This Phase 3 clinical trial, known as TRAILBLAZER-ALZ 3, evaluates donanemab (Kisunla®, LY3002813) in individuals with preclinical Alzheimer's disease - cognitively normal people who have biomarker evidence of amyloid pathology but have not yet developed clinical symptoms. This groundbreaking trial represents a paradigm shift toward preventive treatment of Alzheimer's disease, aiming to intervene before irreversible neurodegeneration occurs.
The trial is conducted by Eli Lilly and Company and represents the next step in the successful donanemab development program, building on the positive results from TRAILBLAZER-ALZ 2 (which led to FDA approval in 2024) by extending the intervention to an even earlier disease stage.
| Parameter |
Value |
| NCT Number |
NCT05026866 |
| Trial Name |
TRAILBLAZER-ALZ 3 |
| Phase |
Phase 3 |
| Status |
Active, not recruiting |
| Sponsor |
Eli Lilly and Company |
| Enrollment |
2,996 participants |
| Enrollment Type |
Estimated |
| Study Type |
Interventional |
| Start Date |
August 27, 2021 |
| Completion Date |
November 1, 2027 |
| Last Updated |
January 21, 2026 |
Preclinical Alzheimer's disease represents the earliest detectable stage of AD pathology, occurring years to decades before the emergence of clinical symptoms. This concept has revolutionized our approach to AD research and treatment development.
According to the NIA-AA research framework, AD is conceptualized as a biological continuum:
| Stage |
Characteristics |
Clinical Status |
| Stage 1 |
Amyloid positivity only |
Cognitively normal |
| Stage 2 |
Amyloid + subtle cognitive changes |
Cognitively normal |
| Stage 3 |
Amyloid + cognitive decline |
MCI due to AD |
| Stage 4 |
Mild dementia |
Dementia due to AD |
TRAILBLAZER-ALZ 3 targets individuals in Stage 1-2 - those with amyloid pathology but no measurable cognitive impairment.
The rationale for preclinical intervention is compelling:
-
Neuropathological accumulation begins decades before symptoms
- Amyloid plaques begin accumulating 20-30 years before clinical diagnosis
- Neuronal loss is already underway by the time MCI appears
- Early intervention may prevent irreversible damage
-
Greater therapeutic window
- The brain's compensatory mechanisms are still intact
- Synaptic and neuronal populations are preserved
- Treatment may have greater efficacy
-
Preventing rather than slowing decline
- Disease-modifying treatments at later stages can only slow progression
- Preclinical intervention may prevent the development of symptoms entirely
- May preserve function and quality of life
-
Amyloid removal is easier at early stages
- Lower plaque burden means faster and more complete clearance
- Less time required for amyloid removal
- Potentially shorter treatment duration needed
The ability to identify preclinical AD relies on biomarkers:
| Biomarker |
What It Measures |
Preclinical Significance |
| Amyloid PET |
Amyloid plaque burden |
Elevated in Stage 1 |
| CSF Aβ42/40 |
Amyloid processing |
Decreased in Stage 1 |
| Plasma p-tau181/217 |
Tau pathology |
Elevated in Stage 2 |
| FDG-PET |
Brain metabolism |
Normal in Stage 1, subtle changes in Stage 2 |
| MRI |
Brain structure |
Normal in Stage 1 |
¶ Donanemab: Mechanism and Background
Donanemab is a monoclonal antibody that targets pyroglutamate-modified amyloid-beta (pE3-Aβ) - a particularly toxic form of amyloid that is present in plaques. It was developed by Eli Lilly and received FDA approval in July 2024 for treatment of early-stage AD.
¶ Antibody Properties
- Target: Pyroglutamate-modified amyloid-beta (pE3-Aβ) plaques
- Epitope: N-terminal truncation with pyroglutamate modification
- Mechanism: Antibody binds plaques, triggers microglial clearance via Fc-mediated phagocytosis
- Administration: Intravenous infusion every 4 weeks
| Antibody |
Target |
Epitope |
FDA Status |
| Donanemab |
Plaques (pE3-Aβ) |
N-terminal pyroglutamate |
Approved 2024 |
| Lecanemab |
Protofibrils |
Aβ1-16 |
Approved 2023 |
| Aducanumab |
Plaques |
Aβ3-7 |
Withdrawn |
The pyroglutamate modification makes this epitope particularly relevant because:
- pE3-Aβ is highly fibrillar and stable
- It represents an early form of plaque
- Antibodies targeting this epitope may be more effective at plaque removal
- Results: Met primary endpoint (iADRS), 32% slower decline
- Population: Early symptomatic AD (MCI and mild dementia)
- Key finding: Significant amyloid plaque reduction
- Population: Early symptomatic AD (MCI and mild dementia)
- Results: 35% slowing of clinical decline on iADRS, 36% on CDR-SB
- Approval: FDA approval July 2024 for early AD treatment
- Population: Preclinical AD (cognitively normal, amyloid-positive)
- Goal: Prevent development of clinical symptoms
This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial - the gold standard for establishing efficacy and safety.
The TRAILBLAZER-ALZ 3 design incorporates several key features:
- Randomization: Participants randomly assigned to donanemab or placebo
- Double-blind: Neither participants nor investigators know treatment assignment
- Multi-center: Conducted at multiple sites worldwide for diverse population
- Controlled: Placebo comparison provides clear evidence of treatment effect
The trial enrolls individuals who are:
- Cognitively normal: No measurable cognitive impairment on standard testing
- Biomarker-positive: Evidence of amyloid pathology (PET or CSF)
- At risk: Likely to develop symptoms within the study timeframe
- Age-appropriate: Typically 60-80 years old
| Parameter |
Details |
| Drug |
Donanemab (LY3002813) |
| Dose |
Tiered dosing (700 mg then 1400 mg Q4W) |
| Duration |
Approximately 2 years |
| Route |
Intravenous infusion |
| Loading |
3 initial doses at higher level |
The tiered dosing approach:
- Loading phase: Higher initial doses for faster amyloid reduction
- Maintenance: Standard dose for sustained effect
- Optional stop: Treatment may be discontinued after amyloid clearance
The primary endpoint is time to clinical progression measured by the Clinical Dementia Rating Global Score (CDR-GS).
