Few Early Alzheimer’s Patients Qualify for Lecanemab

Few people with early Alzheimer’s disease met eligibility criteria for the new anti-amyloid monoclonal antibody treatments lecanemab (Leqembi) and aducanumab (Aduhelm), cross-sectional data from the Mayo Clinic Study of Aging showed.

Of 237 people with mild cognitive impairment or mild dementia and increased brain amyloid on PET, clinical trial inclusion and exclusion criteria narrowed the number who would qualify for a lecanemab trial to 19, or 8% of the cohort, reported Maria Vassilaki, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and co-authors.

Modifying the lecanemab exclusion criteria by not applying additional cognitive criteria led to 17.4% of participants with mild cognitive impairment being eligible for trial, the researchers wrote in Neurology.

Likewise, trial inclusion and exclusion criteria for aducanumab reduced the number of qualified candidates to 12 people, or 5.1% of the cohort.

“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” Vassilaki said in a statement.

“In general, clinical trial participants are healthier than the general population,” she pointed out. “Additional research is needed to examine the safety and efficacy of monoclonal antibodies targeting amyloid-beta plaques in larger, more diverse populations, as well as in less healthy populations, before these therapies may be more widely available to people with Alzheimer’s disease.”

Lecanemab received full approval to treat Alzheimer’s disease in July 2023 following accelerated approval in January. Full approval expanded lecanemab’s Medicare coverage, giving more Alzheimer’s patients access to the drug. Aducanumab received accelerated approval to treat Alzheimer’s in 2021.

“At first glance, applying clinical trial criteria to real-world practice may seem overly conservative,” noted Stephen Salloway, MD, of Brown University in Providence, Rhode Island, and co-authors, in an accompanying editorial.

“However, appropriate use recommendations for lecanemab and aducanumab defined by experts closely mirror the rigorous trial inclusion/exclusion criteria due to the resource-intensive nature of the monoclonal antibody therapies and their potential for adverse events, restricting initial use to those who are most likely to benefit and least likely to be harmed,” the editorialists observed.

While anti-amyloid drugs may have positive clinical benefits, they can cause amyloid-related imaging abnormalities (ARIA) — either effusions and edema (ARIA-E) or bleeding (ARIA-H, including microhemorrhage, macrohemorrhage, or superficial siderosis).

“ARIA is typically transient and asymptomatic, but it can be serious and even fatal,” Salloway and co-authors pointed out. “Patients who carry one or two copies of the APOE4 allele and those with significant underlying cerebral amyloid angiopathy are at increased risk for cerebral edema and microhemorrhage, and those taking anticoagulants and lecanemab have a higher rate of macrohemorrhage.”

Lecanemab’s prescribing information was updated in July after full approval and contains a black box warning about ARIA, recommending caution when treating patients on anticoagulants. Because anticoagulation increases hemorrhage risk, the appropriate use recommendations are more restrictive, stating patients who require anticoagulants should not receive lecanemab until more data are available.

The Mayo Clinic Study of Aging was established in 2004 in Olmsted County, Minnesota. Participants undergo baseline and follow-up visits about every 15 months using the same evaluation protocol. Some also have neuroimaging studies.

Among the 237 participants included in the analysis, the mean age was 80.9. Nearly all (97.5%) were white and 54.9% were male. All were diagnosed with mild cognitive impairment (222 people) or mild dementia (15 people). All showed increased brain amyloid burden on PET. Inclusion and exclusion criteria came from the phase III trials of lecanemab (CLARITY-AD) and aducanumab (EMERGE and ENGAGE).

Lecanemab inclusion criteria reduced the study population to 112 participants; exclusion criteria further trimmed it to 19. These included cardiopulmonary contraindications (41 people), central nervous system-related exclusions such as Parkinson’s disease or epilepsy, (37 people), imaging exclusions (42 people) and history of malignancy (20 people).

A total of 104 participants fulfilled the aducanumab clinical trial’s inclusion criteria. Exclusion criteria lowered the number of eligible participants to 12, for many of the same reasons as lecanemab.

The study had several limitations, the researchers noted. Not all inclusion or exclusion criteria could be defined as they were in the trials. Importantly, the sample was not racially and ethnically diverse, and it’s unclear how the findings apply to underrepresented populations. Real-world data about the eligibility, safety, and efficacy of anti-amyloid monoclonal antibodies should be collected in registries like ALZ-NET, they added.