Big News: Lecanemab Offers Small Benefit for Alzheimer’s Dementia

EBM Focus - Volume 17, Issue 42

Reference: N Engl J Med. 2022 Nov 29 early online

Practice Point: While there are sure to be patients and families begging for this new Alzheimer’s treatment, temper expectations by explaining that the magnitude of benefit may be very small with a real risk of harm.

EBM Pearl: In this trial, the very small p value indicates consistency of effect, not a large magnitude of effect.

A year ago, we wrote about how our hopes for a miracle drug to treat Alzheimer’s disease (aducanumab) were dashed when the identical EMERGE and ENGAGE trials were stopped early due to futility. We speculated that because of the dose-dependent harms that seemed to outpace any clinical benefit, future trials might be unethical. Well, scratch that. A recently published phase 3 clinical trial of a similar monoclonal antibody against beta-amyloid, lecanemab, found a small clinical benefit at 18 months, although again at a cost.

Investigators randomized 1795 adults aged 50 to 90 with early stage Alzheimer’s dementia to receive either 10 mg/kg IV lecanemab or placebo every two weeks. Patients were followed up at 18 months for a primary endpoint of Clinical Dementia Rating-Sum of Boxes score (CDR-SB; range 0 to 18, with higher scores indicating greater impairment) and other secondary clinical outcomes. As an aside, we have evaluated many trials recently that had significant baseline differences between groups, which when present suggests a problem with randomization. The authors here did an impressive job executing randomization, as the groups were nearly identical on all measures. The multiple levels of blinding also invoke confidence in the internal validity of the study.

In a modified intention-to-treat analysis, lecanemab was associated with a slower increase in CDR-SB score by -0.45 points (95% CI -0.67 to -0.23; p<0.001) at 18 months compared to placebo (mean baseline CDR-SB scores were 3.2 in both groups). This difference was statistically significant, however what half a point translates to outside of cognitive decline is not known (think keeping folks out of nursing homes, etc.).

Interestingly, in a phase 2b dose-finding trial of lecanemab, no benefit was found over placebo at 12 months, suggesting that perhaps lecanemab takes a while to work or that the benefits accumulate over time, much like the beta-amyloid plaque causing the problems. Another interesting (although disease-oriented) finding was the striking reduction in amyloid burden seen on PET scans at 18 months in a substudy of 698 patients, which found a decrease of 55 centiloids in the lecanemab group over placebo (from baseline of 75-78 centiloids).

Ultimately we must balance the small clinical benefit with the risk of harms. Rates of symptomatic amyloid-related imaging abnormalities (ARIA) were less than 4% with lecanemab, with discontinuation rates due to any adverse event (including severe ARIA, infusion reactions, headaches, and falls) of 9% and 2.9% in patients receiving lecanemab and placebo, respectively. We would be remiss not to mention the overall cost and burden of this treatment which involves indefinite infusions every two weeks and frequent MRIs to monitor for ARIA.

We will exercise restraint on further speculation about the future of Alzheimer's treatment for now and leave the door open for hope (it is the holiday season, after all). Perhaps longer trials (like the ongoing open-label extension of this one) will demonstrate a more clinically meaningful benefit of lecanemab without increasing the rate of severe ARIA.

For more information, see the topic Alzheimer Dementia in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.