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Lecanemab Slows Alzheimer Disease Progression, But More Studies Needed
The monoclonal antibody lecanemab reduced amyloid markers and slowed the rate of decline in early Alzheimer disease, according to the highly anticipated results of the Clarity AD study published in The New England Journal of Medicine.
“[The drug] resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse effects,” said Christopher H. van Dyck, MD, professor of psychiatry, neurology, and neuroscience, School of Medicine, Yale University, and co-authors. “Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer disease.”
Lecanemab is a monoclonal antibody administered intravenously every 2 weeks that works to clear “sticky” amyloid plaques from the brain by binding to amyloid-beta (Aβ), thought to be a key mechanism in the deterioration experienced in Alzheimer disease. Drug manufacturers Eisai and Biogen funded the study.
The 18-month, multicenter, double-blind, phase 3 trial enrolled 1795 participants with early Alzheimer disease ranging from 50 to 90 years of age (mean=71). Patients were randomly assigned on a 1:1 ratio to received lecanemab (10-mg per kilogram of body weight administered intravenously every 2 weeks) or placebo.
The primary endpoint was patient score changes from baseline at 18 months on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, higher score signaling greater impairment). Secondary endpoints included the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher score signaling greater impairment), the Alzheimer Disease Composite Score (ADCOMS; range, 0 to 1.97; higher score signaling greater impairment), and the Alzheimer Disease Cooperative Study—Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower score signaling greater impairment).
At baseline, the mean CDR-SB score was approximately 3.2 in both study groups. The adjusted least-squared mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). The mean difference for the ADAS-cog14 score was -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS was -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score was 2.0 (95% CI, 1.2 to 2.8; P<0.001)
Common adverse effects experienced during the trial included reactions in 26.4% of the participants to the infusions administered intravenously as well as amyloid-related imaging abnormalities (ARIA) in 12.6% of the participants, such as brain swelling and bleeding. The latter is expected to some degree as a consequence of clearing amyloid from the brain.
There were also 13 study participants, 6 receiving lecanemab and 7 receiving placebo, who passed away during the course of the trial. “No deaths were considered by the investigators to be related to lecanemab or occurred with ARIA,” the study authors wrote.
Two deaths that occurred after the conclusion of the 18-month trial, however, have raised concerns about how the drug will perform in the general population, a question made even more pressing by the US Food and Drug Administration’s intention to decide whether it will grant accelerated approval for lecanemab by January 6, 2023.
Both patients had chosen to receive lecanemab in an open-label extension study. A 65-year-old woman with cerebral amyloid angiopathy sought treatment for stroke, was treated with tissue plasminogen activator (tPA), and died a few days later from serious brain bleeding. Her case and autopsy report, summarized in an unpublished case report on Science.org, has raised concerns among experts about drug interactions between lecanemab and tPA.
The second patient, a man in his late 80s taking prescribed the blood thinner apixaban (Eliquis), died of a brain hemorrhage in October. Some experts question whether the episode may be linked to an interaction between apixaban and lecanemab.
“It is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” the company said in a statement about the deaths, citing existing medical conditions and medication use in the 2 individuals.
In addition to the open-label extension study, the AHEAD 3-45 clinical trial is evaluating whether lecanemab is an effective and safe treatment for patients with preclinical Alzheimer disease and patients with early preclinical Alzheimer disease. Results from the placebo-controlled, double-blind, parallel-treatment arm, 216 week study are expected in October 2027.
References
Eisai, Inc. AHEAD 3-45 Study: A study to evaluate efficacy and safety of treatment with lecanemab in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid. NCT04468659. July 13, 2020. Accessed December 5, 2022. https://clinicaltrials.gov/ct2/show/NCT04468659.
