Lecanemab: Looking Before We Leap.

Lecanemab, a novel amyloid-sequestering agent, recently received accelerated FDA approval for the treatment of mild Dementia due to Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). Approval was based on a large Phase 3 trial, Clarity, which demonstrated reductions in amyloid plaque burden and cognitive decline with lecanemab. Three major concerns should give us pause before adopting this medication: its beneficial effects are small, its harms are substantial and its potential costs are unprecedented.While lecanemab has a clear and statistically significant effect on cognition, its effect size is small and may not be clinically significant. The magnitude of lecanemab's cognitive effect is smaller than independent estimates of the minimally important clinical difference, implying that the effect may be imperceptible to a majority of patients and caregivers. Lecanemab's cognitive effects were numerically smaller than the effect of cholinesterase inhibitors and may be much smaller. The main argument in lecanemab's favor is that it may lead to greater cognitive benefit over time. While plausible, there is a lack of evidence to support this conclusion.Lecanemab's harms are substantial. In Clarity, it caused symptomatic brain edema in 11% and symptomatic intracranial bleeding in 0.5% of participants. These estimates likely significantly underestimate these risks in general practice for three reasons:. 1. Lecanemab likely interacts with other medications that increase bleeding, an effect minimized in Clarity. 2. The Clarity population is much younger than the real-world population with mild AD dementia and MCI (71 years of age vs 85) and bleeding risk increases with age. 3. Bleeding rates in trials are typically much lower than in clinical practice.Lecanemab's costs are unprecedented. Its proposed price of $26,500 is based on cost effectiveness analyses with tenuous assumptions. But, even if cost effective, it is likely to result in higher expenditures than any other medication. If its entire target population were treated, the aggregate medication expenditures would be $120 billion USD per year -more than is currently spent on all medications in Medicare Part D.Before adopting lecanemab, we need to know that lecanemab isn't less effective, vastly more harmful, and 100x more costly than donepezil.