A study examining eligibility criteria for Alzheimer agent trials showed that a significant proportion of older adults with early cognitive impairment may not qualify for these therapies because of health conditions and other factors.
New research published in Neurology showed that only a limited amount of older adults are eligible to receive newer monoclonal antibody medications such as lecanemab (Leqembi, Eisai) and aducanumab (Aduhelm; Biogen), for the treatment of early Alzheimer disease (AD).1
The trial’s primary aim was to apply the clinical trial criteria for lecanemab to participants with early AD of the population-based Mayo Clinic Study of Aging (MCSA) and assess the generalizability of antiamyloid treatment. Among a cohort of 237 MCSA participants with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden, lecanemab’s trial criteria reduced the study sample to 112 (47%) participants. After the addition of exclusion criteria, only 8% (n = 19) of patients would have been eligible for treatment. Notably, modifying exclusion criteria to include all patients with MCI and omit additional memory and thinking tests resulted in 17.4% of participants eligible for lecanemab treatment.
In the aducanumab trial, researchers observed that only 44% (n = 104) of MCSA patients met the trial’s criteria to participate. The addition of the trial’s exclusion criteria, which consisted of health factors such as stroke, cardiovascular disease, uncontrolled high blood pressure, and a history of cancer or brain scan findings, resulted in only 5% (n = 12) of patients being eligible for participation.
“There is hope that these new therapies for AD may slow progression of the disease for many people, although the fact remains that the drugs have only been studied in people with the earliest forms of the disease,” senior author Maria Vassilaki, MD, PhD, assistant professor of epidemiology at Mayo Clinic.1 “The inclusion and exclusion criteria of the clinical trials that led to FDA accelerated approval of these therapies form the basis of how people should be invited or discouraged from receiving one of these drugs. Our study estimates that only a small percentage of older people with early cognitive impairment because of AD may be eligible to be treated with monoclonal antibodies for amyloid-ß in the brain.”
The cross-sectional analysis study included 237 people aged between 50 and 90 who had MCI or mild dementia, and whose brain scans showed increased amounts of amyloid-ß plaques (mean age80.9 [SD, 6.3] years; men, 54.9%; White, 97.5 %). Following the data collection, the investigators looked at the eligibility criteria for clinical trials in both lecanemab and aducanumab.
Lecanemab’s trial inclusion criteria required specific scores on a variety of thinking and memory tests, as well as a body mass index (BMI) between 17 and 35. Similarly, the clinical trial inclusion criteria for aducanumab required patients to be between the ages of 50 and 85, with specific scores on thinking and memory tests. After examining the inclusion criteria, researchers looked at the exclusions of the trials. Those with multiple health factors such as stroke, cardiovascular disease, a history of cancer, or brain scan findings that showed abnormalities like old, small brain bleeds or brain injuries because of insufficient blood supply were considered excluded from these studies.
In a statement, Vassilaki noted older Black and Hispanic patients are underrepresented in these clinical trials, despite the higher risk of having AD or other dementias. She also noted that participants in clinical trials should represent all patients at risk for cognitive impairment. Since the majority of the participants in the studies were White, Vassilak strongly encouraged the importance of assessing these eligibility criteria in more diverse populations.
“Our study results show only a small percentage of people with early AD may be eligible to receive treatment, mostly because of chronic health conditions and brain scan abnormalities common in older adults,” Vassilaki said in a statement.1 “In general, clinical trial participants are healthier than the general population. Additional research is needed to examine the safety and efficacy of monoclonal antibodies targeting amyloid-ß plaques in larger, more diverse populations, as well as in less healthy populations, before these therapies may be more widely available to people with AD.”
While this study was ongoing, the FDA granted accelerated approval to lecanemab in January 2023. Aducanumab was approved by the agency in June 2021; however, it remains approved under the accelerated approval pathway, with phase 4 studies still needed to confirm its benefit. After months of review and an FDA AdComm meeting, the agency traditionally approved lecanemab in July based on findings from the confirmatory phase 3 Clarity AD (NCT03887455) study, where treatment with the agent resulted in significant reductions in amyloid-ß in the brain.