On Nov. 29, Biogen and Eisai unveiled the full clinical results for their Alzheimer’s disease drug candidate lecanemab at the Clinical Trials for Alzheimer’s Disease conference and via publication in the New England Journal of Medicine (2022, DOI: 10.1056/NEJMoa2212948).
The details of the 18-month Phase 3 trial, called Clarity AD, followed the companies’ preliminary announcement in September of the drug’s success in delaying the progression of Alzheimer’s and media reports in November of two participant deaths.Lecanemab is one of several monoclonal antibodies that aim to clear protein deposits called amyloid plaque in the brains of those with the disease.
Lecanemab is so far the only candidate to have unequivocally passed Phase 3 trials. Its benefit was measurable as early as 6 months into the trial and increased over time. “These are the most encouraging results that we’ve seen in clinical trials in Alzheimer’s to date,” says Rebecca Edelmayer of the Alzheimer’s Association. Her organization wasn’t involved in the Clarity trial but funds ongoing clinical studies using lecanemab.
Lecanemab’s safety was discussed at length at the conference. Of a total of 1,795 volunteers, the Clarity trial recorded 6 deaths in the group receiving lecanemab and 7 in the placebo group. Eisai said none of the deaths in the treatment group resulted from antibody-associated side effects of brain hemorrhage and swelling called amyloid-related imaging abnormalities (ARIA). Instead, Eisai said, they were attributed to incidents such as heart attack and stroke. The company maintained that the death in June of an 87-year-old man on blood thinners, as reported by Stat, was not ARIA related.
The death of a 65-year-old woman on lecanemab, described in a news report in Science, occurred after the 18-month double-anonymized portion of the trial—during an extension period, in which participants know they are taking the drug. The patient was on a tissue plasminogen activator (TPA) anticoagulant known to cause bleeding. “Hemorrhage did occur,” Marwan Sabbagh of the Barrow Neurological Institute and a coauthor of the NEJM study told conference attendees. “But again, it was in the setting of TPA and lecanemab.”Lecanemab is generally well tolerated, Sabbagh said. “The rate of macro hemorrhage is low. . . . It does go up with anticoagulation, and that might be a relative risk that needs to be managed.”
The results confirmed that safety was no worse than with aducanumab, which the FDA approved last year despite mixed clinical results, says Harvard University neuroscientist Rudolph Tanzi, who wasn’t involved in the clinical study. “I don’t think safety is going to get in the way of potential approval,” which would come Jan. 6, 2023, he tells C&EN.
Despite its risks, lecanemab offers an option in a disease landscape where there is virtually none. “The decision should lie within a discussion between a physician, a patient, and their families about what risk they’re willing to take,” Edelmayer says.
Also at the meeting, a team reported that Eli Lilly and Company’s donanemab, an antibody that targets established plaques instead of their earlier forms, as lecanemab does, reduced amyloid biomarkers in the first 6 months of its ongoing Phase 3 trial. The team cautions that the benefit to patients remains unknown.