall monitoring and she said someone from the company would get in touch within 24 to 48 hours,” Jiles says from a First Nations reserve near Montreal.

“I never got a call back. I never got an email”

At home, her son’s fever broke after three days, but gas pains stuck with him, she says. It took a couple weeks for him to get back to normal.

“In hindsight, I should have taken him (to the hospital) but we just tried to see if we could nurse him at home because wait times are pretty extreme,” Jiles says, “and I don’t have child care at the moment.”

Joseph Desmond, 50, Sydney, N.S.

Joseph Desmond says he suffered a seizure and fell off his sofa on July 9. He went to the emergency room, where they ran an electroencephalogram (EEG) test, and then returned home. Within hours, he had a second seizure and went back to hospital.

His third seizure happened the next morning while walking to the nurse’s station.

In severe cases of listeriosis, bacteria can spread to the central nervous system and cause seizures, according to Health Canada.

“The last two months have really been a nightmare,” says Desmond, who has joined the proposed lawsuit.

When he returned home from the hospital, his daughter took a carton of Silk dark chocolate almond milk out of the fridge and asked if he had heard about the recall. By that point, Desmond says he was on his second two-litre carton after finishing the first in June.

“It was pretty scary. Terrifying. I honestly thought I was going to die.”

Cheryl McCombe, 63, Haliburton, Ont.

The morning after suffering a second episode of vomiting, feverish sweats and diarrhea in the middle of the night in early July, Cheryl McCombe scrolled through the news on her phone and came across the recall.

A few years earlier, McCombe says she started drinking plant-based milks because it seemed like a healthier choice to splash in her morning coffee. On June 30, she bought two cartons of Silk cashew almond milk.

“It was on the (recall) list. I thought, ‘Oh my God, I got listeria,’” McCombe says. She called her doctor’s office and visited an urgent care clinic hoping to get tested and confirm her suspicion, but she says, “I was basically shut down at the door.”

Public Health Ontario does not recommend listeria testing for infected individuals with mild symptoms unless they are at risk of developing severe illness, such as people who are immunocompromised, elderly, pregnant or newborn.

“No wonder they couldn’t connect the dots,” she adds, referencing that it took close to a year for public health officials to find the source of the outbreak.

“I am a woman in my 60s and sometimes these signs are of, you know, when you’re vomiting and things like that, it can be a sign in women of a bigger issue,” McCombe says. She was seeking confirmation that wasn’t the case.

Disappointed, with her stomach still feeling off, she says she decided to boost her gut health with probiotics. After a couple weeks she started to feel like herself.

But since then, McCombe says, “I’m back on Kawartha Dairy cream in my coffee.”

This report by The Canadian Press was first published Sept. 16, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

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B.C. mayors seek ‘immediate action’ from federal government on mental health crisis

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VANCOUVER – Mayors and other leaders from several British Columbia communities say the provincial and federal governments need to take “immediate action” to tackle mental health and public safety issues that have reached crisis levels.

Vancouver Mayor Ken Sim says it’s become “abundantly clear” that mental health and addiction issues and public safety have caused crises that are “gripping” Vancouver, and he and other politicians, First Nations leaders and law enforcement officials are pleading for federal and provincial help.

In a letter to Prime Minister Justin Trudeau and Premier David Eby, mayors say there are “three critical fronts” that require action including “mandatory care” for people with severe mental health and addiction issues.

The letter says senior governments also need to bring in “meaningful bail reform” for repeat offenders, and the federal government must improve policing at Metro Vancouver ports to stop illicit drugs from coming in and stolen vehicles from being exported.

Sim says the “current system” has failed British Columbians, and the number of people dealing with severe mental health and addiction issues due to lack of proper care has “reached a critical point.”

Vancouver Police Chief Adam Palmer says repeat violent offenders are too often released on bail due to a “revolving door of justice,” and a new approach is needed to deal with mentally ill people who “pose a serious and immediate danger to themselves and others.”

This report by The Canadian Press was first published Sept. 16, 2024

The Canadian Press. All rights reserved.

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