Full findings from the CLARITY AD trial released last week show that treatment with the monoclonal antibody lecanemab led to modest cognitive benefit in patients with early Alzheimer’s disease (AD) — but at a cost of increased risk of amyloid-related edema and effusions.
Yet, the modest benefit got lost in some mainstream news coverage; one headline hailed lecanemab as a “momentous breakthrough.”
A Lancet editorial published December 3 hopes to temper “hype and hope” regarding lecanemab.
“The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy. Whether lecanemab is the game changer that some have suggested remains to be seen,” the editorial states.
As reported by Medscape Medical News, full data from the phase 3 CLARITY AD trial were presented at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) Conference simultaneously published November 29 in The New England Journal of Medicine.
The full trial results of lecanemab have been eagerly anticipated following positive topline data released in September.
The CLARITY AD trial included 1795 adults with mild cognitive impairment (MCI) or early AD and confirmed amyloid pathology in the brain. Treatment consisted of lecanemab 10 mg/kg biweekly or matching placebo.
After 18 months of treatment, lecanemab slowed cognitive decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), by 27% compared with placebo — an absolute difference of 0.45 points (change from baseline 1.21 for lecanemab vs 1.66 with placebo, P < .001).
While this is “welcome news,” a 0.45-point difference on the CDR-SB might not be clinically meaningful, the Lancet editorial cautions.
The editorial cites a 2019 study suggesting that a minimal clinically important difference for the CDR-SB of 0.98 for people with MCI and presumed Alzheimer’s etiology, and 1.63 for those with mild AD.
In addition, in CLARITY, amyloid-related imaging abnormalities (ARIA) that manifest as edema or microhemorrhages were seen in 1 in 5 patients taking lecanemab. This could potentially lead to unmasking, introducing bias, the Lancet editorial notes.
While most cases of ARIA were asymptomatic and detected incidentally, news reports have linked a second death to the drug in the ongoing open-label extension phase of the study.
The death was possibly linked to co-administration of the thrombolytic drug alteplase, raising concerns about lecanemab’s safety in patients taking blood-thinners.
Prevention Remains the Priority
The US Food and Drug Administration is expected to decide about possible approval of lecanemab next month.
“However, the immediate impact of lecanemab should not be overstated,” the Lancet editorial says.
The cost of the drug will likely be “prohibitive” for low-income and middle-income countries and many health systems lack the infrastructure to enable widespread rollout of lecanemab,
“The availability of PET imaging to determine treatment eligibility is patchy, memory clinics will need the personnel to facilitate bi-weekly intravenous drug infusions, and the capacity for regular MRI scanning to detect ARIA will need to be scaled up,” the editorial points out.
Lecanemab “might well pave the way for much needed treatments for AD. But for now, the key public health message for Alzheimer’s disease remains [what was] laid out in the 2020 Lancet Commission on dementia prevention, intervention, and care: target the modifiable risk factors for dementia — such as hypertension, smoking, diabetes, and obesity — to maintain brain health across the lifespan,” the editorial concludes.
Lancet. Published online December 3, 2022. Editorial