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Scientists hail Alzheimer’s breakthrough despite two trial candidates’ deaths

While the eagerly-awaited findings of a trial involving nearly 1 800 people was widely celebrated as a major breakthrough in the treatment of Alzheimer's, some scientists warned that the results should be cautiously welcomed following news that two of the trial participants had died.

The results of the trial involving people aged between 50 and 90 were unveiled on Tuesday in San Francisco and in The New England Journal of Medicine, feeding hopes that this could be the ultimate cure for the condition that affects millions of people worldwide.

And in another promising development on Alzheimer's research, Chinese scientists have identified urine biomarkers which could lead to early diagnosis of the disease, notes Medical Brief.

“This is the first drug that provides a real treatment option for Alzheimer’s patients,” Bart De Strooper, director of University College London’s (UCL) UK Dementia Research Institute said of the trial involving lecanamab.

“While the clinical benefits appear somewhat limited, it can be expected that they will become more apparent over time.”

Scientists found that lecanamab, when delivered as an intravenous drip every fortnight, slowed memory decline by 27% over 18 months. While the disease still progressed in those taking the drug and those given a placebo, it did so significantly more slowly among the 50% of participants given lecanemab.

The severity of their dementia was assessed using a clinical scale which measured symptoms such as forgetfulness, problem-solving skills and their ability to live independently, reports The Independent.

Scientists also used blood tests and brain scans to search for levels of amyloid among the participants, discovering that they had fallen so significantly in those given lecanemab that some patients no longer technically met the threshold for an Alzheimer’s diagnosis.

Some scientists suggested it was possible that lecanemab could raise the risk of bleeding, and cautioned against the use of blood thinners with the drug, and in fact, the manufacturers’ triumph was somewhat eclipsed by the fact that a 65-year-old woman who had been receiving the experimental treatment had died from a massive brain haemorrhage, linked by some researchers to the drug.

The clinical trials death, described in an unpublished case report obtained by the journal Science, is the second thought to be associated with lecanemab. The newly disclosed fatality intensifies questions about its safety and how widely lecanemab should be prescribed if ultimately approved by regulators.

The woman, who received infusions of the antibody as part of the trial, suffered a stroke and swelling and bleeding previously seen with such antibodies, which bind to and remove forms of amyloid-beta, a protein widely theorised to cause Alzheimer’s.

After the stroke was diagnosed at Northwestern University Medical Centre in Chicago, she was given a common intervention, the powerful blood-clot busting medication tissue plasminogen activator (tPA).

Science reports that substantial bleeding throughout her brain’s outer layer immediately followed, and she died a few days later.

Rudolph Castellani, a neuropathologist who studies Alzheimer’s and conducted an autopsy at the request of the patient’s husband, called the case “very dramatic.” The report, co-authored by Castellani, concluded that the woman, like the other person whose death was linked to lecanemab, had amyloid deposits surrounding many of her brain’s blood vessels.

This pre-existing condition, found in both Alzheimer’s patients and to a lesser degree in the general population, frequently goes undetected other than by autopsy. It probably contributed to her brain haemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels. The vessels apparently burst when exposed to tPA – known to cause brain bleeds even in some conventional stroke cases.

“It was a one-two punch,” Castellani says. “There’s zero doubt that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab she would be alive today.”

Castellani, his co-authors, and other researchers say the death suggests that tPA and perhaps other, less potent blood thinners pose safety considerations for Alzheimer’s patients receiving the anti-amyloid antibody drugs, including lecanemab.

The 30-page consent form for trial participants, obtained by Science, carries this warning about blood thinners: “You may continue with these medications, but you and the investigator should discuss the risk of bleeding since medications which prevent clots and (lecanemab)are both associated with a slight risk of bleeding in the brain.” It does not address tPA directly.

The woman’s husband says the events surrounding her death were fully disclosed to Great Lakes Clinical Trials, the Chicago-based contract research organisation that administered lecanemab to his wife as part of the antibody’s international, multicentre study.

Details of the case were shared by the medical team with Eisai, the Japanese company that originally developed lecanemab with the Swedish firm BioArctic and sponsored the trial with its US biotech partner Biogen.

Eisai declined to comment on the woman’s case, including whether it knew about the death. “All available safety information indicates lecanemab therapy is not associated with an increased risk of death overall or from any specific cause,” the company told Science.

It also declined to describe any other deaths in the trial.

At the official announcement this week, Eisai provided the first detailed account of the phase 3 trial, known as Clarity AD. Scientists have been eager to scrutinise the data to assess whether the modest benefits announced in September in a brief press release – that people on lecanemab had less amyloid in the brain and 27% less cognitive decline than participants who received a placebo over an 18-month period – hold up and outweigh any safety concerns.

