In a new study published in the New England Journal of Medicine, lecanemab, an experimental Alzheimer's drug developed by Eisai and Biogen, produced "moderately less decline on measures of cognition and function" compared to those receiving a placebo—but the authors concluded more research is needed to "determine the efficacy and safety" of the drug.
Similar to Aduhelm, lecanemab reduces abnormal clumps of beta amyloid in patients' brains, proteins that are typically a sign of Alzheimer's disease.
For the study, 1,795 patients with mild cognitive impairment caused by Alzheimer's disease, or early-stage Alzheimer's, were enrolled. Among the participants, 898 were given lecanemab and 897 were given a placebo over the course of 18 months.
The patients were then tested using the Clinical Dementia Rating sum of boxes (CDR-SB), which measures six domains of cognitive decline with a score ranging from zero to 18, with a higher score meaning more severe cognitive decline.
The study found that patients receiving lecanemab saw 27% slower cognitive decline, translating to a 0.45 score improvement on the CDR-SB, than those receiving a placebo.
However, the drug was also associated with "serious adverse events," which occurred in 14% of lecanemab patients compared to 11% of placebo patients, the researchers found. Almost 7% of patients taking lecanemab dropped out of the trial because of the drug's negative side effects, nearly twice the number of patients who dropped out in the placebo group.
More than a quarter of patients taking lecanemab experienced infusion-related reactions, including fever and flu-like symptoms, typically after the first dose of the drug. A small percentage of those in the placebo group experienced the same.
Six deaths were reported among the patients receiving lecanemab compared to seven deaths among those receiving the placebo. However, two additional deaths among patients in the study were reported recently after the study period was over, but Eisai denied the deaths were related to lecanemab. While it's unknown whether the two patients were in the placebo or lecanemab group during the original study period, both were recipients of lecanemab during an extension study.
FDA is expected to decide by Jan. 6 whether lecanemab will receive "accelerated approval," a designation that can be given to drugs providing an uncertain benefit for a serious disease that has few treatment options available. The designation would require Eisai and Biogen to conduct additional trials to prove the drug's benefit.
Marwan Sabbagh, a neurologist at the Barrow Neurological Institute and co-author of the study, said the two additional deaths after the study period raised some concern about lecanemab's safety, but added that "[c]ausality with lecanemab is a little difficult," noting that both patients had underlying health issues.
Sabbagh added that, while the rate of brain bleeding is low with lecanemab, risk seems to increase with medications that prevent blood clotting. "That might be a relative risk that needs to be managed," Sabbagh said.
Matthew Schrag, a neurology professor at Vanderbilt University Medical School, said the lecanemab study was well-designed and showed strong statistical results, but added he doubts the drug would cause a noticeable improvement for those with Alzheimer's and noted the drug could cause significant side effects.
"I worry any minor benefit may be washed out by the practical difficulties of living with the drug and the substantial risks associated with taking the drug," he said.
Similarly, Madhav Thambisetty, a neurologist and senior investigator at the National Institute on Aging, said, "From the perspective of a physician caring for Alzheimer's patients, the difference between lecanemab and placebo is well below what is considered to be a clinically meaningful treatment effect." He added that "it's very unlikely that these differences are going to be noticeable by individual patients in their everyday lives."
However, Thambisetty added that "from the perspective of a scientist, it is exciting that an experimental treatment targeting brain amyloid in Alzheimer's disease appears to slow cognitive decline."
Kristine Yaffe, a professor of neurology and psychiatry at the University of California, San Francisco (UCSF), said that "of all the amyloid antibody trials, this one seems most clearly positive and convincing," which she added can be considered "good news overall for the field."
John Hardy, group leader at the UK Dementia Research Institute at University College London, said, "This trial is an important first step, and I truly believe it represents the beginning of the end."
However, for "real world" patients with more varied Alzheimer's pathology, "the effect will most likely be even less," Yaffe added.
Gil Rabinovici, a neurologist at UCSF, said the trial is "unambiguously positive" while also acknowledging the "potentially serious safety concern that will require a discussion with patients." Still, Rabinovici said, "for the first time in over a century, we have modified the course of Alzheimer's disease, and that is great news for the field and most importantly for patients."
In a statement, the Alzheimer's Association, said the trials "show lecanemab will provide patients more time to participate in daily life and live independently. It could mean many months more of recognizing their spouse, children and grandchildren" and called on CMS to reverse its policy of limiting coverage of drugs like lecanemab to patients enrolled in clinical trials or CMS-approved comparative studies.
"This evidence has now been delivered and CMS can begin its review immediately," the Association said. "The Alzheimer's Association calls on CMS to revise its policy with the utmost urgency." (Gilbert, Washington Post, 11/29; Belluck, New York Times, 11/29; Hamilton, "Shots," NPR, 11/30; Owens/Gonzalez, Axios, 11/30; Salmon, The Independent, 11/30)