A recent Phase III clinical trial found that lecanemab reduces cognitive decline in patients with early Alzheimer’s disease (AD). The findings indicate that participants who received the new drug candidate, a monoclonal antibody, showed a statistically significant 27% reduction in cognitive decline. A press release detailed the preliminary results. While some researchers maintain skepticism, awaiting further analysis of the trial, others are quite hopeful about the implications of the results.
Developed in collaboration between Eisai, a Japan-based pharmaceutical company, and Biogen, a biotechnology firm in the United States, lecanemab targets the accumulation of amyloid-β deposits in the brain. First suggested in 1991 by John Hardy and David Allsop, the somewhat controversial amyloid-β, or Aβ hypothesis holds that disease progression is due to toxic deposits of the protein amyloid-β that build up in AD patients’ brains, leading to dementia. Since then, doubts surrounding the theory contend that while amyloid-β is associated with AD, it is not necessarily the underlying cause. In a 2018 Nature article about the skepticism surrounding the Aβ hypothesis, it was noted that “The greatest stimulus of objections to the hypothesis … is the disappointing track record in clinical trials of drugs that target amyloid-β.” That being said, the positive results of the lecanemab study potentially support the hypothesis after showing both reduction in amyloid-β along with modest cognitive benefit.
Small Steps Forward
Cognition assessments for the lecanemab study were done using the Clinical Dementia Rating—Sum of Boxes (CDR—SB), which is a score calculated based on sets of interview questions posed to both patients and their caregivers. The scale measures areas such as problem-solving and memory. After a full 18
months of treatment, those participants who received intravenous infusions of lecanemab scored an average of 0.45 points more on the CDR—SB than did those who received placebo infusions. According to a recent Nature article on the topic, some researchers “differ in what a clinically important result would be, they give a range of 0.5 to 2 points.” Despite such opinions, the evidence of a decrease in amyloid-β may be enough to support approval by the Food and Drug Administration (FDA). Lecanemab is already being reviewed for ‘accelerated approval’ with an expected announcement from the agency on January 6, 2023. In 2021, the monoclonal antibody aducanumab, also developed by Biogen, received FDA approval based on only partial positive results from two incomplete Phase III trials. As explained in Nature, although lecanemab is not without risk, it appears to be less risky than aducanumab. “During the trial, about 20% of participants who received lecanemab showed abnormalities on their brain scans that indicated swelling or bleeding, although less than 3% of those in the treatment group experienced symptoms of these side effects. By contrast, during the Phase III trials for aducanumab, 40% of participants showed signs of brain swelling on their scans.”
Targeting amyloid-β alone is not sufficient to treat AD. Studies have shown that another protein, called tau, has been strongly linked to AD symptoms such as dementia and memory loss. Directing treatment at both amyloid-β and tau along with support and education for both patients and caregivers may be the best path to explore in treating AD at this time. Hope remains for continued progress in both understanding the causes of AD symptoms and treating those causes.
While the debate continues about whether the small reduction in cognitive decline is enough to warrant the hope surrounding lecanemab, the study results do seem to point to the correlation between amyloid-β and AD symptoms. In fact, other biotech companies, such as Roche, in Switzerland and Eli Lilly, in the United States, are in the midst of Phase III trials for their own monoclonal antibody candidates with results expected next year.
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