Last month, MedicalBrief reported that lecanemab’s trial had sparked renewed optimism in a field that has had numerous false dawns. It also offered the manufacturer a second chance after its disastrous launch of Aduhelm (aducanumab), which despite scant evidence last year, won regulatory approval for Alzheimer’s and has since bombed commercially.

If approved, lecanemab would be the second antiamyloid drug to reach the clinic after aducanumab, although many Alzheimer’s researchers have questioned the evidence that aducanumab works and were surprised it received US Food and Drug Administration (FDA) approval.

Now some urge caution about its potential successor. “(Regulators) should take this case report seriously into account, because we're talking about significant side effects,” says Andreas Charidimou, a neuroscientist at Boston University who examined the report on the woman’s death for Science. “When there are so many unknowns it’s better to be more conservative.”

Lecanemab targets a soluble, “protofibril” version of amyloid-beta, and also binds – albeit more weakly – to the extracellular amyloid deposits known as plaques, a hallmark of Alzheimer’s disease. Other antibodies, including Aduhelm, bind to those plaques more strongly. Many physicians and Alzheimer’s experts already advise against combining Aduhelm and blood thinners.

STAT recently reported that a man in his late 80s in lecanemab’s phase 3 trial died of a brain haemorrhage linked to possible interaction between the experimental antibody and the blood thinner apixaban, sold under the name Eliquis.

Doctors commonly prescribe the drug for atrial fibrillation, and Eisai conceded in adverse event reports for the trial that its drug could have played a part in the fatal brain haemorrhage. But the company later called the death unrelated and the case remains under investigation.

The woman who died after receiving tPA for her stroke had remained physically active throughout the lecanemab trial. During the 18-month core trial, she might have received either the antibody or the placebo.

But there was no question she was given the antibody during the month before her death as part of an open-label trial extension, in which participants who want to take the experimental medication can do so.

Several physicians and researchers not involved in the trial or the woman’s care reviewed the case report at Science’s request and concurred with its findings that lecanemab probably contributed to her death. They said the woman probably received the placebo during the first part of the trial, because the inflammation seen in her blood vessels typically occurs within the first weeks of treatment with antiamyloid antibodies.

In its statement, Eisai said: “It can be difficult to determine what contributed to the death in any given patient, in particular when they are elderly, have multiple medical problems and may have recently received a concomitant treatment or intervention for an acute condition.”

As in other trials of antiamyloid antibodies, many of the people who received lecanemab in the phase 3 trial experienced amyloid-related imaging abnormalities (ARIA), a term for brain swelling and bleeding. ARIA occurred in more than 21% of those on the drug; 17% experienced brain bleeds, but none of the ARIA cases was life-threatening, according to the Eisai and Biogen press release.

Still, one reason to think lecanemab contributed to the woman’s death is that her autopsy revealed widespread cerebral amyloid angiopathy (CAA), a condition in which amyloid deposits gradually replace the smooth muscle of blood vessel walls.

Castellani, Nicoll, and others who reviewed her case suspect CAA made her blood vessels vulnerable to weakening when lecanemab did what it is expected to do: strip amyloids from the brain. The tPA treatment then probably ruptured those weakened vessels, leading to serious ARIA, and apparently fatal brain bleeding.

Nearly half of Alzheimer’s patients also have CAA, including the man whose death was previously linked to combining lecanemab and blood thinners. Eisai screened potential trial participants with tests often used to detect moderate or serious CAA.

For example, applicants had MRI brain scans and anyone whose scan showed more than four “microhaemorrhages” or other signs of possibly serious CAA were not allowed to enrol. But the condition can be hard to detect says Charidimou, who studies CAA. The two deaths show that even in the trial population, some patients with serious CAA slipped through.

Training physicians to interpret tests for CAA will be key to ensure vulnerable Alzheimer’s patients and their caregivers are properly informed and warned about the possible hazards of lecanemab, Charidimou says.

Meanwhile, on the other side of the world, Chinese scientists are elated after their research revealed that a molecule in urine might give indications of early-stage Alzheimer’s, the study suggesting this could pave the way for an inexpensive and convenient test for the disease.

The scientists say their study shows it might be possible that a simple urine test to analyse formic acid – a sensitive urinary biomarker – could reveal if someone has early-stage Alzheimer’s.

The Independent reports that the researchers tested 574 people who had Alzheimer’s of different levels of severity or healthy people, to identify differences in urinary biomarkers.