For this trial, clinical progression is defined as:
- CDR-GS change from 0 to ≥0.5
- This represents transition from cognitively normal to Mild Cognitive Impairment (MCI)
- Meaningful outcome: Transition from normal to MCI is clinically meaningful
- Sensitive to early change: Detects subtle functional changes
- Relevant to preclinical population: Appropriate for early-stage trial
- Regulatory acceptance: FDA and EMA accept this endpoint for early-stage trials
- CDR: Semi-structured interview with participant and informant
- Domains: Memory, orientation, judgment, problem-solving, community affairs, home/hobbies, personal care
- Scoring: Each domain 0-3, global score derived from scores
The trial includes multiple secondary endpoints to fully characterize treatment effects:
- ADAS-Cog13: Alzheimer's Disease Assessment Scale - Cognitive subscale
- MMSE: Mini-Mental State Examination
- Rey Auditory Verbal Learning Test: Verbal memory assessment
- ADCS-ADL: Alzheimer's Disease Cooperative Study - Activities of Daily Living
- Functional Activities Questionnaire: Daily functioning assessment
- Amyloid PET: Change in plaque burden (Centiloid)
- Tau PET: Change in regional tau accumulation
- CSF biomarkers: Aβ42/40, total tau, phosphorylated tau
- MRI: Brain volume changes
- Adverse events: Incidence and severity
- ARIA: Amyloid-related imaging abnormalities
- Laboratory changes: Hematology, chemistry
¶ Rationale and Significance
The extension of donanemab to preclinical AD is based on:
- Mechanistic rationale: Removing amyloid earlier should prevent downstream tau pathology and neurodegeneration
- Clinical data: Donanemab effectively removes amyloid in early AD
- Safety profile: Established safety in symptomatic populations
- Regulatory pathway: FDA has expressed interest in early intervention
If successful, TRAILBLAZER-ALZ 3 could:
- Prevent symptomatic AD: Delay or prevent cognitive decline
- Establish prevention paradigm: Define role of anti-amyloid therapy in prevention
- Reduce disease burden: Decrease future dementia prevalence
- Transform healthcare: Shift from treatment to prevention
¶ Challenges and Considerations
- Long follow-up needed: Prevention trials require years of observation
- Biomarker correlation: Need better understanding of amyloid-cognition relationship
- Risk-benefit balance: Treating healthy people requires excellent safety
- Patient selection: Identifying those most likely to benefit
| Trial |
Intervention |
Population |
Status |
| A4 Study |
Solanezumab |
Preclinical AD |
Completed (negative) |
| DIAN-TU |
Various |
Autosomal dominant AD |
Ongoing |
| GenerAtor |
Various |
At-risk populations |
Ongoing |
| TRAILBLAZER-ALZ 3 |
Donanemab |
Preclinical AD |
Ongoing |
The A4 (Anti-Amyloid in Asymptomatic Alzheimer's) trial tested solanezumab in preclinical AD but did not meet its primary endpoint. This taught important lessons:
- Mechanism matters: Solanezumab targeted monomeric Aβ; donanemab targets plaques
- Population selection: Need better biomarkers to identify progressors
- Endpoint sensitivity: Subtle cognitive changes may be hard to detect
- Treatment duration: May need longer treatment or earlier start
TRAILBLAZER-ALZ 3 builds on these lessons with a more potent antibody and better-designed endpoint.
Individuals who:
- Are 60-80 years old
- Are cognitively normal (no memory complaints, normal test scores)
- Have evidence of amyloid in the brain
- Have a study partner (family member or friend)
- Are willing to undergo extensive testing
- Screening: Cognitive testing, PET scans, MRI, lumbar puncture
- Treatment: Monthly infusions for up to 2 years
- Monitoring: Regular cognitive testing, brain scans, safety assessments
- Follow-up: Extended follow-up after treatment discontinuation
- Access to investigational therapy
- Regular monitoring of brain health
- Contribution to Alzheimer's research
- Potential to slow or prevent cognitive decline
- Infusion reactions
- Amyloid-related imaging abnormalities (ARIA)
- Unknown long-term effects
- Time commitment
¶ Amyloid Cascade and Prevention
The amyloid cascade hypothesis proposes that amyloid accumulation is the initiating event in AD, leading to:
- Tau aggregation
- Synaptic loss
- Neuronal death
- Cognitive decline
If this hypothesis is correct, removing amyloid before symptoms emerge should prevent the downstream cascade entirely. TRAILBLAZER-ALZ 3 tests this hypothesis directly.
Research suggests there is a critical window for amyloid removal:
- Before symptoms: Greatest potential for prevention
- Early symptoms: Significant benefit possible
- Moderate disease: Modest benefit only
- Advanced disease: Minimal benefit
This trial targets the optimal window - before irreversible damage occurs.
¶ Current Status and Timeline
- Start date: August 27, 2021
- Enrollment: Approximately 3,000 participants enrolled
- Status: Active, not recruiting
- Completion: November 2027
Results are expected in the 2026-2027 timeframe, which will:
- Determine if donanemab can prevent symptomatic AD
- Establish the role of anti-amyloid therapy in prevention
- Inform future prevention strategies