Anti-amyloid antibodies lecanemab and donanemab are now in clinical use, but research continues to refine their application and explore next-generation therapies. Recent updates from the Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid highlight ongoing and new studies aimed at earlier intervention and improved treatment outcomes. Eisai has completed its FDA submission for subcutaneous lecanemab, offering a weekly maintenance dose of 360 mg after the intravenous course. European regulators have also reversed their initial rejection and are now recommending approval for lecanemab.
Lecanemab: AHEAD 3-45 Trial Fully Enrolled
The AHEAD 3-45 study, comprising two sister trials, is designed to assess lecanemab's efficacy in delaying the onset of Alzheimer's symptoms in cognitively healthy individuals with existing amyloid plaques. The A3 trial includes participants with 20-40 centiloids of plaque, while A45 focuses on those with over 40 centiloids.
Reisa Sperling of Brigham and Women’s Hospital shared insights into the screening process for AHEAD, which concluded enrollment in October. The combination of plasma p-tau217 ratio, Aβ42/40 ratio, age, and APOE genotype yielded an AUC of 0.95 in identifying amyloid-positive individuals. This prescreening method significantly improved the success rate of amyloid PET scans, with approximately 60% of screened participants qualifying for the trial, compared to 25% prior to plasma prescreening.
Overall, 20,721 individuals were screened, and 4,443 PET scans were conducted to enroll 1,621 participants (448 in A3 and 1,173 in A45). Paul Aisen from the University of Southern California presented baseline characteristics, noting an average age of 68 in A3 and 70 in A45, with nearly two-thirds of participants being women and most having a college education. Both trials will run for four years, with A3 participants receiving monthly doses and A45 participants receiving bi-weekly doses for the first two years, then monthly.
Donanemab: Trailblazer-Alz3 and Real-World Evidence
Eli Lilly’s donanemab is also under investigation in the Trailblazer-Alz3 secondary prevention study, which completed enrollment in August 2024. The trial employs a decentralized design to enhance recruitment, utilizing the modified telephone interview for cognitive status (TICS-m) and plasma p-tau217 for initial screening. This approach allowed enrollment from 40 U.S. states.
Karen Holdridge of Lilly detailed that 63,124 individuals were screened in the U.S. and Japan to find 2,196 participants, with 1,697 ultimately enrolled. The average age is 70, with two-thirds being women. Notably, about one-third of the cohort has mild cognitive impairment (CDR 0.5), but baseline amyloid and tau PET scans indicate an earlier AD population compared to donanemab’s Phase 3 Trailblazer-Alz2 trial.
Lilly is also conducting two real-world evidence studies: PEARL and Trailblazer-Real US. PEARL remotely collects data from patients on immunotherapy, leveraging Medicare claims. Trailblazer-Real US compares outcomes of patients on donanemab versus standard care over five years, focusing on loss of independence, neuropsychiatric status, and caregiver burden. Donanemab was approved in the U.S. in July, with approximately 700 patients currently receiving the treatment.
Remternetug: A Next-Generation Antibody Enters Phase 3
Lilly’s remternetug, a successor to donanemab, targets the same amyloid species but aims for faster plaque removal with fewer adverse reactions. It is designed for subcutaneous injection. Kevin Biglan at Lilly presented the new Phase 3 Trailrunner-Alz3 trial, which began enrollment in October with a goal of 1,200 participants aged 55-80 with preclinical AD or mild cognitive impairment. The trial will not exclude individuals with prior amyloid immunotherapy.
Trailrunner-Alz3 is also decentralized, with participants self-administering doses at home. The primary outcome is time to clinical worsening on the CDR, with cognitive tests as secondary outcomes. The trial includes an amyloid and tau PET substudy with 400 participants. Participants will receive remternetug or placebo for 18 months, followed by an observation period and an open-label extension.
