TRAILRUNNER-ALZ 1: Remternetug for Early Alzheimer's Disease (NCT05463731)

TRAILRUNNER-ALZ 1: Remternetug for Early Alzheimer's Disease

Overview

TRAILRUNNER-ALZ 1: Remternetug for Early Alzheimer's Disease

Overview

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["@chen2024"].

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["@post2021"].

Trial Details

| 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 |

Conditions and Eligibility

Conditions Studied

• [Alzheimer's Disease](/diseases/alzheimers-disease) Early Symptomatic Alzheimer's Disease
• Mild Cognitive Impairment due to Alzheimer's Disease
• Mild Dementia due to Alzheimer's Disease

Inclusion Criteria

• Age 60-85 years
• Confirmed early symptomatic AD meeting NIA-AA criteria
• Evidence of amyloid pathology via PET scan or CSF analysis
• MMSE score between 20-28
• CDR score of 0.5 or 1.0
• Stable concomitant medications for at least 4 weeks
• Availability of a reliable study partner

Exclusion Criteria

• Significant neurological disease other than AD
• Psychiatric disorders that could interfere with assessments
• Prior exposure to anti-amyloid antibodies or vaccines
• Contraindications to MRI or PET imaging
• Active malignancy or recent cancer treatment

Scientific Background

Amyloid Pathology in Alzheimer's Disease

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[@selkoe2023].

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[@vanDyck2023].

Remternetug Mechanism of Action

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:

• Soluble Aβ oligomers
• Aβ protofibrils
• Parenchymal amyloid plaques
• Vascular amyloid (CAA)

Comparison to Other Anti-Amyloid Antibodies

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 |

Study Design

Primary Objectives

Investigational Arms

The trial uses a randomized, double-blind, placebo-controlled design with multiple active dose arms:

• High Dose Arm: Full dose regimen based on Phase 2 results
• Low Dose Arm: Reduced dose to assess dose-response relationship
• Placebo Arm: Matching vehicle infusion

Treatment Schedule

• Intravenous infusion every 4 weeks
• Treatment duration of 76 weeks (approximately 18 months)
• Extensive MRI monitoring for safety assessment

Key Assessments

• Amyloid PET: Quantitative SUVR measurements at baseline, week 52, and week 76
• Tau PET: Regional tau burden assessment in subset of participants
• MRI: Volumetric MRI and ARIA monitoring at regular intervals
• Cognitive batteries: CDR, ADAS-Cog14, MMSE, ADCS-MCI-ADL
• Biomarkers: Plasma Aβ42/40, p-tau181, total tau

Outcome Measures

Primary Endpoints

Secondary Endpoints

• Change in CDR-SB score
• Change in ADAS-Cog14 score
• Change in MMSE score
• Change in ADCS-MCI-ADL score
• Time to clinical progression
• Pharmacokinetic and pharmacodynamic parameters

Safety Endpoints

• Incidence and severity of ARIA-E (edema)
• Incidence and severity of ARIA-H (hemorrhage)
• Treatment-emergent adverse events
• Vital signs and laboratory abnormalities

Clinical Significance

Advancing Anti-Amyloid Therapy

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.

Implications for AD Treatment

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:

• Earlier intervention in the disease course
• Combination approaches targeting multiple pathological mechanisms
• Personalized treatment based on biomarker profiles[@cummings2024]

Safety Considerations

Amyloid-Related Imaging Abnormalities

ARIA remains the primary safety concern for all anti-amyloid antibodies. In the remternetug development program:

Monitoring Protocol:

• Baseline MRI prior to first dose
• MRI at weeks 4, 12, 24, 52, and 76
• Additional MRI if symptoms suggest ARIA

• ApoE ε4 homozygosity (highest risk)
• Higher doses
• Pre-existing cerebral amyloid angiopathy
• Concurrent anticoagulant use

• Temporary discontinuation for moderate-severe ARIA
• Dose modification for recurrent ARIA
• Permanent discontinuation for life-threatening events

Other Safety Considerations

• Infusion-related reactions (typically mild to moderate)
• Hypersensitivity reactions
• Potential immunogenicity (anti-drug antibodies)

Future Directions

Results from TRAILRUNNER-ALZ 1 will inform:

Related Resources

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Amyloid Beta](/proteins/amyloid-beta)
• [Anti-Amyloid Antibodies](/mechanisms/anti-amyloid-immunotherapy)
• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05463731)
• [Eli Lilly Alzheimer's Pipeline](https://investor.lilly.com)
• [Alzheimer's Association Clinical Trials](https://www.alz.org)

References