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 randomized 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 1,795 adults aged 50 to 90 with early-stage Alzheimer 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 (such as keeping folks out of nursing homes) is not known.

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 four percent with lecanemab, with discontinuation rates due to any adverse event (including severe ARIA, infusion reactions, headaches, and falls) of nine percent and 2.9 percent in patients receiving lecanemab and placebo, respectively. We would be remiss not to mention the overall cost and burden of this treatment which involves infusions every two weeks for an indefinite period of time and frequent MRIs to monitor for ARIA.

We will exercise restraint on further speculation about the future of Alzheimer treatment for now and leave the door open for hope. 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.

Practice Point: While there are sure to be patients and families begging for this new Alzheimer 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.

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

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