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"Momentous" Breakthrough as Alzheimer’s Drug Modestly Slows Cognitive Decline

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A new monoclonal antibody treatment can slow cognitive decline in people with early-stage Alzheimer’s disease, a study shows. The Eisai-developed drug, lecanemab, produced a small but robust effect. The clinical significance of the finding remains up for debate, and the presence of some side effects may reduce the drug’s long-term use. Nevertheless, lecanemab is the first anti-amyloid antibody to show convincing effects in Alzheimer’s disease and the first new treatment for the most common form of dementia in nearly two decades, barring the disputed results of the Biogen compound aducanumab in 2021.

Amyloid: At the root of Alzheimer’s?

Amyloid-beta is a common brain protein that has been the primary researcher target of the Alzheimer’s field for nearly three decades, since research in the early 1990s suggested that “plaques” formed by amyloid were responsible for driving the disease processes.

Numerous multi-billion-dollar clinical trials into therapies targeting amyloid have followed, with virtually all failing to show clinical efficacy. The field hoped that this losing streak had ended last year, with the release of data on the antibody treatment aducanumab. However, the results from two trials testing the compound were contradictory, and while the drug was controversially approved by the US Food and Drug Administration (FDA), it has failed to gain approval in Europe and many US-based insurers have refused to offer coverage for the drug.

Now, with lecanemab, a clinical trial team funded by drug giant Eisai hope they can score the first big win against Alzheimer’s in 20 years, since the approval of memantine in 2003.

After releasing headline results from their trial –  named CLARITY – of 1795 patients earlier this year, Eisai have now published the full trial data in the New England Journal of Medicine. These findings tell a story of a drug that has far more robust efficacy than aducanumab, but which shares that compound’s small effect sizes.

Cognitive findings

The primary outcome of the trial was the measurement of cognitive decline among volunteers given either lecanemab (n=898) or placebo (n=897). The trial participants all had either mild dementia due to Alzheimer’s disease or mild cognitive impairment, a cognitive presentation that is considered a precursor step to dementia. The volunteers, all aged between 50 and 90, were dosed over 18 months with intravenous lecanemab every 2 weeks. As a headline result, the researchers measured how the participants’ cognitive performance declined using the Clinical Dementia Rating–Sum of Boxes (CDR-SB), an 18-point scale where higher scores indicate greater impairment. Patients given placebo saw their scores increase by an average of 1.66 points over the 18-month trial period, while those given lecanemab saw just a 1.21-point increase. During their topline results presentation, Eisai pointed out that this represents a 27% slowing in cognitive decline, but the clinical benefit of a 0.45-point difference in an 18-point scale has been questioned.

The secondary endpoints of the trial supported the CDR-SB findings. In a subset of the patients (n= 698), slower decline on a range of other cognitive measurements was seen, including the Alzheimer’s Disease Assessment Scale (ADAS-cog14), the Alzheimer’s Disease Composite Score (ADCOMS) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCSMCI- ADL). Using positive emission tomography (PET) imaging, the team showed that these cognitive signs were accompanied by reductions in the amount of amyloid present in participants’ brains.

Side effect concern

The treatment, nevertheless, came with some side effects. The study mentions that “infusion-related reactions” occurred in 26.4% of patients, and a condition called amyloid-related imaging abnormalities (ARIA), characterized by swelling or microhemorrhages in the brain that are often only detectable via brain imaging, occurred in 12.6% of patients. More pressing was the report, published by Science prior to the release of the full trial results, of the death of a CLARITY participant who was rushed to hospital after suffering a stroke. Upon being given routine blood thinners to treat the stroke, the patient suffered a massive brain hemorrhage and died shortly after. The case study authors have speculated that the cause of death was related to the weakening of blood vessels during lecanemab treatment, a finding that may disqualify people taking such blood thinning medication from being prescribed the drug – should it be approved.

Excitement and caution

The findings were met with excitement by leading Alzheimer’s research charities. Dr. Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “These exciting findings represent a major step forward for dementia research and could herald a new era for people with Alzheimer’s disease. This is the first time a drug has been shown to both reduce the disease in the brain and slow memory decline in clinical trials.”

The reaction from researchers was more mixed. Prof. Sir John Hardy, a group leader at the UK Dementia Research Institute at University College London (UCL), who is credited with being a pioneer of the amyloid theory of Alzheimer’s disease, called the trial “very impressive”.

“There is a long way to go for approval and the use of these drugs in standard clinical practice… but undoubtedly this is the first stage,” he added.

Prof. Rob Howard, a professor of old age psychiatry at UCL, said, “My heart says that this is wonderful and hope-filled news for the field… it feels momentous and historic.”

Howard added, “I have a head too. This is concerned about three aspects of today’s data.” He highlighted the potential for unblinding as a result of lecanemab’s side effects, the small magnitude of the effect size involved and the risk of serious side effects like stroke as being reasons for caution.

“I suspect that the lack of demonstrable clinical effectiveness will mean that lecanemab will not be taken up widely within healthcare systems around the world, although there will always be those whose heart rules their head. We need to keep looking for better and safer dementia treatments and today’s results show that we are now on a believable path to doing so,” Howard concluded.

Reference: van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. NEJM. 2022. doi:10.1056/NEJMoa2212948.