Lecanemab (Leqembi) showed clinical benefit in early Alzheimer's disease and its risks do not appear to preclude traditional approval, FDA reviewers said in a ahead of an advisory committee meeting.
The document signals FDA support for the monoclonal antibody even before the agency's Peripheral and Central Nervous System Drugs Advisory Committee to discuss the drug and its risk/benefit profile.
Lecanemab met its prespecified primary endpoint in a confirmatory study, demonstrating a statistically significant treatment effect compared with placebo, the agency said. The drug's safety profile was "consistent with the findings observed in the original review of lecanemab and consistent with findings associated with the class of monoclonal antibodies directed against aggregated forms of beta amyloid," the FDA reviewers added.
In January, lecanemab was approved under the pathway to treat Alzheimer's disease -- the second anti-amyloid agent approved for Alzheimer's this way, the first being aducanumab (Aduhelm). As part of the accelerated approval, drugmakers Eisai and Biogen were required to conduct a postmarketing trial verifying lecanemab's clinical benefit.
That confirmatory study -- the phase III trial -- showed that 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 in CLARITY AD was the change from baseline to 18 months 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 (95% CI -0.67 to -0.23, P<0.001). All key secondary endpoints were met.
Infusion-related reactions emerged in 26% of lecanemab-treated participants. Amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E) occurred in 13% of people who received lecanemab. ARIA with hemosiderin deposition (ARIA-H), which includes cerebral hemorrhage and superficial siderosis, occurred in 17%.
ARIA risk can be mitigated, the FDA said. The describes ARIA and provides monitoring and dose management guidelines, the agency pointed out.
People who carried an APOE4 allele, especially APOE4 homozygotes, had a higher risk of ARIA. In addition, the "risk of cerebral hemorrhage is increased in patients exposed to anticoagulant medications," the FDA noted.
An unanswered question is whether the risk of serious outcomes from ARIA is increased in people with underlying cerebral amyloid angiopathy (CAA). In the lecanemab trials, people with MRI findings consistent with CAA were excluded from the studies. "However, there is a high background rate of CAA in Alzheimer's disease and many individuals with CAA do not have the characteristic findings on MRI," the agency noted.
Several people died during lecanemab trials, though it's not clear what role the drug may have played in their deaths.
"Two deaths occurred in subjects who had cerebral hemorrhage after treatment with lecanemab and one death occurred in a patient with a possible cerebrovascular accident and severe ARIA-E and ARIA-H," the reviewers stated. "Uncertainty regarding the role of lecanemab in these cases includes the role of concomitant medications, possible contribution of ARIA, the possible presence of cerebral amyloid angiopathy and related vasculitis and its role in such events."
On Friday, the FDA's advisory committee will vote on whether the CLARITY AD results verify lecanemab's clinical benefit. The panel also will discuss lecanemab's overall risk/benefit profile, paying special attention to three subgroups: APOE4 homozygotes, people with CAA, and people who require concomitant treatment with anticoagulant agents.
The FDA is expected to make its final decision about traditional approval for lecanemab by . Traditional approval will expand the drug's , giving more Alzheimer's patients access to the drug.
The agency often follows the advice of its advisory committees, but isn't required to do so.