They found that urinary formic acid is a sensitive marker of subjective cognitive decline (self-reported experience of worsening or more frequent confusion or memory loss) that may indicate the very early stages of Alzheimer’s.

The study authors from Shanghai Jiao Tong University, and Institute of Biophysics, Chinese Academy of Sciences analysed people’s urine and blood samples and performed psychological evaluations, and found that urinary formic acid levels were significantly increased in all of the Alzheimer’s groups compared with the healthy people, including the early-stage cognitive decline group, and correlated with a cognitive decline.

This, they said, suggests formic acid could act as a sensitive biomarker for early-stage Alzheimer’s. When formic acid levels were analysed in combination with blood tests, the study found what stage of the disease the patient was experiencing could be more accurately predicted.

The study authors say further research is needed to understand the link between Alzheimer’s and formic acid. But writing in the Frontiers in Aging Neuroscience journal, they said: “Urinary formic acid showed an excellent sensitivity for early Alzheimer’s screening.

“The detection of urine biomarkers of Alzheimer’s is convenient and cost-effective, and should be performed during routine physical examinations of the elderly.”

Sian Gregory, research information manager at the UK’s Alzheimer’s Society, said: “This is an exciting discovery and has never been more important, with diagnosis rates for dementia at a five-year low.”

Study 1 details

Lecanemab in Early Alzheimer’s Disease

Christopher van Dyck, Chad Swanson, Paul Aisen, Randall Bateman, Christopher Chen, Michelle Gee, Michio Kanekiyo, David Li, Larisa Reyderman, Sharon Cohen, Lutz Froelich, Sadao Katayama, et al.

Published in The New England Journal of Medicine on 29 November 2022

Abstract

Background
The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanised IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.

Methods
We conducted an 18-month, multicentre, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

Results
A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

Conclusions
Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.

Study 2 details

Systematic evaluation of urinary formic acid as a new potential biomarker for Alzheimer’s disease

Yifan Wang, Ying Wang, Jinhang Zhu, Yihui Guan, Fang Xie, Xiao Cai, Jiale Deng, Yan Wei, Rongqiao He, Zhuo Fang and Qihao Guo.

Published in Frontiers in Ageing Neuroscience on 30 November 2022

Introduction
The accumulation of endogenous formaldehyde is considered a pathogenic factor in Alzheimer’s disease (AD). The purpose of this study was to investigate the relationship between urinary formic acid and plasma biomarkers in AD.

Materials and methods
Five hundred and seventy-four participants were divided into five groups according to their diagnosis: 71 with normal cognitive (NC), 101 with subjective cognitive decline (SCD), 131 with cognitive impairment without mild cognitive impairment (CINM), 158 with mild cognitive impairment (MCI), and 113 with AD.

Results
With the progression of the disease, urinary formic acid levels showed an overall upward trend. Urinary formic acid was significantly correlated with Mini-Mental State Examination (MMSE) scores, the Chinese version of Addenbrooke’s Cognitive Examination III (ACE-III) scores, and Montreal Cognitive Assessment-Basic (MoCA-B) time. The areas under the receiver operating characteristic curves (AUC) of urinary formic acid in distinguishing NC from AD was 0.797, which was similar to that of plasma neurofilament light chain (NfL; AUC = 0.768) and better than other plasma biomarkers (Aβ40, Aβ42, Aβ42/Aβ40, T-tau, P-tau181, and P-tau181/T-tau). We also found that using urinary formic acid and formaldehyde levels could improve the accuracy of using plasma biomarkers to determine AD disease stage.

Discussion
Our study revealed the possibility of urinary formic acid as a potential novel biomarker for the early diagnosis of AD.

 

NEJM article – Lecanemab in Early Alzheimer’s Disease (Open access)

 

Science article – Second death linked to potential antibody treatment for Alzheimer’s disease (Open access)

 

Frontiers in Ageing Neuroscience article – Systematic evaluation of urinary formic acid as a new potential biomarker for Alzheimer’s disease (Open access)

 

The Independent article – Molecule in urine ‘could be the first to reveal early-stage Alzheimer’s disease’ (Open access)

 

The Independent article – Scientists hail major breakthrough in fight against Alzheimer’s as drug proven to slow disease (Open access)

 

See more from MedicalBrief archives:

 

Alzheimer’s drug slows cognitive decline in trial – breakthrough or another false dawn?

 

Patient’s death in Alzheimer’s trial raises concern about risk

 

America’s Veteran Affairs shuns controversial Alzheimer’s drug, noting ‘known safety signal’

 

Hopes dashed as Roche’s potential Alzheimer’s drug fails trials

 

 

 

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