Lecanemab (Leqembi) showed clinical benefit in early Alzheimer's disease in its confirmatory trial, paving the way for traditional approval of the drug, an FDA advisory committee said Friday.
In a 6-0 vote, the agency's Peripheral and Central Nervous System Drugs Advisory Committee fully backed the evidence supporting the anti-amyloid monoclonal antibody.
"I thought the evidence for the clinical benefit was very clear," said FDA panelist Merit Cudkowicz, MD, of Harvard Medical School and Massachusetts General Hospital in Boston.
"Most of our questions were around the safety in the subgroups," she added. But the findings were "robust on the primary and all the key secondary" outcomes, she said. "I was also impressed that the effect was seen relatively early -- in 6 months, and then it seemed to get bigger with time."
Traditional approval will expand the drug's , giving more Alzheimer's patients access to the drug. In briefing documents released early this week, FDA reviewers appeared receptive to granting lecanemab traditional approval, though they voiced concerns about the risks of adverse events that have emerged.
Lecanemab was approved under the pathway to treat Alzheimer's disease in January. As part of the accelerated approval, drugmakers Eisai and Biogen were required to conduct a postmarketing trial verifying lecanemab's clinical benefit.
The confirmatory study, the phase III trial, showed treatment with lecanemab led to modestly less decline on cognitive and functional measures in early Alzheimer's disease, but was associated with adverse events.
The primary efficacy endpoint was change on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a scale that ranges from 0-18, with higher scores indicating worse impairment. From a baseline score of about 3.2 on the CDR-SB, mean worsening at 18 months was 1.21 with lecanemab and 1.66 with placebo, a difference of 0.45 points. All key secondary endpoints were met.
Adverse events included amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E), which occurred in 13% of people who received lecanemab. ARIA with hemosiderin deposition (ARIA-H), which includes cerebral hemorrhage and superficial siderosis, occurred in 17%.
Three subgroups appeared to have a higher risk of adverse events: APOE4 homozygotes, people with underlying cerebral amyloid angiopathy (CAA), and people who require concomitant treatment with anticoagulant agents.
Advisory committee members voiced concerns that excluding these subgroups from receiving lecanemab may be too restrictive. In addition, many people with Alzheimer's disease have CAA and may not be aware of it -- an issue also raised by the FDA.
"I think it's imperative that, on this one, we make sure the warnings are clear and clean and concise," said committee member and patient representative, Colette Johnson of Moab, Utah.
"In that warning, it has to be stated that CAA is a condition that you may not know you have, or may not present itself," Johnson continued. "And then, we leave it up to the clinicians and the patients and the caregivers to make the decision."
Reports have indicated that three people died during the lecanemab open-label extension study, though it was unclear what role the drug may have played. Recent research also suggested that anti-amyloid therapies for Alzheimer's disease accelerated brain atrophy, a point raised at the advisory committee meeting by panelist Tanya Simuni, MD, of Northwestern University in Chicago.
The agency is expected to make its final decision about lecanemab by . The FDA isn't required to follow the recommendations of its advisors, but it often does.