Lecanemab Will Be Evaluated in Preclinical Alzheimer Disease with Novel Study Design

Less than a week after the FDA granted traditional approval to Eisai’s antiamyloid agent lecanemab (Leqembi), the Alzheimer’s Clinical Trial Consortium announced a new study, AHEAD (NCT04468659), that will assess the agent in individuals with preclinical Alzheimer disease (AD) who have no cognitive symptoms present.

Funded by the National Institutes of Health, the trial aims to enroll 1165 participants from North America and to evaluate whether lecanemab can help stave off the memory problems caused by AD. The study will comprise than 100 locations worldwide and use change from baseline in Preclinical Alzheimer Cognitive Composite 5 (PACC5) score and change in amyloid PET standard uptake value ratio (SUVr) over a 216-week period as the primary end points.

"The advances in treating people who already have cognitive problems due to Alzheimer disease are incredibly exciting, but to have the greatest impact on the public health crisis of Alzheimer's disease, we may need treatments to start even earlier,” Reisa Sperling, MD, professor of neurology at Harvard Medical School, and co-principal investigator of AHEAD, said in a statement. "The AHEAD Study is the first study to test whether removing amyloid plaques from the brain before symptoms are evident could be effective at preventing memory problems from the beginning."

The study will enroll healthy individuals age 55 to 80 years old with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid. Those aged 55 to 64 years, a demographic less likely to have amyloid positivity, must have 1 of the following additional risk factors before screening: first degree relative diagnosed with dementia before age 75; known to possess at least 1 apolipoprotein e4 variant allele; or, known before screening to have elevated brain amyloid according to previous PET or cerebrospinal fluid testing.

Eligible patients must have a Global Clinical Dementia Rating score of 0 at screening, with a Mini-Mental State Examination score greater than or equal to 27. The study will exclude women who are breastfeeding or pregnant at screening, females of childbearing potential, those with a history of transient ischemic attacks, stroke, or seizures within 12 months of screening. Other exclusion criteria include current or history within the past 2 years of psychiatric diagnosis or symptoms that, in the opinion of the investigator, could interfere with study procedures.

AHEAD Trial Design

AHEAD is split into 2 trials, the A45 trial, which will assess whether lecanemab is superior to placebo on change in PACC5, and the A3 trial, comparing the 2 arms in reduction of amyloid accumulation based on PET scans. Secondary outcomes of A45 include change in amyloid PET SUVr, tau PET SUVr, and Cognitive Function Index; the sole registered secondary outcome of A3 will be change in tau PET SUVr.

In the A45 trial, participants will receive lecanemab 5 mg/kg, administered intravenously, every 2 weeks from week 0 to 6, followed by 10 mg/kg every 2 weeks from week 8 to 94, and 10 mg/kg every 4 weeks from week 96 to 216. Those in the A3 trial will receive lecanemab 5 mg/kg every 4 weeks from week 0 to 4, then 10 mg/kg every 4 weeks from week 8 to 216.

Lecanemab, an antiamyloid therapy, was granted traditional approval based on results from the phase 3 Clarity AD trial (NCT03887455), which further confirmed and verified its clinical benefit. With the approval, it became the second early AD treatment to get FDA greenlight in the past 20 years following the contentious approval of aducanumab (Aduhelm; Eisai/Biogen) in 2021, which remains under conditional approval.3

Lecanemab comes with a boxed warning and is contraindicated for patients with serious hypersensitivity to lecanemab-irmb or to any of its inactive ingredients. The prescribing information states that testing for apolipoprotein e4 status should be performed before starting treatment with lecanemab to inform the risk of developing amyloid-related imaging abnormalities (ARIA).

REFERENCES
1. The AHEAD study is testing lecanemab at the stage of preclinical Alzheimer’s disease. News release. Alzheimer’s Clinical Trials Consortium. July 11, 2023. Accessed July 12, 2023. https://www.prnewswire.com/news-releases/the-ahead-study-is-testing-lecanemab-at-the-stage-of-preclinical-alzheimers-disease-301874434.html
2. AHEAD 3-45 study: a study to evaluate efficacy and safety of treatment with lecanemab in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid. Clinicaltrials.gov. Updated June 28, 2023. Accessed July 12, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04468659
3. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. FDA. News release. July 6, 2023. Accessed July 12, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval