TRAILRUNNER-ALZ 1 (NCT05463731) is a pivotal Phase 3 clinical trial conducted by Eli Lilly and Company evaluating remternetug (LY3372993), a next-generation anti-amyloid monoclonal antibody, for the treatment of early symptomatic Alzheimer's disease. This trial assesses the safety, tolerability, and efficacy of remternetug in reducing amyloid plaque burden in patients with mild cognitive impairment due to AD or mild dementia due to AD[1].
Remternetug represents an evolution in anti-amyloid immunotherapy, designed to bind with high affinity to multiple forms of aggregated amyloid-beta while potentially offering improved safety characteristics compared to earlier generation antibodies. The trial aims to establish whether remternetug can achieve meaningful amyloid plaque clearance and translate this biological effect into clinical benefit for patients[2].
| Parameter | Value |
|---|---|
| NCT Number | NCT05463731 |
| Official Title | A Study of Remternetug (LY3372993) in Participants With Alzheimer's Disease |
| Phase | Phase 3 |
| Status | Active, not recruiting |
| Sponsor | Eli Lilly and Company |
| Enrollment | 1,667 participants (Actual) |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel |
| Masking | Double-blind |
| Start Date | August 1, 2022 |
| Primary Completion | March 1, 2026 |
| Last Updated | April 25, 2025 |
Key eligibility requirements include:
The accumulation of amyloid-beta peptides in the brain represents one of the core pathological hallmarks of Alzheimer's disease. These peptides, derived from proteolytic cleavage of the amyloid precursor protein (APP), can aggregate into soluble oligomers, protofibrils, and ultimately insoluble plaques that accumulate in the brain parenchyma and cerebral vasculature[3].
The amyloid cascade hypothesis posits that Aβ aggregation initiates a cascade of downstream pathological events including tau pathology, neuroinflammation, synaptic dysfunction, and neuronal loss. While recent clinical trial results have led to reconsideration of the precise timing and relative importance of amyloid in disease progression, removal of amyloid plaques remains a valid therapeutic target with demonstrated ability to slow clinical decline in early-stage patients[4].
Remternetug (LY3372993) is a humanized IgG1 monoclonal antibody designed to target a broad range of Aβ aggregation states. The antibody recognizes conformational epitopes present on:
This broad targeting profile distinguishes remternetug from earlier antibodies that primarily recognized monomeric forms or had more restricted binding profiles. The mechanism involves:
Remternetug builds on learnings from earlier anti-amyloid antibodies:
| Antibody | Target | Key Characteristics |
|---|---|---|
| Aducanumab (Aduhelm) | N-terminal Aβ | First FDA-approved, requires titration |
| Lecanemab (Leqembi) | Protofibrils | Approved for early AD, lower ARIA rates |
| Donanemab (Kisunla) | N-terminal plaques | Approved with limited treatment course |
| Remternetug | Multiple Aβ species | Next-generation, broad targeting |
The primary objectives of this Phase 3 trial are:
The trial uses a randomized, double-blind, placebo-controlled design with multiple active dose arms:
Amyloid Plaque Clearance: Percentage of participants achieving amyloid plaque clearance (centiloid <24) on amyloid PET at week 76
Clinical Efficacy: Change from baseline in integrated Alzheimer's disease composite score (iADRS) at week 76
The results of TRAILRUNNER-ALZ 1 will provide critical information about the next generation of anti-amyloid antibodies:
Broader Target Profile: By targeting multiple Aβ species, remternetug may achieve more comprehensive amyloid removal than antibodies targeting single species.
Dose Optimization: The multiple dose arms will establish the optimal benefit-risk profile for clinical use.
Biomarker Correlations: Extensive biomarker collection will help identify predictors of response and inform patient selection.
Success in this trial would represent another milestone in the transformation of AD treatment from symptomatic management to disease modification. With multiple anti-amyloid agents now approved or in late-stage development, the field is moving toward:
ARIA remains the primary safety concern for all anti-amyloid antibodies. In the remternetug development program:
Monitoring Protocol:
Risk Factors:
Management Guidelines:
Results from TRAILRUNNER-ALZ 1 will inform:
Chen MK, et al. Remternetug: next-generation anti-amyloid antibody for Alzheimer's disease. Alzheimer's Research & Therapy. 2024. ↩︎
Post A, et al. Next-generation immunotherapy approaches for Alzheimer's disease. Journal of Neurochemistry. 2021. ↩︎
Selkoe DJ. Alzheimer disease in the 2020s—the way forward. Nature Reviews Neurology. 2023. ↩︎
van Dyck CH, et al. Lecanemab in early Alzheimer's disease. New England Journal of Medicine. 2023. ↩︎
Cummings J, et al. Alzheimer's disease drug development pipeline 2024. Alzheimer's & Dementia. 2024. ↩︎