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Alzheimer’s drug lecanemab slows cognitive decline but concerns linger

Alzheimer's may be caused by the accumulation of protein plaques and tangles in the brain

Alzheimer’s disease may be caused by the accumulation of protein plaques and tangles in the brain

Andrew Brookes

A drug called lecanemab is the first treatment that has been shown to slow cognitive decline in people with early Alzheimer’s disease. It also decreases plaques and tangles in the brain that are thought to drive the condition’s progression.

While it may sound promising, some question whether these effects are substantial enough to have a meaningful impact on Alzheimer’s symptoms.

Potential concerns have also been raised about the drug’s safety. During an 18-month study made up of almost 1800 people with early Alzheimer’s disease, 0.7 per cent of those who received lecanemab died, compared with 0.8 per cent of those having placebo infusions.

In a statement released on 30 November, the Japan-based pharmaceutical firm Eisai, which developed lecanemab, said that none of these deaths were related to the drug. In October, however, STAT had reported that lecanemab may have contributed to one participant’s death. On 27 November, Science reported that a second participant died from a massive brain haemorrhage that some researchers linked to lecanemab.

Eisai told Science that, whilst it could not comment on individual cases due to privacy concerns, “All the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause”.

Nevertheless, the reports have prompted some to ask whether lecanemab’s benefits outweigh its potential risks, a question raised by New Scientist when Eisai released preliminary results in late September.

Lecanemab binds to and removes clumps of protein in the brain known as amyloid plaques. For decades, researchers have believed these plaques are a key cause of Alzheimer’s disease, yet many treatments that target them haven’t shown benefits in trials, including the controversial drug aducanumab.

In a phase III trial, people aged 50 to 90 with early Alzheimer’s disease received intravenous infusions of either lecanemab or a placebo once every two weeks for 18 months. All the participants had evidence of amyloid accumulations in their brain.

Christopher van Dyck at Yale School of Medicine and his colleagues measured the participants’ cognitive function before the trial and then every three months up to month 18. This was assessed via interviews with the participants and their caregivers. The participants also completed questionnaires that gauged their quality of life before, during and after the study.

By the end of the trial, both groups showed signs of cognitive decline. However, this was 27 per cent slower in the lecanemab group, on average, compared with the control group. Though this may seem substantial, the effect is quite small – a 0.45-point difference on a scale of 0 to 18.

“Most Alzheimer’s experts feel that slowing this very bad disease by 20 to 30 per cent is meaningful to patients,” said researcher Sharon Cohen, at the Toronto Memory Program in Canada, during a press conference held by Eisai in late November.

Lecanemab also appears to have a cumulative effect, said Cohen. Statistical modelling suggests that about two years of treatment could delay the progression of Alzheimer’s disease by up to three years.

When it came to quality of life, the control group reported about a 50 per cent greater reduction, on average, from the start to the end of the study, compared with the lecanemab group, according to results presented at the 2022 Clinical Trials on Alzheimer’s Disease conference in San Francisco, California.

A subset of about 400 participants also underwent brain scans to assess any changes to their amyloid plaques. Those treated with lecanemab had about a 70 per cent lower amyloid score, on average, from the start to the end of the trial. In comparison, the control group saw their scores increase by almost 5 per cent, on average.

The lecanemab group also had substantial decreases to the number of misfolded proteins in the brain called tau tangles. These proteins increased in the control group. “Tau is the abnormal protein in Alzheimer’s disease that has the best correlation with clinical decline,” says Lea Grinberg at the University of California, San Francisco.

Overall, these results may sound promising, however, lecanemab has safety concerns.

More than 17 per cent of people in the lecanemab group had some degree of bleeding in the brain, compared with 9 per cent in the placebo group. In addition, almost 13 per cent of those given the drug experienced brain swelling and inflammation, compared with less than 2 per cent of those having placebo infusions.

“Some people say the effect of this drug is so small, that maybe it’s not worth it, especially in people at high risk [of complications],” says Grinberg.

In its 30 November press release, Eisai said: “The convergence of evidence across cognition and function, disease progression, health related quality of life, and caregiver burden demonstrate that lecanemab treatment may provide meaningful benefits to patients, their care partners, physicians and society.”

Journal reference: The New England Journal of Medicine, DOI: 10.1056/NEJMoa2212948

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