Author: Shreeya Nanda
“Longer trials are warranted to determine the efficacy and safety of lecanemab” in this setting, write Christopher van Dyck (Yale School of Medicine, New Haven, Connecticut, USA) and co-investigators in The New England Journal of Medicine.
They explain that lecanemab “binds with high affinity to soluble amyloid-beta (Aβ) protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils.”
The team adds that a prior phase 2 study “showed dose- and time-dependent clearance of amyloid with lecanemab” at 18 months “and the drug was associated with less clinical decline on some measures than placebo.”
van Dyck and colleagues therefore conducted the double-blind Clarity AD trial, which recruited 1795 individuals aged 50–90 years with mild cognitive impairment or mild dementia due to Alzheimer’s disease and randomly assigned them to receive lecanemab 10 mg/kg or placebo every 2 weeks for 18 months.
In the modified intention-to-treat (ITT) population comprising 1734 participants, the adjusted mean change in the Clinical Dementia Rating–Sum of Boxes (CDR–SB) score from baseline to 18 months was lower among those treated with lecanemab than placebo, at 1.21 and 1.66, respectively, a significant difference favouring the monoclonal antibody.
“Results for secondary clinical end points were in the same direction as those for the primary end point”, say the researchers.
For instance, in a substudy involving 698 individuals, amyloid levels on positron emission tomography decreased at the 18-month timepoint in the lecanemab group, but rose in the placebo group. The adjusted mean changes from baseline were −55.48 and 3.64 centiloids, respectively, with once again a significant between-group difference.
And in the modified ITT population, lecanemab-treated patients experienced a significantly lower decline on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale as well as on the Alzheimer’s Disease Composite Score relative to those given placebo, with adjusted mean changes at 18 months of 4.14 versus 5.58 and 0.16 versus 0.21, respectively.
“For each of these assessments, separation of the trial groups was apparent by visual inspection of graphs at 3 months”, note van Dyck and colleagues. “However, no conclusions can be drawn because there was no prespecified plan for analysis that included adjustment of confidence intervals for multiple comparisons at any intermediate time point.”
They also assessed the safety, finding that the majority of patients in the lecanemab and placebo groups experienced adverse events.
The most common events in the former group were infusion-related reactions (26.4 vs 7.4%) and amyloid-related imaging abnormalities with cerebral microhaemorrhages, cerebral macrohaemorrhages or superficial siderosis (ARIA-H; 14.0 vs 7.7%) or with oedema or effusions (ARIA-E; 12.6 vs 1.7%).
The study authors point out, however, that only 0.7% of the ARIA-H cases and 2.8% of the ARIA-E cases in lecanemab-treated patients were symptomatic.
A total of 6.9% of participants in the lecanemab arm discontinued treatment due to toxicity, as did 2.9% of those in the placebo arm. And the mortality rate in the two arms was a respective 0.7% and 0.8%.
Noting that “[a]mong the limitations of this trial is that it includes data for only 18 months of treatment”, the investigators conclude: “An open-label extension study of Clarity AD is ongoing to provide additional safety and efficacy data beyond 18 months.”
In an independent comment to the press, 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.
“With all this excitement, there are still many questions and challenges we need to address.”
She highlighted the relatively short treatment period of the trial and said: “Longer-term studies that are ongoing will tell us whether the modest improvements seen in the trial change the trajectory of the disease longer-term.”
The commentator also pointed out that “it will be important for regulators to understand the safety profile of the drug before it is given a full license for use.”
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This independent news story was supported by an educational grant from L’Institut Servier, Suresnes, France.
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